METHOD AND COMPOSITION FOR TREATING AIRWAY HYPERRESPONSIVENESS

Abstract: This invention relates to a method to inhibit interleukin-10 (IL-10) to reduce or prevent airway hyperresponsiveness in an animal wherein the airway hyperresponsiveness is associated with inflammatin. Also disclosed are methods for identifying compounds useful in the present method.

Description: METHOD AND COMPOSITION FOR TREATING AIRWAY HNPERRESPONSINENESS FIELD OF THE INNENTION The present invention generally relates to a composition and method for reducing or preventing airway hyperresponsiveness in an animal. In particular, the present invention relates to the inhibition of interleukin-10 (EL- 10) to reduce or prevent airway hyperresponsiveness in an animal wherein the airway hyperresponsiveness is associated with inflammation. BACKGROUND OF THE INVENTION A variety of inflammatory agents can provoke airflow limitation, including allergens, cold air, exercise, infections and air pollution. In particular, allergens and other agents in allergic or sensitized mammals (i.e., antigens and haptens) cause the release of inflammatory mediators that recruit cells involved in inflammation. Such cells include lymphocytes, eosinophils, mast cells, basophils, neutrophils, macrophages, monocytes, fibroblasts and platelets. A common consequence of inflammation is airway hyperresponsiveness (AHR). A variety of studies have linked the degree, severity and timing of the inflammatory process with the degree of airway hyperresponsiveness. Asthma is a significant disease of the lung which effects nearly 20 million Americans. Asthma is typically characterized by periodic airflow limitation and/or hyperresponsiveness to various stimuli which results in excessive airways narrowing. Other characteristics can include inflammation of airways, eosinophilia and airway fϊbrosis. Airway hyperresponsiveness in asthma increases after exposure to allergen. The level of responsiveness can be demonstrated by showing increased responses to bronchoconstrictors such as methacholine (MCh). This heightened responsiveness is thought to result from a complex inflammatory cascade involving several cell types, including T lymphocytes and eosinophils 1,2 . T lymphocytes exert many of their effects by secreting an array of cytokines. In allergic asthma, type 2 helper T cell (Th2) cytokines dominate over Thl cytokines and several studies suggest a critical role for EL-4, EL-5 and EL-13 in the development of AHR 3 . The mechanisms underlying cytokine-mediated influences on the tone of the airways are still largely unknown. Studies of EL- 10 published prior to the present invention have typically disclosed that EL- 10 regulates inflammation by suppressing the production and/or activity of proinflammatory cytokines, such as TNF-α and EL-1 , and of other cytokines, such as EL-4 and EL-5, which are involved in allergic responses. In addition, some investigators have observed that EL- 10 can decrease the recruitment of cells, such as eosinophils and neutrophils, into the lungs. More particularly, interleukin-10 was originally described in mice as a factor which inhibited cytokine production from murine Thl clones 4 . Subsequent studies showed that EL- 10 can also downregulate Th2 clones and their production of EL-4 and EL-5 5 . In addition, EL- 10 expresses a wide variety of effects on other immune cells, including stimulation of B cell differentiation and immunoglobulin secretion 6 . The true biological effects of EL- 10 have been difficult to delineate since the activities of this molecule on immune responsiveness varies considerably 7 . However, it is known that adult mice, deficient in EL- 10 (EL- 10-/-), develop a CD4 T cell-dependent and interferon-γ mediated enterocolitis 8 . The data concerning the role of EL- 10 in allergic inflammation and airway hyperresponsiveness (AHR) are contradictory. A few reports have found reduced EL- 10 mRNA expression both in peripheral blood mononuclear cells and BAL lymphocytes of asthmatic patients 5 whereas others have demonstrated elevated levels in asthmatics 9"11 . Because of its immunosuppressive properties in vitro and in animal models, EL- 10 has been suggested as a potential therapy of allergic inflammation and asthma 12 . Taken together, the bulk of research regarding EL- 10 and its relationship to inflammation and airway hyperresponsiveness prior to the present invention would lead one of skill in the art to the conclusion that EL- 10 would be useful for the reduction of inflammation and is produced by cells involved in the resolution of allergic inflammation. A variety of patents have issued which are directed to the treatment of inflammation and/or lung conditions by administering various cytokines, including EL- 10, to treat various conditions associated with inflammation (U.S. Patent No. 5,780,012; U.S. Patent No. 5,753,218 and U.S. PatentNo. 5,726,156). PCT Publication No. WO 97/2627 is directed to the use of EL- 10 agonists to treat a variety of conditions, which include fibrosis of the lung, asthma, lung inflammation, acquired respiratory distress syndrome and reperfusion syndrome. U.S. PatentNo.5,837,232 is directed to EL-10 and EL-10 antagonists. This patent notes that EL-10 has anti-inflammatory activity and suggests its use in the treatment of conditions such as superantigen-mediated toxicity, and in general, as an anti-inflammatory agent in infection or injury. In summary, research to date has indicated that EL-10 is a useful anti-inflammatory agent which would be expected to have activity related to the resolution of inflammation, including allergic inflammation and airway hyperresponsiveness. SUMMARY OF THE INVENTION Directly contrary to the research prior to the present invention, which indicated a positive role for EL- 10 in reduction of inflammation and airway hyperresponsiveness (AHR), the present inventors have discovered that EL-10 plays a major role in the development of altered airway function. More specifically, the present inventors demonstrate herein that in the absence of EL-10, mice which were sensitized and challenged to an antigen in an art- accepted model of AHR, fail to develop AHR despite a significant eosinophilic airway inflammatory response. Only following reconstitution with EL-10 was airway hyperresponsiveness restored. Therefore, contrary to the indications of previous research, inhibition of EL-10 is likely to have a beneficial affect on patients suffering from airway hyperresponsiveness associated with inflammation. One embodiment of the present invention relates to a method to reduce or prevent airway hyperresponsiveness in an animal. The method includes the steps of inhibiting interleukin-10 (EL-10) in an animal that has, or is at risk of developing, airway hyperresponsiveness associated with inflammation. In one embodiment, the airway hyperresponsiveness is associated with allergic inflammation. Diseases associated with allergic inflammation include, but are not limited to, asthma, chronic obstructive pulmonary disease, allergic bronchopulmonary aspergillosis, hypersensitivity pneumonia, eosinophilic pneumonia, emphysema, bronchitis, allergic bronchitis bronchiectasis, cystic fibrosis, tuberculosis, hypersensitivity pneumonitis, occupational asthma, sarcoid, reactive airway disease syndrome, interstitial lung disease, hyper-eosinophilic syndrome, rhinitis, sinusitis, exercise-induced asthma, pollution-induced asthma and parasitic lung disease. In one embodiment, the allergic inflammation is associated with a disease selected from the group of asthma, occupational asthma and reactive airway disease syndrome. In another embodiment, the airway hyperresponsiveness is associated with viral-induced inflammation. En a preferred embodiment, the inflammation is associated with chronic obstructive disease of the airways. In one embodiment of the method of the present invention, the step of inhibiting comprises administering to the animal an agent effective to inhibit interleukin-10 (EL-10). The agent can include, but is not limited to, an inhibitor of EL-10 expression, an inhibitor of EL-10 biological activity, an inhibitor of EL-10 receptor expression or an inhibitor of EL-10 receptor biological activity. More specifically, such an agent can include, but is not limited to, an isolated nucleic acid molecule that reduces expression of EL-10 by selectively hybridizing to a nucleic acid molecule encoding EL-10; a ribozyme specific for EL-10 RNA; an EL-10 antagonist; an antibody that selectively binds to EL-10; a soluble EL-10 receptor; an EL-10 receptor antagonist; or an antibody which binds to an EL-10 receptor and blocks EL-10 from binding to the receptor. The agent useful in the present method is preferably administered by a route of administration selected from the group consisting of oral, nasal, inhaled, topical, intratracheal, transdermal, rectal and parenteral routes. In one embodiment, the agent is administered to the animal in an amount effective to measurably reduce airway hyperresponsiveness in the animal as compared to prior to administration of the agent. In another embodiment, the agent is administered to the animal in an amount effective to measurably reduce airway hyperresponsiveness in the animal as compared to a level of airway hyperresponsiveness in a population of animals having allergic inflammation wherein the agent was not administered. In yet another embodiment, administration of the agent decreases methacholine responsiveness in the animal. In another embodiment, administration of the agent reduces the airway hyperresponsiveness of the animal such that the FEN ! value of the animal is improved by at least about 5%. In yet another embodiment, administration of the agent results in an improvement in the animal's PC 20methacho ii ne FEV 1 value such that the PC 20methacho ii ne -FEV 1 value obtained before administration of the agent when the animal is provoked with a first concentration of methacholine is the substantially the same as the PC 20metlmclMlIine FEN 1 value obtained after administration of the agent when the animal is provoked with double the amount of the first concentration of methacholine. In this aspect, the first concentration of methacholine is preferably between about 0.01 mg/ml and about 8 mg/ml. Preferably, the agent is administered in a pharmaceutically acceptable excipient. In one embodiment, the animal is a mammal. Another embodiment of the present invention relates to a method to reduce airway hyperresponsiveness in an animal that has, or is at risk of developing, airway hyperresponsiveness associated with inflammation. The method includes the step of administering to the animal an agent that inhibits interleukin-10 (EL-10) in the animal, wherein the agent is selected from the group of: an isolated nucleic acid molecule that reduces expression of EL-10 by selectively hybridizing to a nucleic acid molecule encoding EL-10; a ribozyme specific for EL-10 RNA; an EL-10 antagonist; an antibody that selectively binds to EL- 10; a soluble EL- 10 receptor; an EL- 10 receptor antagonist; and an antibody which binds to an EL-10 receptor and blocks EL-10 from binding to the receptor. In this embodiment, the agent is administered in an amount effective to measurably reduce methacholine responsiveness in the animal. Yet another embodiment of the present invention relates to a formulation that reduces or prevents airway hyperresponsiveness associated with inflammation. The formulation includes: (a) an inhibitor of EL-10 selected from the group of: an isolated nucleic acid molecule that reduces expression of EL-10 by selectively hybridizing to a nucleic acid molecule encoding EL-10; a ribozyme specific for EL-10 RNA; an EL-10 antagonist; an antibody that selectively binds to EL-10; a soluble EL-10 receptor; an EL-10 receptor antagonist; and or an antibody which binds to an EL-10 receptor and blocks EL-10 from binding to the receptor; and, (b) an anti-inflammatory agent suitable for reducing inflammation in an animal that has, or is at risk of developing, airway hyperresponsiveness associated with inflammation. In one embodiment, the anti-inflammatory agent is selected from the group consisting of corticosteroids, (oral, inhaled and injected), β-agonists (long or short acting), leukotriene modifiers (inhibitors or receptor antagonists), cytokine or cytokine receptor antagonists, anti-IgE, phosphodiesterase inhibitors, sodium cromoglycate, nedocrimal, theophylline, inhibitors of T cell function. Yet another embodiment of the present invention relates to a method to identify a compound that reduces or prevents airway hyperresponsiveness associated with inflammation. The method includes the steps of: (a) contacting a putative regulatory compound with a cell that expresses EL-10 wherein in the absence of the putative regulatory compound, the EL-10 can be expressed and is biologically active; (b) detecting whether the putative regulatory compound inhibits EL-10 expression or activity in the cell; and (c) administering the putative regulatory compound to a non-human animal in which airway hyperresponsiveness can be induced, and identifying animals in which airway hyperresponsiveness is reduced or prevented as compared to in the absence of the putative regulatory compound. A putative regulatory compound that inhibits EL-10 expression or activity and that reduces or prevents airway hyperresponsiveness in the non-human animal is indicated to be a compound for reducing or preventing hyperresponsiveness associated with inflammation. In one embodiment, the step (b) of detecting is selected from the group of measurement of EL-10 transcription, measurement of EL-10 translation, measurement of EL-10 receptor ligand binding activity, and measurement of EL-10 biological activity associated with the cell. En another embodiment, the step (a) of contacting comprises contacting the putative regulatory compound with a cell containing transcripts of the EL-10, and the step (b) of detecting comprises detecting translational inhibition of the EL-10 transcript. Yet another embodiment of the present invention relates to a method to identify a compound that reduces or prevents airway hyperresponsiveness associated with inflammation. The method includes the steps of: (a) contacting a cell or cell lysate which expresses an interleukin-10 (EL-10) receptor with a putative regulatory compound; (b) detecting whether the putative regulatory compound inhibits an EL-10 receptor function selected from the group consisting of EL-10 receptor expression, EL-10 receptor ligand binding or EL-10 receptor biological activity; and (c) administering the putative regulatory compound to a non-human animal in which airway hyperresponsiveness can be induced, and identifying animals in which airway hyperresponsiveness is reduced or prevented as compared to in the absence of the putative regulatory compound. A putative regulatory compound that inhibits EL-10 receptor expression, ligand binding or biological activity and that reduces or prevents airway hyperresponsiveness in the non-human animal is indicated to be a compound for reducing or preventing hyperresponsiveness associated with inflammation. In one embodiment, the step (a) of contacting comprises contacting the putative regulatory compound with a cell or cell lysate containing a reporter gene operatively associated with a regulatory element of the EL-10 receptor, and the step (b) of detecting comprises detecting expression of the reporter gene product. In another embodiment, the step (a) of contacting comprises contacting the putative regulatory compound with a cell or cell lysate containing transcripts of the EL-10 receptor, and the step (b) of detecting comprises detecting translational inhibition of the EL-10 receptor transcript. BRIEF DESCRIPTION OF THE FIGURES OF THE INVENTION Fig. 1A is a line graph showing lung resistance as a measure of airway hyperresponsiveness to methacholine after sensitization with ovalbumin and challenge with either ovalbumin or PBS in EL- 10-deficient (EL-10-/-) and wild-type mice. Fig. IB is a line graph showing dynamic compliance as a measure of airway hyperresponsiveness to methacholine after sensitization with ovalbumin and challenge with either ovalbumin or PBS in EL-10-defιcient (EL-10-/-) and wild-type mice. Fig.2 is a bar graph showing the cellular composition of B AL fluid in EL- 10-deficient (EL-10-/-) and wild-type mice after sensitization and challenge to ovalbumin. Fig. 3 A is a bar graph showing eosinophilic peroxidase (EPO) in EL-10 -/- and WT mice sensitized and challenged with OVA or PBS. Fig. 3B is a bar graph showing leukotriene C4 (LTC4) levels in EL-10 -/- and WT mice sensitized and challenged with OVA or PBS. Fig. 4 is a bar graph showing airway responsiveness in EL-10 -/- and WT mice measured by electrical field stimulation. Fig. 5A is a line graph showing lung resistance as a measure of airway hyperresponsiveness to MCh after sensitization and challenge with OVA in EL- 10-deficient and WT mice following adenovirus-mediated transfer of the EL-10 gene. Fig. 5B is a line graph showing dynamic compliance as a measure of airway hyperresponsiveness to MCh after sensitization and challenge with OVA in EL- 10-deficient and WT mice following adenovirus-mediated transfer of the EL-10 gene. Fig. 6 is a line graph showing lung resistance as a measure of airway hyperresponsiveness to MCh after sensitization and challenge with OVA in EL- 10-deficient and WT mice following adenovirus-mediated transfer of the EL-10 gene and administration of EL-5. DETAILED DESCREPTEON OF THE INVENTION The present invention generally relates to a method to reduce or prevent airway hyperresponsiveness (AHR) in an animal that has, or is at risk of developing, airway hyperresponsiveness, by inhibiting EL-10 in the animal. En the method of the present invention, the animal has, or is at risk of developing, airway hyperresponsiveness associated with inflammation. For example, airway hyperresponsiveness is commonly associated with allergic inflammation and/or viral-induced inflammation. Airway hyperresponsiveness associated with allergic inflammation can occur in a patient that has, or is at risk of developing, a condition including, but not limited to, any chronic obstructive disease of the airways. Such conditions include, but are not limited to: asthma, chronic obstructive pulmonary disease, allergic bronchopulmonary aspergillosis, hypersensitivity pneumonia, eosinophilic pneumonia, emphysema, bronchitis, allergic bronchitis bronchiectasis, cystic fibrosis, tuberculosis, hypersensitivity pneumonitis, occupational asthma, sarcoid, reactive airway disease syndrome, interstitial lung disease, hyper-eosinophilic syndrome, rhinitis, sinusitis, exercise-induced asthma, pollution-induced asthma and parasitic lung disease. Airway hyperresponsiveness associated with viral-induced inflammation can occur in a patient that has, or is at risk of developing, an infection by a virus including, but not limited to, respiratory syncytial virus (RSN), parainfluenza virus (PIN), rhinovirus (RN) and adeno virus. The present invention is based on the present inventors' discovery that EL-10 plays a major role in the development of altered airway function, and that the inhibition of EL-10 in patient's that have, or are at risk of developing, airway hyperresponsiveness will have a beneficial effect. To define the role of EL-10 in controlling the development of inflammation and AHR, the present inventors used an established mouse model of eosinophilic airway inflammation and allergen-driven alterations in airway function. As demonstrated in the Examples below, the present inventors have discovered that EL- 10-defϊcient mice, when sensitized and challenged to ovalbumin (ONA), fail to develop AHR despite a significant eosinophilic airway inflammatory response. Only following reconstitution with EL- 10 could changes in airway responsiveness be detected. These data indicated a major role for EL-10 in the regulation of airway function downstream of the inflammatory cascade. Prior to the present invention, important roles for a number of cytokines, including EL-4, EL-5 and EL- 13, have been shown in the development of allergic asthma in humans and increased airway responsiveness in experimental models 2 ' 3 . Similarly, a group of negative regulators of allergic inflammation have also been implicated in asthma pathogenesis, among them EL- 10. The present inventors investigated the role of EL- 10 in the development of AHR and pulmonary inflammation in an experimental model of allergic sensitization by using genetically-deficient mice. The major finding in the present inventors' study was that EL-10 deficient mice, also referred to herein as EL-10 -/- mice, after sensitization to and challenge with ovalbumin (ONA), failed to develop AHR in response to inhaled methacholine (MCh), as measured by altered lung resistance (RL) and altered dynamic compliance (Cdyn) whereas, under the same conditions, wild type mice developed AHR. This failure to respond to inhaled MCh, which detects airway responsiveness in vivo, was paralleled in in vitro studies of tracheal smooth muscle responsiveness to electrical field stimulation (EFS). This latter system detects increased acetylcholine release from nerves and muscarinic (M2) receptor dysfunction following allergen exposure 15 ' 22 . Therefore, EL-10 was demonstrated to play a major role in the development of altered airway function. Evidence that this was not simply the consequence of a developmental defect was provided by EL-10 gene reconstitution experiments which showed that both in vivo ox in vitro, altered airway function could be fully restored. Inflammation, and particularly eosinophilic inflammation, is a hallmark of asthma. In many, but not all animal models, development of altered airway function, in vivo or in vitro, has been linked to eosinophil accumulation in the lungs 14 ' 19 ' 21 ' 23 . In these studies, prevention of eosinophilic accumulation in the lungs was associated with attenuation of AHR. In the absence of AHR, EL- 10-deficient mice were shown to exhibit a robust airway eosinophil response. In addition, indirect evidence for eosinophil activation in the deficient mice was provided by the elevated levels of eosinophil peroxidase (EPO) and leukotriene C4 (LTC4) following sensitization and challenge. Further, following reconstitution of the deficient mice with EL-10, which reconstituted AHR, anti-EL-5 administration markedly reduced eosinophil inflammation and normalized lung function, suggesting that the development of altered airway function in these mice did not follow an aberrant pathway but was associated with eosinophil accumulation as in wild-type (WT) mice. Cumulatively, these data indicate that EL-10 modulates airway function in allergic mice, but downstream of the eosinophil inflammatory cascade. As discussed above, prior to the present invention, the bulk of research regarding IL- 10 and its relationship to inflammation and airway hyperresponsiveness would lead one of skill in the art to the conclusion that EL- 10 would be useful for the reduction of inflammation and is produced by cells involved in the resolution of allergic inflammation. In contrast to the present inventors' findings, Grunig et al. (1997) found that EL-10-/- mice developed comparable AHR as controls following bronchopulmonary aspergillosis. In addition, they demonstrated exaggerated airway inflammation in the EL- 10-deficient mice. Bronchopulmonary aspergillosis is a complex combination of both infection and allergic sensitization involving the activation of several different types of inflammatory reactions, including both Th-1 and Th-2 responses. Given the discovery by the present inventors herein, and without being bound by theory, the present inventors believe that in the infectious model of Grunig et al, the effects of EL- 10 deficiency on airway function appear to have been overcome, confirming that airway responsiveness in EL-10-/- mice is not intrinsically abnormal. Also in contrast to previous research, the reconstitution with the EL-10 gene before allergen challenge in the present inventors' studies did not result in diminished pulmonary inflammation, such as has been reported by Zuany-Amorim et al. (1995), nor did it alter levels of EL-4, EL-5, EL- 13 or EFN-γ in the bronchoalveolar lavage fluid (BALF). Zuany- Amorim et al. administered EL-10 (protein) to normal mice at the time of allergen challenge and showed a significant reduction in eosinophil inflammation. In contrast, the present inventors have shown that genetic reconstitution of EL- 10-deficient mice resulted in an increase in eosinophil numbers and mucus production. This increase in mucus production was observed in both EL- 10-deficient and wild-type (WT) mice. Cumulatively, the present inventors' data indicate that EL-10 is not required for eosinophilic inflammation and activation, for cytokine release or for IgE production. Without being bound by theory, this suggests the possibility that, in the presence of eosinophilic inflammation, EL-10 acts on smooth muscle directly or via an intermediate which is not eosinophil-derived. Direct effects of other cytokines, EL-lβ and EL- 13, on airway smooth muscle constrictor responses have recently been identified 24 . In summary, these studies reveal a novel and critical role for EL- 10 in the development of AHR following allergic sensitization. This role appears to be downstream but nevertheless dependent on the airway inflammatory cascade, including eosinophil accumulation and activation. One embodiment of the present invention relates to a method to reduce or prevent airway hyperresponsiveness in an animal. This method includes a step of inhibiting interleukin-10 (EL-10) in an animal that has, or is at risk of developing, airway hyperresponsiveness associated with inflammation. According to the present invention, "airway hyperresponsiveness" or "AHR" refers to an abnormality of the airways that allows them to narrow too easily and/or too much in response to a stimulus capable of inducing airflow limitation. AHR can be a functional alteration of the respiratory system caused by inflammation or airway remodeling (e.g., such as by collagen deposition). Airflow limitation refers to narrowing of airways that can be irreversible or reversible. Airflow limitation or airway hyperresponsiveness can be caused by collagen deposition, bronchospasm, airway smooth muscle hypertrophy, airway smooth muscle contraction, mucous secretion, cellular deposits, epithelial destruction, alteration to epithelial permeability, alterations to smooth muscle function or sensitivity, abnormalities of the lung parenchyma and infiltrative diseases in and around the airways. Many of these causative factors can be associated with inflammation. The present invention is directed to airway hyperresponsiveness that is associated with inflammation, and typically is associated with inflammation of airways, eosinophilia and inflammatory cytokine production. AHR can be measured by a stress test that comprises measuring an animal's respiratory system function in response to a provoking agent (i.e., stimulus). AHR can be measured as a change in respiratory function from baseline plotted against the dose of a provoking agent (a procedure for such measurement and a mammal model useful therefore are described in detail below in the Examples). Respiratory function can be measured by, for example, spirometry, plethysmograph, peak flows, symptom scores, physical signs (i.e., respiratory rate), wheezing, exercise tolerance, use of rescue medication (i.e., bronchodialators) and blood gases. In humans, spirometry can be used to gauge the change in respiratory function in conjunction with a provoking agent, such as methacholine or histamine. In humans, spirometry is performed by asking a person to take a deep breath and blow, as long, as hard and as fast as possible into a gauge that measures airflow and volume. The volume of air expired in the first second is known as forced expiratory volume (FEV j ) and the total amount of air expired is known as the forced vital capacity (FNC). In humans, normal predicted FEN ! and FNC are available and standardized according to weight, height, sex and race. An individual free of disease has an FEN, and a FNC of at least about 80% of normal predicted values for a particular person and a ratio of FEN,/FNC of at least about 80%. Values are determined before (i.e, representing a mammal's resting state) and after (i.e., representing a mammal's higher lung resistance state) inhalation of the provoking agent. The position of the resulting curve indicates the sensitivity of the airways to the provoking agent. The effect of increasing doses or concentrations of the provoking agent on lung function is determined by measuring the forced expired volume in 1 second (FEV,) and FE V ! over forced vital capacity (FEVj/FVC ratio) of the mammal challenged with the provoking agent. In humans, the dose or concentration of a provoking agent (i.e., methacholine or histamine) that causes a 20% fall in FEVi (PD 20 FEVι) is indicative of the degree of AHR. FEV 1 and FVC values can be measured using methods known to those of skill in the art. Pulmonary function measurements of airway resistance (RJ and dynamic compliance (CJ and hyperresponsiveness can be determined by measuring transpulmonary pressure as the pressure difference between the airway opening and the body plethysmograph. Volume is the calibrated pressure change in the body plethysmograph and flow is the digital differentiation of the volume signal. Resistance (R L ) and compliance (C L ) are obtained using methods known to those of skill in the art (e.g., such as by using a recursive least squares solution of the equation of motion). The measurement of lung resistance (R L ) and dynamic compliance (C,) are described in detail in the Examples. It should be noted that measuring the airway resistance (R- value in a non-human mammal (e.g., a mouse) can be used to diagnose airflow obstruction similar to measuring the FEV ! and or FEVj/FVC ratio in a human. A variety of provoking agents are useful for measuring AHR values. Suitable provoking agents include direct and indirect stimuli. Preferred provoking agents include, for example, an allergen, methacholine, a histamine, a leukotriene, saline, hyperventilation, exercise, sulfur dioxide, adenosine, propranolol, cold air, an antigen, bradykinin, acetylcholine, a prostaglandin, ozone, environmental air pollutants and mixtures thereof. Preferably, Mch is used as a provoking agent. Preferred concentrations of Mch to use in a concentration-response curve are between about 0.001 and about 100 milligram per milliliter (mg/ml). More preferred concentrations of Mch to use in a concentration-response curve are between about 0.01 and about 50 mg/ml. Even more preferred concentrations of Mch to use in a concentration-response curve are between about 0.02 and about 25 mg/ml. When Mch is used as a provoking agent, the degree of AHR is defined by the provocative concentration of Mch needed to cause a 20% drop of the FEVj of a mammal (PC 20methacholine FEV 1 ). For example, in humans and using standard protocols in the art, a normal person typically has a PCao methacho ii ne FEV ! >8 mg/ml of Mch. Thus, in humans, AHR is defined as PC 20methacholine FEV 1 <8 mg/ml of Mch. According to the present invention, respiratory function can also be evaluated with a variety of static tests that comprise measuring an animal's respiratory system function in the absence of a provoking agent. Examples of static tests include, for example, spirometry, plethysmographically, peak flows, symptom scores, physical signs (i.e., respiratory rate), wheezing, exercise tolerance, use of rescue medication (i.e., bronchodialators) and blood gases. Evaluating pulmonary function in static tests can be performed by measuring, for example, Total Lung Capacity (TLC), Thoracic Gas Volume (TgV), Functional Residual Capacity (FRC), Residual Volume (RV) and Specific Conductance (SGL) for lung volumes, Diffusing Capacity of the Lung for Carbon Monoxide (DLCO), arterial blood gases, including pH, P 02 and P C02 for gas exchange. Both FEV ! and FEV^FVC can be used to measure airflow limitation. If spirometry is used in humans, the FEVj of an individual can be compared to the FEV ! of predicted values. Predicted FEV ! values are available for standard normograms based on the animal's age, sex, weight, height and race. A normal animal typically has an FEVi at least about 80% of the predicted FEVi for the animal. Airflow limitation results in a FEVj or FVC of less than 80% of predicted values. An alternative method to measure airflow limitation is based on the ratio of FEVj and FVC (FEVi/FVC). Disease free individuals are defined as having a FEV FVC ratio of at least about 80%. Airflow obstruction causes the ratio of FEVi/FVC to fall to less than 80% of predicted values. Thus, an animal having airflow limitation is defined by an FEVj/FVC less than about 80%. As used herein, to reduce airway hyperresponsiveness refers to any measurable reduction in airway hyperresponsiveness and/or any reduction of the occurrence or frequency with which airway hyperresponsiveness occurs in a patient. A reduction in AHR can be measured using any of the above-described techniques or any other suitable method known in the art. Preferably, airway hyperresponsiveness, or the potential therefor, is reduced, optimally, to an extent that the animal no longer suffers discomfort and/or altered function resulting from or associated with airway hyperresponsiveness. To prevent airway hyperresponsiveness refers to preventing or stopping the induction of airway hyperresponsiveness before biological characteristics of airway hyperresponsiveness as discussed above can be substantially detected or measured in a patient. In one embodiment, the method of the present invention decreases methacholine responsiveness in the animal. Preferably, the method of the present invention results in an improvement in a mammal's PC 20methacholine FEV ! value such that the PC 20methachoIine FEVι value obtained before use of the present method when the mammal is provoked with a first concentration of methacholine is the same as the PC 20methacholine FEN 1 value obtained after use of the present method when the mammal is provoked with double the amount of the first concentration of methacholine. Preferably, the method of the present invention results in an improvement in a mammal's PC 20methacho ι ine FEVι value such that the PC 20methacho ι ine FEV ι value obtained before the use of the present method when the animal is provoked with between about 0.01 mg/ml to about 8 mg/ml of methacholine is the same as the PC 20methachollne FEN 1 value obtained after the use of the present method when the animal is provoked with between about 0.02 mg/ml to about 16 mg/ml of methacholine. In another embodiment, the method of the present invention results in improves an animal's FEV, by at least about 5%, and more preferably by between about 6% and about 100%, more preferably by between about 7% and about 100%, and even more preferably by between about 8% and about 100% of the mammal's predicted FEN*. In another embodiment, the method of the present invention improves an animal's FEVi by at l east about 5%, and preferably, at least about 10%, and even more preferably, at least about 25%, and even more preferably, at least about 50%, and even more preferably, at least about 75%. In yet another embodiment, the method of the present invention results in an increase in the PC 20methacholine FEN 1 of an animal by about one doubling concentration towards the PC 20methacholine FEN 1 of a normal animal. A normal animal refers to an animal known not to suffer from or be susceptible to abnormal AHR. A patient, or test animal refers to an animal suspected of suffering from or being susceptible to abnormal AHR. Therefore, an animal that has airway hyperresponsiveness associated with inflammation, is an animal in which airway hyperresponsiveness is measured or detected, such as by using one of the above methods for measuring airway hyperresponsiveness, wherein the airway hyperresponsiveness is associated with inflammation. To be associated with inflammation, the airway hyperresponsiveness is apparently or obviously, directly or indirectly associated with (e.g., caused by, a symptom of, indicative of, concurrent with) an inflammatory condition or disease (i.e., a condition or disease characterized by inflammation). Typically, such an inflammatory condition or disease is at least partially characterized by inflammation of pulmonary tissues. Such conditions or diseases are discussed above. An animal that is at risk of developing airway hyperresponsiveness is an animal that has a condition or disease associated with inflammation which is likely to be associated with at least a potential for airway hyperresponsiveness, but does not yet display a measurable or detectable characteristic or symptom of airway hyperresponsiveness. An animal that is at risk of developing airway hyperresponsiveness also includes an animal that is identified as being predisposed to or susceptible to such a condition or disease. Inflammation is typically characterized by the release of inflammatory mediators (e.g., cytokines or chemokines) which recruit cells involved in inflammation to a tissue. For example, a condition or disease associated with allergic inflammation is a condition or disease in which the elicitation of one type of immune response (e.g., a Th2-type immune response) against a sensitizing agent, such as an allergen, can result in the release of inflammatory mediators that recruit cells involved in inflammation in a mammal, the presence of which can lead to tissue damage and sometimes death. Airway hyperresponsiveness associated with allergic inflammation can occur in a patient that has, or is at risk of developing, any chronic obstructive disease of the airways, including, but not limited to, asthma, chronic obstructive pulmonary disease, allergic bronchopulmonary aspergillosis, hypersensitivity pneumonia, eosinophilic pneumonia, emphysema, bronchitis, allergic bronchitis bronchiectasis, cystic fibrosis, tuberculosis, hypersensitivity pneumonitis, occupational asthma, sarcoid, reactive airway disease syndrome, interstitial lung disease, hyper-eosinophilic syndrome, rhinitis, sinusitis, exercise-induced asthma, pollution-induced asthma and parasitic lung disease. Preferred conditions to treat using the method of the present invention include asthma, occupational asthma, exercise-induced asthma, pollution- induced asthma and reactive airway disease syndrome. Niral-induced inflammation typically involves the elicitation of another type of immune response (e.g., a Thl-type immune response) against viral antigens, resulting in production of inflammatory mediators the recruit cells involved in inflammation in a an animal, the presence of which can also lead to tissue damage. Airway hyperresponsiveness associated with viral-induced inflammation can occur in a patient that has, or is at risk of developing, an infection by a virus including, but not limited to, respiratory syncytial virus (RSN), parainfluenza virus (PIN), rhinovirus (RN) and adeno virus. The method of the present invention can be used in any animal, and particularly, in any animal of the Vertebrate class, Mammalia, including, without limitation, primates, rodents, livestock and domestic pets. Preferred mammals to treat using the method of the present invention include humans. The method of the present invention includes a step of inhibiting interleukin-10 (EL- 10 in an animal that has, or is at risk of developing AHR, associated with inflammation. According to the present invention, to inhibit EL-10 in an animal refers to inhibiting the expression and/or the biological activity of IL-10. Inhibition of EL-10 according to the present invention can be accomplished by directly affecting EL-10 expression (transcription or translation) or biological activity, or by directly affecting the ability of an EL- 10 receptor to bind to or be activated by EL-10. En other words, the method of inhibiting EL-10 is specific for EL-10, and does not substantially directly affect (i.e., act on) other molecules, and particularly, other cytokines. Therefore, the method of the present invention is intended to be specifically targeted to EL-10 expression and/or biological activity, and is intended to exclude, therefore, methods by which an inhibitory effect on EL-10 is a downstream effect of an action on a different molecule. For example, the step of inhibiting EL-10 does not include the administration of a cytokine having a biological activity that counters (i.e., antagonizes) the biological activity of EL-10, such as EL-12, because such a method does not act directly and specifically on EL-10. It is noted, however, that other molecules and cytokines can be indirectly affected as a result of the direct inhibition or down-regulation of EL-10 (e.g., as a downstream effect of the inhibition of EL-10). More specifically, in one embodiment, inhibition of EL-10 is defined herein as any measurable (detectable) reduction (i.e., decrease, downregulation, inhibition) of the expression of EL- 10. As used herein, the expression of EL- 10 refers to either the transcription of EL- 10 or the translation of EL- 10. Therefore, in one embodiment, the method of the present invention inhibits the transcription and/or the translation of EL- 10 by a cell in the animal that naturally expresses EL-10. Methods for inhibiting the expression of EL-10 include, but are not limited to, administering an agent that inhibits the expression of EL-10 and genetically modifying an animal to have reduced EL-10 expression. Preferably, EL-10 expression is inhibited by administration of an agent to the animal that directly inhibits EL-10 expression. Such agents include, but are not limited to : a ribozyme that is specific for EL- 10 RNA; a DNA binding protein or a drug that binds to a gene encoding EL-10 and inhibits expression of EL- 10; a protein or drug that binds to EL- 10 intracellularly and prevents secretion of EL- 10 by the cell which expresses EL-10; and, an isolated nucleic acid molecule that reduces expression of EL-10 by hybridizing under high stringency conditions to a gene encoding EL-10 in a cell of the animal (i.e., an anti-sense nucleic acid molecule). Ribozymes, DNA binding proteins, drugs, and anti-sense molecules that selectively inhibit EL-10 expression can be produced using techniques known to those of skill in the art. In another embodiment of the present invention, inhibition of EL- 10 is defined herein as any measurable (detectable) reduction (i.e., decrease, downregulation, inhibition) of the biological activity of EL-10. The biological activity or biological action of a protein refers to any function(s) exhibited or performed by a naturally occurring form of the protein as measured or observed in vivo (i.e., in the natural physiological environment of the protein) or in vitro (i.e., under laboratory conditions). For example, a biological activity of a EL-10 can include, but is not limited to, receptor binding activity, inhibition of Thl lymphocyte activity, stimulation of mast cell proliferation, stimulation of MHC Class II production, inhibition of macrophage function, contraction of airway smooth muscle. According to the present invention, EL-10 biological activity is inhibited by directly preventing or inhibiting (reducing, decreasing) the ability of EL-10 to bind to and/or activate its receptor, thereby inhibiting downstream events resulting from such binding. Preferably, EL-10 biological activity is inhibited by administering an agent including, but not limited to, an agent that binds to EL-10 or its receptor in a manner that the ability of EL-10 to bind to and/or activate its receptor is inhibited or prevented. Such an agent includes, but is not limited to EL-10 antagonists and EL-10 receptor antagonists, antibodies, and soluble EL-10 receptors that selectively bind to EL-10 or its receptor such that EL-10 biological activity is inhibited or prevented. Accordingly, the method of the present invention includes the use of a variety of agents (i.e., regulatory compounds) which, by acting directly on EL-10, its receptor, or the genes encoding EL- 10 or its receptor, inhibit the expression and or biological activity of EL- 10 in a cell such that airway hyperresponsiveness is reduced in an animal. Agents useful in the present invention include, for example, proteins, nucleic acid molecules, antibodies, and compounds that are products of rational drug design (i.e., drugs). Such agents are generally referred to herein as EL-10 inhibitors. According to the present invention, an EL-10 inhibitor is any agent which inhibits, either by direct inhibition or competitive inhibition, the expression and/or biological activity of EL-10, and includes agents which act on EL-10 or the EL-10 receptor. EL- 10 inhibiting agents as referred to herein include, for example, compounds that are products of rational drug design, natural products, and compounds having partially defined EL-10 regulatory properties. An EL-10-regulatory agent can be a protein-based compound, a carbohydrate-based compound, a lipid-based compound, a nucleic acid-based compound, a natural organic compound, a synthetically derived organic compound, an antibody, or fragments thereof. In one embodiment, EL-10 regulatory agents of the present invention include drugs, including peptides, oligonucleotides, carbohydrates and/or synthetic organic molecules which regulate the production and/or function of EL-10. Such an agent can be obtained, for example, from molecular diversity strategies (a combination of related strategies allowing the rapid construction of large, chemically diverse molecule libraries), libraries of natural or synthetic compounds, in particular from chemical or combinatorial libraries (i.e., libraries of compounds that differ in sequence or size but that have the same building blocks) or by rational drug design. See for example, Maulik et al., 1997, Molecular Biotechnology: Therapeutic Applications and Strategies, Wiley-Liss, Inc., which is incorporated herein by reference in its entirety. In a molecular diversity strategy, large compound libraries are synthesized, for example, from peptides, oligonucleotides, carbohydrates and/or synthetic organic molecules, using biological, enzymatic and/or chemical approaches. The critical parameters in developing a molecular diversity strategy include subunit diversity, molecular size, and library diversity. The general goal of screening such libraries is to utilize sequential application of combinatorial selection to obtain high-affinity ligands against a desired target, and then optimize the lead molecules by either random or directed design strategies. Methods of molecular diversity are described in detail in Maulik, et al., supra. In a rational drug design procedure, the three-dimensional structure of a regulatory compound can be analyzed by, for example, nuclear magnetic resonance (NMR) or X-ray crystallography. This three-dimensional structure can then be used to predict structures of potential compounds, such as potential regulatory agents by, for example, computer modeling. The predicted compound structure can be used to optimize lead compounds derived, for example, by molecular diversity methods. In addition, the predicted compound structure can be produced by, for example, chemical synthesis, recombinant DNA technology, or by isolating a mimetope from a natural source (e.g., plants, animals, bacteria and fungi). Various other methods of structure-based drug design are disclosed in Maulik et al., 1997, supra. Maulik et al. disclose, for example, methods of directed design, in which the user directs the process of creating novel molecules from a fragment library of appropriately selected fragments; random design, in which the user uses a genetic or other algorithm to randomly mutate fragments and their combinations while simultaneously applying a selection criterion to evaluate the fitness of candidate ligands; and a grid-based approach in which the user calculates the interaction energy between three dimensional receptor structures and small fragment probes, followed by linking together of favorable probe sites. An isolated nucleic acid molecule that is particularly useful as an agent for inhibiting EL- 10 is an anti-sense nucleic acid molecule. As used herein, an EL- 10 anti-sense nucleic acid molecule is defined as an isolated nucleic acid molecule that reduces expression of FL- 10 by hybridizing under high stringency conditions to a gene encoding EL- 10. Similarly, an EL- 10 receptor anti-sense nucleic acid molecule is defined as an isolated nucleic acid molecule that reduces expression of EL-10 receptor (EL-10R) by hybridizing under high stringency conditions to a gene encoding EL-10R. Such a nucleic acid molecule is sufficiently similar to EL-10 or EL-IOR, respectively, that the molecule is capable of hybridizing under high stringency conditions to the coding or complementary strand of the gene or RNA encoding the natural EL-10 or EL-IOR. An EL-10 gene (or an EL-IOR gene) includes all nucleic acid sequences related to an EL-10 gene (or an EL-IOR gene) such as regulatory regions that control production of the protein encoded by that gene (such as, but not limited to, transcription, translation or post-translation control regions) as well as the coding region itself. The genes encoding EL- 10 and its receptor have been previously cloned and sequenced and are available to those of skill in the art. For example, the gene encoding human EL-10 is available in Genbank at Accession Nos. X78437, U63015, Z30175 and U16720, and the gene encoding the human EL-10 receptor is available in Genbank at Accession Nos. U00672 andNM001558. Genes encoding various chains of the EL-10 receptor are also disclosed, for example, in U.S. Patent No. 5,843,697, U.S. Patent No. 5,789,192, and U.S. Patent No. 5,716,804. An isolated nucleic acid molecule is a nucleic acid molecule that has been removed from its natural milieu (i.e., that has been subject to human manipulation) and can include DNA, RNA, or derivatives of either DNA or RNA. As such, "isolated" does not reflect the extent to which the nucleic acid molecule has been purified. An isolated nucleic acid molecule of the present invention can be isolated from its natural source or produced using recombinant DNA technology (e.g., polymerase chain reaction (PCR) amplification, cloning) or chemical synthesis. Anti-sense molecules that bind to EL-10 receptor are described in U.S. Patent No. 5,843,697, incorporated herein by reference in its entirety. As used herein, stringent hybridization conditions refer to standard hybridization conditions under which nucleic acid molecules are used to identify similar nucleic acid molecules. Such standard conditions are disclosed, for example, in Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Labs Press, 1989. Sambrook et al., ibid., is incorporated by reference herein in its entirety (see specifically, pages 9.31- 9.62, 11.7 and 11.45-11.61). In addition, formulae to calculate the appropriate hybridization and wash conditions to achieve hybridization permitting varying degrees of mismatch of nucleotides are disclosed, for example, in Meinkoth et al., 1984, Anal. Biochem. 138, 267- 284; Meinkoth et al., ibid., is incorporated by reference herein in its entirety. More particularly, high stringency hybridization conditions, as referred to herein, refer to conditions which permit isolation of nucleic acid molecules having at least about 70% nucleic acid sequence identity with the nucleic acid molecule being used to probe in the hybridization reaction, more particularly at least about 75%, and most particularly at least about 80%. Such conditions will vary, depending on whether DNA:RNA or DNA:DNA hybrids are being formed. Calculated melting temperatures for DNA:DNA hybrids are 10 ° C less than for DNA:RNA hybrids. In particular embodiments, stringent hybridization conditions for DNA:DNA hybrids include hybridization at an ionic strength of 0.1X SSC (0.157 M Na + ) at a temperature of between about 20°C and about 35°C, more preferably, between about 28°C and about 40°C, and even more preferably, between about 35°C and about 45 °C. In particular embodiments, stringent hybridization conditions for DNA:RNA hybrids include hybridization at an ionic strength of 0.1X SSC (0.157 M Na + ) at a temperature of between about 30°C and about 45°C, more preferably, between about 38°C and about 50°C, and even more preferably, between about 45°C and about 55°C. These values are based on calculations of a melting temperature for molecules larger than about 100 nucleotides, 0% formamide and a G + C content of about 50%. Alternatively, T m can be calculated empirically as set forth in Sambrook et al., supra, pages 11.55 to 11.57. In one embodiment of the present invention, the agent used for inhibiting EL- 10 is an antibody. En one aspect, the antibody selectively binds to EL-10 in a manner such that EL-10 is inhibited or prevented from binding to its receptor. In another aspect, the antibody selectively binds to EL-10 in a manner such that EL-10 is inhibited or prevented from activating its receptor, even though the EL-10 may at least partially bind to its receptor. In another aspect, the antibody selectively binds to EL-10R in a manner such that EL-10 is inhibited or prevented from binding to EL- 1 OR. In yet another aspect, the antibody selectively binds to EL- 1 OR in a manner such that EL- 10 is inhibited or prevented from activating EL- 1 OR, even though EL-10 may at least partially bind to EL-10R. As used herein, the term "selectively binds to" refers to the ability of antibodies of the present invention to preferentially bind to specified proteins (e.g., EL-10 or EL-10R). Binding can be measured using a variety of methods standard in the art including enzyme immunoassays (e.g., ELISA), immunoblot assays, radioimmunoassays, etc. Isolated antibodies of the present invention can include serum containing such antibodies, or antibodies that have been purified to varying degrees. Antibodies of the present invention can be polyclonal or monoclonal, functional equivalents such as antibody fragments (e.g., Fab fragments or Fab 2 fragments) and genetically-engineered antibodies, including single chain antibodies or chimeric antibodies, including bi-specific antibodies that can bind to more than one epitope. Antibodies which bind to EL-10 receptors are disclosed, for example, in U.S. Patent No. 5,863,796, incorporated herein by reference in its entirety. Generally, in the production of an antibody, a suitable experimental animal, such as a rabbit, hamster, guinea pig or mouse, is exposed to an antigen against which an antibody is desired. Typically, an animal is immunized with an effective amount of antigen that is injected into the animal. An effective amount of antigen refers to an amount needed to induce antibody production by the animal. The animal's immune system is then allowed to respond over a pre-determined period of time. The immunization process can be repeated until the immune system is found to be producing antibodies to the antigen. In order to obtain polyclonal antibodies specific for the antigen, serum is collected from the animal that contains the desired antibodies. Such serum is useful as a reagent. Polyclonal antibodies can be further purified from the serum by, for example, treating the serum with ammonium sulfate. In order to obtain monoclonal antibodies, the immunized animal is sacrificed and B lymphocytes are recovered from the spleen. The differentiating and proliferating daughter cells of the B lymphocytes are then fused with myeloma cells to obtain a population of hybridoma cells capable of continual growth in suitable culture medium. Hybridomas producing a desired antibody are selected by testing the ability of an antibody produced by a hybridoma to bind to the antigen. Also included in the present invention are therapeutic molecules known as ribozymes. A ribozyme typically contains stretches of complementary RNA bases that can base-pair with a target RNA ligand, including the RNA molecule itself, giving rise to an active site of defined structure that can cleave the bound RNA molecule (See Maulik et al., 1997, supra). Therefore, a ribozyme can serve as a targeting delivery vehicle for the nucleic acid molecule encoding EL-10 or EL-IOR, or alternatively, the ribozyme can target and bind to RNA encoding a EL- 10 or EL- 1 OR protein, and thereby effectively inhibit the translation of the EL- 10 or EL-IOR protein. Also included in the present invention are soluble EL-10 receptors. Soluble EL-10 receptors are useful agents for inhibiting EL- 10 because such receptors compete with naturally occurring EL- 10 receptors for binding to EL- 10, thereby reducing the biological activity of the EL-10. EL-10 receptors have been described in detail in U.S. Patent No. 5,863,796, U.S. Patent No. 5,789,192 and U.S. Patent No. 5,843,697, each of which is incorporated herein by reference in their entirety. Another agent for use in the present invention includes EL-10 analogs and EL-10 receptor analogs which are antagonists of EL-10 and/or EL-10 receptor activity (i.e., EL-10 antagonists or EL-IOR antagonists, respectively). Such analogs are defined herein as homologues or mimetics of a naturally occurring EL-10 protein or EL-IOR, wherein such compound has reduced biological activity as compared to the naturally occurring peptide (i.e., prototype) upon which the homologue or mimetic is based. Such a compound is effective to antagonize the biological activity of EL-10 or its receptor by a mechanism which can include blocking the action of EL- 10, for example by binding to and blocking the receptor for EL-10. Such an antagonist is typically sufficiently similar in structure to EL-10 or it receptor that is effectively a competitive inhibitor of EL-10 or its receptor. As used herein, the term "homologue" is used to refer to a peptide which differs from a naturally occurring peptide (i.e., the "prototype") by minor modifications to the naturally occurring peptide, but which maintains the basic peptide and side chain structure of the naturally occurring form. Such changes include, but are not limited to: changes in one or a few amino acid side chains; changes in one or a few amino acids, including deletions (e.g., a truncated version of the peptide) insertions and/or substitutions; changes in stereochemistry of one or a few atoms; and/or minor derivatizations, including but not limited to: methylation, glycosylation, phosphorylation, acetylation, myristoylation, prenylation, palmitation, amidation and/or addition of glycosylphosphatidyl inositol. Preferably, a homologue that is an antagonist has diminished biological activity as compared to the naturally occurring protein. A mimetic refers to any peptide or non-peptide compound that is able to mimic the biological action of a naturally occurring peptide, often because the mimetic has a basic structure that mimics the basic structure of the naturally occurring peptide and or has the salient biological properties of the naturally occurring peptide. Mimetics can include, but are not limited to: peptides that have substantial modifications from the prototype such as no side chain similarity with the naturally occurring peptide (such modifications, for example, may decrease its susceptibility to degradation); anti-idiotypic and/or catalytic antibodies, or fragments thereof; non- proteinaceous portions of an isolated protein (e.g., carbohydrate structures); or synthetic or natural organic molecules, including nucleic acids and drugs identified through combinatorial chemistry, for example. Such mimetics can be designed, selected and/or otherwise identified using a variety of methods known in the art. Various methods of drug design, useful to design mimetics or other therapeutic compounds useful in the present invention are disclosed in Maulik et al., 1997, supra, and have been discussed above in detail. Antagonists (homologues and mimetics) of EL- 10 and EL- 1 OR have been previously described in the art, and all are intended to be encompassed for use in the method of the present invention. For example, such antagonists are disclosed in U.S. PatentNo.5,837,232 and U.S. PatentNo.5,716,804, incorporated herein by reference in their entireties. Methods for using EL-10 receptors to identify EL-10 antagonists are described in U.S. Patent No. 5,863,796, U.S. Patent No. 5,789,192 and U.S. Patent No. 5,843,697, supra. In accordance with the present invention, acceptable protocols to administer an agent including the route of administration and the effective amount of an agent to be administered to an animal can be accomplished by those skilled in the art. An agent of the present invention can be administered in vivo or ex vivo. Suitable in vivo routes of administration can include, but are not limited to, oral, nasal, inhaled, topical, intratracheal, transdermal, rectal, and parenteral routes. Preferred parenteral routes can include, but are not limited to, subcutaneous, intradermal, intravenous, intramuscular, and intraperitoneal routes. Preferred topical routes include inhalation by aerosol (i.e., spraying) or topical surface administration to the skin of amammal. Preferably, an agent is administered by nasal, inhaled, intratracheal, topical, or intravenous routes. Ex vivo refers to performing part of the administration step outside of the patient, such as by transfecting a population of cells removed from a patient with a recombinant molecule comprising an EL- 10 anti-sense molecule or by contacting cells expressing an EL-10 receptor with a regulatory agent of the present invention. Ex vivo methods are particularly suitable when the cell to which the agent is to be delivered can easily be removed from and returned to the patient. According to the method of the present invention, an effective amount of a agent that inhibits EL-10 (also referred to simply as "an agent") to administer to an animal comprises an amount that is capable of reducing airway hyperresponsiveness (AHR) without being toxic to the mammal. An amount that is toxic to an animal comprises any amount that causes damage to the structure or function of an animal (i.e., poisonous). In one embodiment, the effectiveness of an EL- 10 inhibiting agent to protect an animal from AHR in an animal having or at risk of developing AHR can be measured in doubling amounts. For example, the ability of an animal to be protected from AHR (i.e., experience a reduction in or a prevention of) by administration of a given EL-10 inhibitor is significant if the animal's is at 1 mg/ml before administration of the EL-10 inhibitor and is at 2 mg/ml of Mch after administration of the EL-10 inhibitor. Similarly, an EL-10 inhibitor is considered effective if the animal's PC 20methacho ** ne FEN* is at 2 mg/ml before administration of the EL-10 inhibitor and is at 4 mg/ml of Mch after administration of the EL- 10 inhibitor. In one embodiment of the present invention, in an animal that has AHR, an effective amount of an agent to administer to an animal is an amount that measurably reduces AHR in the animal as compared to prior to administration of the agent. In another embodiment, an effective amount of an agent to administer to an animal is an amount that measurably reduces AHR in the animal as compared to a level of airway AHR in a population of animals with inflammation that is associated with AHR wherein the agent was not administered. In one embodiment of the present invention, an effective amount of an agent to administer to an animal includes an amount that is capable of decreasing methacholine responsiveness without being toxic to the animal. A preferred effective amount of an agent comprises an amount that is capable of increasing the PC 20methaoholine FEV 1 of an animal treated with the an agent by about one doubling concentration towards the PC 20methacholine FEV, of a normal animal. A normal animal refers to an animal known not to suffer from or be susceptible to abnormal AHR. A test animal refers to an animal suspected of suffering from or being susceptible to abnormal AHR. In another embodiment, an effective amount of an agent according to the method of the present invention, comprises an amount that results in an improvement in an animal's P omethacho ii ne FEN ! value such that the P o ^th ^-^FEN ! value obtained before administration of the an agent when the animal is provoked with a first concentration of methacholine is the same as the P o^ thac oHne FEN, value obtained after administration of the an agent when the animal is provoked with double the amount of the first concentration of methacholine. A preferred amount of an agent comprises an amount that results in an improvement in an animal's PC 20methacholine FEN 1 value such that the PC Mmetta ^ Iil JΕV 1 value obtained before administration of the an agent is between about 0.01 mg/ml to about 8 mg/ml of methacholine is the same as the PC 20methachoI *.JFΕN 1 value obtained after administration of the an agent is between about 0.02 mg/ml to about 16 mg/ml of methacholine. As previously described herein the effectiveness of an agent to protect an animal having or susceptible to AHR can be determined by measuring the percent improvement in FEV, and or the FEVJFVC ratio before and after administration of the agent. In one embodiment, an effective amount of an agent comprises an amount that is capable of reducing the airflow limitation of an animal such that the FEVJFVC value of the animal is at least about 80%. In another embodiment, an effective amount of an agent comprises an amount that is capable of reducing the airflow limitation of an animal such that the FEV,/FVC value of the animal is improved by at least about 5%, or at least about lOOcc or PGFRG lOL/min. In another embodiment, an effective amount of an agent comprises an amount that improves an animal's FEV, by at least about 5%, and more preferably by between about 6% and about 100%, more preferably by between about 7% and about 100%, and even more preferably by between about 8% and about 100% (or about 200 ml) of the animal's predicted FEV,. In another embodiment, an effective amount of an agent comprises an amount that improves an animal's FEV, by at least about 5%, and preferably, at least about 10%, and even more preferably, at least about 25%, and even more preferably, at least about 50%, and even more preferably, at least about 75%. It is within the scope of the present invention that a static test can be performed before or after administration of a provocative agent used in a stress test. Static tests have been discussed in detail above. A suitable single dose of an EL- 10-inhibitory agent to administer to an animal is a dose that is capable of reducing or preventing airway hyperresponsiveness in an animal when administered one or more times over a suitable time period. In particular, a suitable single dose of an agent comprises a dose that improves AHR by a doubling dose of a provoking agent or improves the static respiratory function of an animal. A preferred single dose of an agent comprises between about 0.01 microgram x kilogram "1 and about 10 milligram x kilogram "1 body weight of an animal. A more preferred single dose of an agent comprises between about 1 microgram x kilogram "1 and about 10 milligram x kilogram "1 body weight of an animal. An even more preferred single dose of an agent comprises between about 5 microgram x kilogram "1 and about 7 milligram x kilogram "1 body weight of an animal. An even more preferred single dose of an agent comprises between about 10 microgram x kilogram "1 and about 5 milligram x kilogram "1 body weight of an animal. A particularly preferred single dose of an agent comprises between about 0.1 milligram x kilogram "1 and about 5 milligram x kilogram "1 body weight of an animal, if the an agent is delivered by aerosol. Another particularly preferred single dose of an agent comprises between about 0.1 microgram x kilogram "1 and about 10 microgram x kilogram "1 body weight of an animal, if the agent is delivered parenterally. In one embodiment, the EL-10-inhibitory agent is administered with a pharmaceutically acceptable carrier, which includes pharmaceutically acceptable excipients and or delivery vehicles, for administering the agent to a patient (e.g., a liposome delivery vehicle). As used herein, a pharmaceutically acceptable carrier refers to any substance suitable for delivering an EL- 10-inhibitory agent useful in the method of the present invention to a suitable in vivo or ex vivo site. Preferred pharmaceutically acceptable carriers are capable of maintaining a recombinant nucleic acid molecule or other agent of the present invention in a form that, upon arrival of the agent in the animal, the agent is capable of interacting with its target (e.g., EL-10, EL-10R or genes encoding EL-10 or EL-10R) such that AHR is reduced or prevented. Suitable excipients of the present invention include excipients or formularies that transport or help transport, but do not specifically target an agent to a cell (also referred to herein as non-targeting carriers). Examples of pharmaceutically acceptable excipients include, but are not limited to water, phosphate buffered saline, Ringer's solution, dextrose solution, serum-containing solutions, Hank's solution, other aqueous physiologically balanced solutions, oils, esters and glycols. Aqueous carriers can contain suitable auxiliary substances required to approximate the physiological conditions of the recipient, for example, by enhancing chemical stability and isotonicity. Suitable auxiliary substances include, for example, sodium acetate, sodium chloride, sodium lactate, potassium chloride, calcium chloride, and other substances used to produce phosphate buffer, Tris buffer, and bicarbonate buffer. Auxiliary substances can also include preservatives, such as thimerosal, — or o-cresol, formalin and benzol alcohol. Compositions of the present invention can be sterilized by conventional methods and or lyophilized. One type of pharmaceutically acceptable carrier includes a controlled release formulation that is capable of slowly releasing a composition of the present invention into an animal. As used herein, a controlled release formulation comprises an agent of the present invention in a controlled release vehicle. Suitable controlled release vehicles include, but are not limited to, biocompatible polymers, other polymeric matrices, capsules, microcapsules, microparticles, bolus preparations, osmotic pumps, diffusion devices, liposomes, lipospheres, and transdermal delivery systems. Suitable delivery vehicles have been previously described herein, and include, but are not limited to liposomes, viral vectors or other delivery vehicles, including ribozymes. Natural lipid-containing delivery vehicles include cells and cellular membranes. Artificial lipid-containing delivery vehicles include liposomes and micelles. As discussed above, a delivery vehicle of the present invention can be modified to target to a particular site in a patient, thereby targeting and making use of an EL-10 inhibitory agent at that site. Suitable modifications include manipulating the chemical formula of the lipid portion of the delivery vehicle and/or introducing into the vehicle a targeting agent capable of specifically targeting a delivery vehicle to a preferred site, for example, a preferred cell type. Other suitable delivery vehicles include gold particles, poly-L-lysine/DNA-molecular conjugates, and artificial chromosomes. Isolated nucleic acid molecules to be administered in a method of the present invention include: (a) isolated nucleic acid molecules useful in the method of the present invention in a non-targeting carrier (e.g., as "naked" DNA molecules, such as is taught, for example in Wolff et al., 1990, Science 247, 1465-1468); and (b) isolated nucleic acid molecules of the present invention complexed to a delivery vehicle of the present invention. Particularly suitable delivery vehicles for local administration of nucleic acid molecules comprise liposomes, viral vectors and ribozymes. Delivery vehicles for local administration can further comprise ligands for targeting the vehicle to a particular site. A pharmaceutically acceptable carrier which is capable of targeting is herein referred to as a "delivery vehicle." Delivery vehicles of the present invention are capable of delivering a formulation, including an EL-10-inhibitory agent to a target site in a mammal. A "target site" refers to a site in a mammal to which one desires to deliver a therapeutic formulation. For example, a target site can be any cell which is targeted by direct injection or delivery using liposomes, viral vectors or other delivery vehicles, including ribozymes. Examples of delivery vehicles include, but are not limited to, artificial and natural lipid- containing delivery vehicles, viral vectors, andribozymes. Natural lipid-containing delivery vehicles include cells and cellular membranes. Artificial lipid-containing delivery vehicles include liposomes and micelles. A delivery vehicle of the present invention can be modified to target to a particular site in a mammal, thereby targeting and making use of a nucleic acid molecule at that site. Suitable modifications include manipulating the chemical formula of the lipid portion of the delivery vehicle and/or introducing into the vehicle a compound capable of specifically targeting a delivery vehicle to a preferred site, for example, a preferred cell type. Specifically, targeting refers to causing a delivery vehicle to bind to a particular cell by the interaction of the compound in the vehicle to a molecule on the surface of the cell. Suitable targeting compounds include ligands capable of selectively (i.e., specifically) binding another molecule at a particular site. Examples of such ligands include antibodies, antigens, receptors and receptor ligands. Manipulating the chemical formula of the lipid portion of the delivery vehicle can modulate the extracellular or intracellular targeting of the delivery vehicle. For example, a chemical can be added to the lipid formula of a liposome that alters the charge of the lipid bilayer of the liposome so that the liposome fuses with particular cells having particular charge characteristics. One preferred delivery vehicle of the present invention is a liposome. A liposome is capable of remaining stable in an animal for a sufficient amount of time to deliver a nucleic acid molecule described in the present invention to a preferred site in the animal. A liposome, according to the present invention, comprises a lipid composition that is capable of delivering a nucleic acid molecule described in the present invention to a particular, or selected, site in a mammal. A liposome according to the present invention comprises a lipid composition that is capable of fusing with the plasma membrane of the targeted cell to deliver a nucleic acid molecule into a cell. Suitable liposomes for use with the present invention include any liposome. Preferred liposomes of the present invention include those liposomes typically used in, for example, gene delivery methods known to those of skill in the art. More preferred liposomes comprise liposomes having a polycationic lipid composition and/or liposomes having a cholesterol backbone conjugated to polyethylene glycol. A liposome comprises a lipid composition that is capable of fusing with the plasma membrane of the targeted cell to deliver a nucleic acid molecule and/or inhibitory agent into a cell. Preferably, the transfection efficiency of a liposome is at least about 0.5 microgram (μg) of DNA per 16 nanomole (nmol) of liposome delivered to about 10 6 cells, more preferably at least about 1.0 μg of DNA per 16 nmol of liposome delivered to about 10 6 cells, and even more preferably at least about 2.0 μg of DNA per 16 nmol of liposome delivered to about 10 6 cells. A preferred liposome is between about 100 and about 500 nanometers (nm), more preferably between about 150 and about 450 nm and even more preferably between about 200 and about 400 nm in diameter. Complexing a liposome with a nucleic acid molecule or inhibitory agent of the present invention can be achieved using methods standard in the art. A suitable concentration of a nucleic acid molecule or inhibitory agent to add to a liposome includes a concentration effective for delivering a sufficient amount of nucleic acid molecule and/or inhibitory agent to a cell such that the expression and/or biological activity of EL- 10 or EL- 10 receptor is reduced in a desired manner. Preferably, nucleic acid molecules are combined with liposomes at aratio offrom about 0.1 μgto about 10 μg ofnucleic acid molecule of the present invention per about 8 nmol liposomes, more preferably from about 0.5 μg to about 5 μg of nucleic acid molecule per about 8 nmol liposomes, and even more preferably about 1.0 μg of nucleic acid molecule per about 8 nmol liposomes. Another preferred delivery vehicle comprises a viral vector. A viral vector includes an isolated nucleic acid molecule useful in the method of the present invention, in which the nucleic acid molecules are packaged in a viral coat that allows entrance of DNA into a cell. A number of viral vectors can be used, including, but not limited to, those based on alphaviruses, poxviruses, adenoviruses, herpesviruses, lentiviruses, adeno-associated viruses and retroviruses. The present invention also includes a formulation that reduces or prevents airway hyperresponsiveness in an animal. The formulation comprises: (a) an inhibitor of EL-10 selected from the group of: an isolated nucleic acid molecule that reduces expression of EL- 10 by selectively hybridizing to a nucleic acid molecule encoding EL- 10; a ribozyme specific for EL- 10 RNA; an EL- 10 antagonist; an antibody that selectively binds to EL- 10; a soluble EL- 10 receptor; an EL- 10 receptor antagonist; and an antibody which binds to an EL- 10 receptor and blocks EL-10 from binding to said receptor; and, (b) an anti-inflammatory agent suitable for reducing inflammation in an animal that has, or is at risk of developing, airway hyperresponsiveness associated with inflammation. Inhibitors of EL- 10 have been described in detail above. The anti-inflammatory agent can be any anti-inflammatory agent which is suitable for use in reducing inflammation in a patient that has an inflammatory condition associated with airway hyperresponsiveness, including, but not limited to: corticosteroids, (oral, inhaled and injected), β-agonists (long or short acting), leukotriene modifiers (inhibitors or receptor antagonists), cytokine or cytokine receptor antagonists, anti-IgE, phosphodiesterase inhibitors, sodium cromoglycate, nedocrimal, theophylline, and inhibitors of T cell function. Particularly preferred anti-inflammatory agents for use in the present formulation include, corticosteroids, leukotriene modifiers, and cytokine or cytokine receptor antagonists. Yet another embodiment of the present invention relates to a method to identify a compound that reduces or prevents airway hyperresponsiveness associated with inflammation. Such a method includes the steps of: (a) contacting a putative regulatory compound with a cell that expresses EL-10 wherein in the absence of the putative regulatory compound, the EL-10 can be expressed and is biologically active; (b) detecting whether the putative regulatory compound inhibits EL-10 expression or activity by the cell; and, (c) administering the putative regulatory compound to a non-human animal in which airway hyperresponsiveness can be induced and identifying animals in which airway hyperresponsiveness is reduced or prevented as compared to in the absence of the putative regulatory compound. A putative regulatory compound that inhibits EL-10 expression or activity and that reduces or prevents airway hyperresponsiveness in the non-human animal is indicated to be a compound for reducing or preventing hyperresponsiveness associated with inflammation. In this method, the step (b) of detecting can include, but is not limited to, a method selected from the group of measurement of EL-10 transcription, measurement of EL-10 translation, measurement of EL- 10 receptor ligand binding activity, and measurement of EL- 10 biological activity associated with the cell. Such methods of detecting an interaction of a ligand with a receptor, including the interaction of a ligand with an EL- 10 receptor, are known in the art as discussed above, and include immunoblots, phosphorylation assays, kinase assays, immunofluorescence microscopy, RNA assays, immunoprecipitation, and other biological assays. Assay kits for EL-10 biological activity are commercially available, for example, from Pharmingen. In one aspect of this embodiment, step (a) of contacting includes contacting the putative regulatory compound with a cell containing transcripts encoding EL- 10, and step (b) of detecting includes detecting translational inhibition of the EL-10 transcript. In an alternate embodiment, such a method can include the steps of: (a) contacting a putative regulatory compound with an isolated EL-10 protein and determining whether the putative regulatory compound binds to the EL-10 protein; an optional step (b) of further detecting whether compounds that bind to EL- 10 in (a) inhibit biological activity of EL- 10 in an assay for EL- 10 biological activity; and (c) administering the putative regulatory compound to a non-human animal in which airway hyperresponsiveness can be induced and identifying animals in which airway hyperresponsiveness is reduced or prevented as compared to in the absence of the putative regulatory compound. Yet another alternate embodiment of the method to identify a compound that reduces or prevents airway hyperresponsiveness associated with inflammation, includes the steps of: (a) contacting a cell or cell lysate which expresses an interleukin-10 (EL-10) receptor with a putative regulatory compound; (b) detecting whether the putative regulatory compound inhibits an EL-10 receptor function selected from the group of EL-10 receptor expression, EL- 10 receptor ligand binding or EL-10 receptor biological activity; and (c) administering the putative regulatory compound to a non-human animal in which airway hyperresponsiveness can be induced, and identifying animals in which airway hyperresponsiveness is reduced or prevented as compared to in the absence of the putative regulatory compound. A putative regulatory compound that inhibits EL-10 receptor expression, ligand binding or biological activity and that reduces or prevents airway hyperresponsiveness in the non-human animal is indicated to be a compound for reducing or preventing hyperresponsiveness associated with inflammation. In an alternate embodiment, step (a) of contacting comprises contacting the putative regulatory compound with a cell or cell lysate containing a reporter gene operatively associated with a regulatory element of the EL-10 receptor, and step (b) of detecting comprises detecting inhibition of the expression of the reporter gene product. In another aspect of this embodiment, step (a) of contacting comprises contacting the putative regulatory compound with a cell or cell lysate containing transcripts of the EL-10 receptor, and step (b) of detecting comprises detecting translational inhibition of the EL-10 receptor transcript. As used herein, the term "putative" refers to compounds having an unknown or previously unappreciated regulatory activity in a particular process. As such, the term "identify" is intended to include all compounds, the usefulness of which as a regulatory compound of EL-10 expression or biological activity for the purposes of reducing airway hyperresponsiveness is determined by a method of the present invention. The above-described methods for identifying a compound of the present invention include contacting a test cell or a cell lysate with a compound being tested for its ability to bind to and/or regulate the activity of EL-10 or its receptor, respectively. For example, test cells can be grown in liquid culture medium or grown on solid medium in which the liquid medium or the solid medium contains the compound to be tested. In addition, as described above, the liquid or solid medium contains components necessary for cell growth, such as assimilable carbon, nitrogen and micro-nutrients. The above described methods, in one aspect, involve contacting cells with the compound being tested for a sufficient time to allow for interaction of the putative regulatory compound with EL-10 with an EL-10 receptor expressed by the cell. The period of contact with the compound being tested can be varied depending on the result being measured, and can be determined by one of skill in the art. For example, for binding assays, a shorter time of contact with the compound being tested is typically suitable, than when activation is assessed. As used herein, the term "contact period" refers to the time period during which cells are in contact with the compound being tested. The term "incubation period" refers to the entire time during which cells are allowed to grow prior to evaluation, and can be inclusive of the contact period. Thus, the incubation period includes all of the contact period and may include a further time period during which the compound being tested is not present but during which growth is continuing (in the case of a cell based assay) prior to scoring. The incubation time for growth of cells can vary but is sufficient to allow for the binding of the EL- 10 or EL- 10 receptor and or inhibition of FL- 10 or EL- 10 receptor. It will be recognized that shorter incubation times are preferable because compounds can be more rapidly screened. A preferred incubation time is between about 1 minute to about 48 hours. The conditions under which the cell or cell lysate of the present invention is contacted with a putative regulatory compound, such as by mixing, are any suitable culture or assay conditions and includes an effective medium in which the cell can be cultured or in which the cell lysate can be evaluated in the presence and absence of a putative regulatory compound. Cells of the present invention can be cultured in a variety of containers including, but not limited to, tissue culture flasks, test tubes, microtiter dishes, and petri plates. Culturing is carried out at a temperature, pH and carbon dioxide content appropriate for the cell. Such culturing conditions are also within the skill in the art. Acceptable protocols to contact a cell with a putative regulatory compound in an effective manner include the number of cells per container contacted, the concentration of putative regulatory compound(s) administered to a cell, the incubation time of the putative regulatory compound with the cell, and the concentration of compound administered to a cell. Determination of such protocols can be accomplished by those skilled in the art based on variables such as the size of the container, the volume of liquid in the container, the type of cell being tested and the chemical composition of the putative regulatory compound (i.e., size, charge etc.) being tested. A preferred amount of putative regulatory compound(s) comprises between about 1 nM to about 10 mM of putative regulatory compound(s) per well of a 96-well plate. Suitable cells for use with the present invention include any cell that endogenously expresses EL-10 or an EL-10 receptor, or which has been transfected with and expresses recombinant EL-10 or a recombinant EL-10 receptor. In one embodiment, host cells genetically engineered to express a functional EL- 10 receptor that respond to activation by EL- 10 or agonists thereof can be used as an endpoint in the assay; e.g., as measured by a chemical, physiological, biological, or phenotypic change, induction of a host cell gene or a reporter gene, change in cAMP levels, activity of other intracellular signal transduction molecules, proliferation, differentiation, etc. Cytokine-producing cells for use with the present invention include mammalian, invertebrate, plant, insect, fungal, yeast and bacterial cells. Preferred cells include mammalian, amphibian and yeast cells. Preferred mammalian cells include primate, non-human primate, mouse and rat. En one embodiment, the test cell (host cell) should express a functional EL- 10 receptor that gives a significant response to EL- 10, preferably greater than 2, 5, or 10-fold induction over background. h one aspect of the method for identifying a compound, a cell expressing an EL-IOR is contacted with EL-10, or an agonist thereof, that binds to and activates the receptor. The EL- 10 can be contacted with the EL- 10 receptor (or the cell expressing such receptor) prior to, simultaneous with, or after contact of the putative regulatory compound with the cell, depending on how the assay is to be evaluated. In one embodiment, the EL-10 is contacted with the receptor after the cell is contacted with the putative regulatory compound so that the test compound can be evaluated for its ability to inhibit activation of the receptor by EL-10. In another embodiment, when binding is to be evaluated, the EL- 10 can be contacted with the receptor at the same time as the test compound. Preferably, the EL-10 is contacted with the cell/receptor in the presence and absence of the test compound for a controlled assay. As disclosed above, the present methods also make use of non-cell based assay systems to identify compounds that can regulate AHR. For example, isolated membranes may be used to identify compounds that interact with the EL-10 receptor being tested. Membranes can be harvested from cells expressing EL-10 receptors by standard techniques and used in an in vitro binding assay. 125 I-labeled EL-10 is bound to the membranes and assayed for specific activity; specific binding is determined by comparison with binding assays performed in the presence of excess unlabeled EL-10. Membranes are typically incubated with labeled ligand in the presence or absence of test compound. Compounds that bind to the receptor and compete with labeled ligand for binding to the membranes reduced the signal compared to the vehicle control samples. Alternatively, soluble EL-10 receptors may be recombinantly expressed and utilized in non-cell based assays to identify compounds that bind to EL- 10 receptors. Recombinantly expressed EL- 10 receptor polypeptides or fusion proteins containing one or more extracellular domains of an EL-10 receptor can be used in the non-cell based screening assays. Alternatively, peptides corresponding to one or more of the cytoplasmic domains of the EL- 10 receptor or fusion proteins containing one or more of the cytoplasmic domains of the EL-10 receptor can be used in non-cell based assay systems to identify compounds that bind to the cytoplasmic portion of the EL-10 receptor; such compounds may be useful to modulate the signal transduction pathway of the EL-10 receptor. In non-cell based assays the recombinantly expressed EL-10 receptor is attached to a solid substrate such as a test tube, microtitre well or a column, by means well known to those in the art. The test compounds are then assayed for their ability to bind to the EL-10 receptor. As discussed above, in vitro cell based assays may be designed to screen for compounds that regulate EL-10 or EL-10 receptor expression at either the transcriptional or translational level. n one embodiment, DNA encoding a reporter molecule can be linked to a regulatory element of the EL-10 gene or the EL-10 receptor gene and used in appropriate intact cells, cell extracts or lysates to identify compounds that modulate EL-10 or EL-10 receptor gene expression, respectively. Appropriate cells or cell extracts are prepared from any cell type that normally expresses the EL-10 or EL-10 receptor gene, thereby ensuring that the cell extracts contain the transcription factors required for in vitro or in vivo transcription. The screen can be used to identify compounds that modulate the expression of the reporter construct. In such screens, the level of reporter gene expression is determined in the presence of the test compound and compared to the level of expression in the absence of the test compound. To identify compounds that regulate EL-10 or EL-10 receptor translation, cells or in vitro cell lysates containing EL- 10 or EL- 10 receptor transcripts may be tested for modulation of EL-10 or EL-10 receptor mRNA translation. To assay for inhibitors of translation, test compounds are assayed for their ability to modulate the translation of EL- 10 or EL- 10 receptor mRNA in in vitro translation extracts. Compounds that decrease the level of EL-10 or EL-10 receptor expression, either at the transcriptional or translational level, may be useful for reduction of AHR. Finally, a putative regulatory compound of the present invention can be evaluated by administering putative regulatory compounds to a non-human test animal and detecting whether the putative regulatory compound reduces AHR in the test animal. Animal models of disease are invaluable to provide evidence to support a hypothesis or justify human experiments. For example, mice have many proteins which share greater than 90% homology with corresponding human proteins. Preferred modes of administration, including dose, route and other aspects of the method are as previously described herein for the therapeutic methods of the present invention. The test animal can be any suitable non-human animal, including any test animal described in the art for evaluation of AHR. The test animal can be, for example, an established mouse model of AHR, as previously described, for example, in Takeda et al., (1997). J. Exp. Med.186, 449-454. This non-human model system is an antigen-driven murine system that is characterized by an immune (IgE) response, a dependence on a Th2-type response, and an eosinophil response. The model is characterized by both a marked and evolving hyperresponsiveness of the airways. Briefly, as an exemplary protocol for this murine model, mice (typically BALB/c) are immunized intraperitoneally with ovalbumin (OVA). The mice are then chronically exposed (i.e., challenged) for 8 days (i.e., 8 exposures of 30 minutes each in 8 days) to aerosolized OVA. It should be noted that both immunization and subsequent antigen challenge are required to observe a response in mice. To characterize the murine model, pulmonary function measurements of airway resistance (R L ) and dynamic compliance (C and hyperresponsiveness are obtained as described in Example 1 below. Alternatively the test animal can be a genetically modified non-human animal comprising a deletion of EL-10 genes as described in Example 1. In this latter embodiment, the non-human EL-10 -/- animal can be reconstituted to restore AHR and compounds can be evaluated for their ability to reduce or inhibit the restoration of AHR as compared to reconstituted test animals in the absence of treatment with the putative test compound. Compounds identified by any of the above-described methods can be used in a method for the reduction or prevention of AHR as described herein.. The following examples are provided for the purposes of illustration and are not intended to limit the scope of the present invention. EXAMPLES Example 1 The following example demonstrates that allergic sensitization does not lead to airway hyperresponsiveness in EL-10-/- mice. Animals. Homozygous EL- 10-deficient mice (EL-10-/-) on a C57BL/6 background (C57BL/6-EL-10(tmlCgn) 13 were originally obtained for use by the present inventors from Dr. Werner Mtlller, Cologne, FRG. These mice were housed in specific pathogen-free conditions and maintained on an ovalbumin (OVA)-free diet in the Biological Resources Center at National Jewish Medical and Research Center. Control wild type C57BL/6 mice (WT) were purchased from the Jackson Laboratory (Bar Harbor, ME). Both female and male mice, 6-10 weeks of age were used in the experiments. Controls were matched with the deficient mice with regard to both age and gender in each experimental group. Sensitization and A irway Challenge. Mice were sensitized by intraperitoneal inj ection of 20 μg of ovalbumin (OVA) (Grade V; Sigma Chemical Co., St. Louis, MO) emulsified in 2.25 mg alum (Alumlmuject; Pierce, Rockford, IL) or received PBS alone in a total volume of 100 μl on days 0 and 14. Mice were challenged via the airways by OVA (1% in PBS) or PBS for 20 min. on days 28, 29 and 30 by ultrasonic nebulization (De Vilbiss Health Care Inc., Somerset, PA, particle size 1-5 μm). On day 32, airway function was measured as described below after which mice were sacrificed and specimens were collected for further analysis 14 . Determination of Airway Resistance and Cdyn. Airway resistance and Cdyn were determined before and after inhalation of aerosolized MCh. Anesthetized, tracheostomized mice were mechanically ventilated and lung function was assessed by a modification of previously described work 14 . A four way connector was attached to the tracheostomy tube (stainless steel cannula, 18G), with two ports connected to the inspiratory and expiratory sides of two ventilators. Ventilation was achieved at a rate of 160 breaths/min, tidal volume of 150 μl with a positive end-expiratory pressure of 2-3 cm H 2 O (ventilator model 683; Harvard Apparatus, South Natick, MA). Aerosolized MCh was administered for 10 breaths at a rate of 60 breaths/min, tidal volume of 500 μl by the second ventilator (model SN-480-7- 3-2T; Shinano Manufacturing Co., Tokyo, Japan) in increasing concentrations (6.25, 12.5, 25, 50, 100 mg/ml). After each aerosol MCh challenge, the data was continuously collected for 1 to 5 min and maximum values of RL and minimum values of Cdyn were taken to express changes in these functional parameters. Experiment. Intraperitoneal ovalbumin (OVA) sensitization and airway challenge of mice is an established model consistently leading to allergic sensitization and airway hyperresponsiveness (AHR) in BALB/c and C57BL/6 mice 19 . Wild type mice that were sensitized according to this protocol as described above developed significant AHR to inhaled methacholine (MCh). Figs. 1A and IB show airway responsiveness to methacholine after sensitization with ovalbumin and challenge with either ovalbumin or PBS in EL-10- deficient (EL-10-/-) and wild-type mice (BL=baseline, SAL=saline). Airway responsiveness was monitored by measuring lung resistance (RL; Fig. 1 A) and dynamic compliance (Cdyn; Fig. IB) as described above. The results for each group are expressed as means ± SEM. Data represent two comparable experiments with a total of 10 mice per group. Significant differences between the groups (ANOVA and Tukey-Kramer, p<0.05) are designated (*). The data were analyzed with JMP statistical software package (SAS Institute Inc., Gary, NC). Analysis of variance was used to determine the levels of difference between all groups. Comparisons for all pairs were performed by Tukey-Kramer honest significant difference (HSD) test. Significance levels were set at p-value of 0.05. Figs. lAand IB illustrate pulmonary resistance and dynamic compliance in response to increasing concentrations of inhaled MCh in wild-type mice. In contrast, OVA-sensitized and challenged EL-10-/- mice did not develop any increase in lung resistance above non- sensitized and OVA challenged control mice. Similarly, monitoring dynamic compliance, there were no significant differences between the sensitized and non-sensitized EL- 10- deficient mice, although there were maj or differences as compared to normal WT mice at all doses of MCh. These results indicate that allergic sensitization does not lead to airway hyperresponsiveness in EL-10-/- mice. Example 2 The following example describes differences in lung inflammation between EL- 10-/- and WT mice. To account for the differences in lung function demonstrated in Example 1, the inflammatory cell populations in the bronchoalveolar lavage fluid (BALF) were examined. BAL fluid (BALF) was obtained from the groups shown in Fig. 1. Briefly, lungs were lavaged via the tracheal tube with Hank's balanced salt solution, (HBSS, lx 1 ml, RT). The volume of collected bronchoalveolar lavage fluid (BALF) was measured in each sample and the number of BALF cells was counted by cell counter (Coulter Counter; Coulter Co., Hialeah, FL). Cytospin slides were stained with Leukostat (Fisher Diagnostics, Pittsburgh, PA) and differentiated in a blinded fashion by counting at least 200 cells under light microscopy. Fig.2 shows the cellular composition of BAL fluid (BALF) in EL- 10-deficient (EL- 10- /-) and wild-type mice after sensitization and challenge to ovalbumin as described in Example 1. The results for each group are expressed as means ± SEM. Significant differences between the groups (ANOVA and Tukey-Kramer, p<0.05) are designated (*). Specifically, Fig. 2 illustrates that eosinophils comprised up to 70% of the cells in WT mice and approximately 50% in the EL-10-/- mice (p<0.01). Neutrophils, on the other hand, were 15% of the total cell population in the EL-10-/- mice and approximately 5% in the WT mice (p<0.01). There were no significant differences in total cell numbers, macrophages or numbers of lymphocytes. After obtaining the BALF, the lungs were inflated through the tracheal tube with 2 ml air and fixed in 10% formalin. Blocks of lung tissue were cut around the main bronchus and embedded in paraffin blocks. Tissue sections, 5 μm thick, were affixed to microscope slides, and deparaffinized. The slides were stained with hematoxylin and eosin (H&E), as well as periodic acid Schiff (PAS) for identification of mucus containing cells, and examined under light microscopy. In these experiments, cells containing major basic protein (MBP) in lung sections were identified by immunohistochemical staining as described using rabbit anti-mouse MBP (provided by Dr. J. Lee, Scottsdale, AZ) 16 . The slides were examined in a blinded fashion with a Nikon microscope equipped with a fluorescein filter system. Number of eosinophils in the perivascular, peribronchial and peripheral tissues were evaluated using the EPLab2 software (Signal Analytics, Vienna, VA) for the Macintosh computer counting 5 sections pre animal (3 mice per group). Lung histology showed a heavy infiltration of inflammatory cells in the perivascular and to a slightly lesser extent, peribronchial spaces, in the OVA sensitized and challenged EL-10-/- and in the WT mice. Both strains of mice exposed to only 3 days of nebulization with OVA alone had no signs of inflammation (data not shown). There were no obvious differences between the two mouse strains when sections stained with hematoxylin and eosin were examined (data not shown). Staining of the mucus producing goblet cells with PAS- stain failed to reveal any differences between the strains of mice (data not shown). Numbers of eosinophils in the lung tissue were evaluated by immunohistochemistry staining for the major basic protein (MBP). Comparison of the numbers of MBP+ cells in peribronchial, perivascular and parenchymal areas of the lung did not reveal significant differences between sensitized and challenged WT and EL-10-/- mice (the numbers ranged from 400-900 eosinophils/mm 2 in these areas). Example 3 The following example describes additional characterization and comparison of the bronchoalveolar lavage fluid from OVA sensitized and challenged wild-type and EL-10 -/- mice. Cytokine Levels in BALF. To further characterize any differences between wild- type and EL-10 -/- mice which might correlate with the differences in airway hyperresponsiveness, levels of EL-4, EL-5, EL- 13 and EFN-γ were assayed in EL- 10+/+ (i.e., WT) and EL-10-/- mice after sensitization and challenge as described in Example 1. Briefly, EFN-γ, EL-4 and EL-5 in the BALF supernatants were detected by enzyme immunoassay (ELA) as previously described 19 . For interleukin-10, the OptEIA set was used according to the manufacturer's directions (PharMingen). For EL-13, a commercial kit was used (R and D Systems). Cytokine levels were determined by comparison with the known standards. The limits of detection were 30 pg/ml for EL-10 and 10 pg/ml for the other cytokines. Essentially, no significant differences in cytokine levels were detected in comparing WT mice to EL-10 -/- mice. In both strains of mice sensitization/challenge resulted in increases in EL-4 and EL-5 levels while EFN-γ levels remained unchanged (data not shown). Following reconstitution of the EL-10 gene in EL-10-/- mice, no changes in cytokine levels were detected when compared to mice receiving the control vector. Leukotriene and eosinophil peroxidase levels. To account for the failure to develop AHR despite the strong eosinophil inflammatory response, it was determined whether EL- 10- /- mice failed to activate eosinophils, which could account for the absence of AHR, by measuring eosinophil peroxidase (EPO) and leukotriene C4 (LTC4) levels in the BALF. Samples for leukotriene measurements were prepared by adding 50 μl of 100% methanol to 200 μl of the BALF supernatants. These samples were loaded onto C-18 Sep- Pak chromatography columns (Varian, Palo Alto, CA). Methanol-water (80% vol/vol) was used to rinse out the tubes and to elute the bound peptide-leukotrienes which were then evaporated to dryness on a rotary evaporator at 30°C. The dry pellet was dissolved in 500 μl of EIA buffer which was then used for ELISA analysis. Peptide-leukotrienes were assayed using leukotriene EIA kits (Cayman Chemical Co., Ann Arbor, MI). The range of the EIA standard curve was 7-1000 pg/ml, with 50% binding at 53 pg/ml. The rabbit antiserum against leukotriene had the following cross reactivities: LTC4 (100%), LTD4 (100%), LTE4 (67%), and N-acetyl-LTE4 (10.5%), but not 5, 12, 15-HETE, LTB4, 20-hydroxy LTB4 or prostaglandins (<0.01%). The limit of detection was 12 pg/ml. Eosinophil peroxidase (EPO) was measured in BAL supernatants collected 48 h after the last airway challenge with o-phenylenediamine hydrochloride substrate as previously described 20 . Horse radish peroxidase was used as a standard starting from 1000 pg/ml with 3-fold dilutions to create a standard curve. EPO levels of the samples were calculated based on this standard curve. Figs. 3A and 3B show the results of these experiments. The results for each group are expressed as means ± SEM (n=8 per group). Significant differences between the groups (ANOVA and Tukey-Kramer, ρ<0.05) are designated (*). Specifically, Figs. 3A and 3B demonstrate that OVA sensitized EL- 10-deficient mice actually had higher EPO (Fig.3 A) and LTC4 (Fig. 3B) levels than the WT mice. This difference was statistically significant for LTC4 and when adjusted to the number of eosinophils present in the BALF. EPO levels were also significantly higher in the EL-10 -/- mice. The concentrations of both mediators were low in naive mice. Serum immunoglobulins. Serum levels of total IgE, OVA-specific IgE and IgGl were measured by ELISA as previously described 18 . The anti-OVA antibody titers of samples were related to internal pooled standards and expressed as ELISA units (EU). Total IgE level was calculated by comparison with known mouse IgE standard (PharMingen). The limit of detection was 100 pg/ml for IgE. Table 1 demonstrates that the total IgE level was more than 7-fold higher and serum levels of OVA-specific IgE more than 2-fold higher in the EL-10-/- mice than the WT mice. OVA-specific IgGl and IgG2a levels were also significantly higher in the EL-10-/- mice. TABLE 1 Concentration of total IgE and OVA-specific IgE and lgG1 in the sera of IL10 -/- and WT mice. Group Total Ova-specific (EU/ml) IgE (ng/ml) IgE lgG1 lgG2a WT/PBS 5.75 ± 4.0 0 0 0 IL10J-/PBS 4.5 ± 3.0 0 0 0 WT/ipNf 37.6 ± 13.0 12.3 ± 5.3 20.7 ± 20.7 5.1 ± 3.8 IL10-/-/ipN 273.5 ± 59.0 * 31.6 ± 4.1* 255 ± 60.2* 53.1 ± 15.0 WT/ovaneb # 1.5 ± 1.5 0 0 0 IL10-/-/ovaneb 99.0 ± 52.6 * 0 0.12 ± 0.12 0 tMice were sensitized to OVA following two intraperitoneal injections of OVA in alum 14 days apart and then exposed to OVA via the airways (1% w/vol in PBS) 20-30 min per day for 3 days. * Significantly different from the WT mice (p<0.001 , Wilcoxon test). * Mice were exposed to aerosolized OVA (1% w/vol in PBS) 20-30 min per day on 10 consecutive days. Example 4 The following example demonstrates that EL- 10-/- mice are hyporesponsive following electric field stimulation of trachea smooth muscle. To assess whether there was a difference in the smooth muscle reactivity of the EL- 10- deficient mice in vitro, isolated tracheal smooth muscle preparations were subjected to electrical field stimulation (EFS) 15 . In these experiments, mice were sensitized by exposure to aerosolized OVA (1 % w/vol in PBS, 20-30 min per day) or PBS for 10 consecutive days. 48 hours after the last challenge, tracheas were removed and 0.5 cm long preparations were placed in Krebs-Henseleit solution suspended by triangular supports transducing the force of contractions. Electrical field stimulation (EFS) with an increasing frequency from 0.5 to 30 Hz was applied and the contractions measured. The duration of the stimulation was 1 millisecond. Frequencies resulting in 50% of the maximal contractions (ES 50 ) were calculated from linear plots for each individual animal and were compared between the different groups. Results are shown in Fig. 4. Results are expressed as the electrical frequency (Hz) required to induce 50% of the maximum contractile response (ES 50 ). The results for each group are expressed as means ± SEM (n=5 per group). Significant differences between the groups (ANOVA and Tukey-Kramer, p<0.05) are designated (*). In contrast to the sensitization and challenge approach described above (Example 1), this approach to sensitization and development of increased sensitivity to EFS has been shown to be IgE/IgGl dependent 18 . Fig.4 demonstrates that the electrical frequency required to induce 50% of the maximum contractile response (ES 50 ) was significantly lower in the OVA exposed WT mice than in their PBS exposed controls (ES 50 2.3 ± 0.37 Hz vs. ES 50 4.3 ± 0.36 Hz, p-=0.0003). In the EL-10-/- mice, no significant differences could be found between the sensitized and non-sensitized mice (ES 50 3.7 ± 0.6 Hz vs. ES 50 3.8 ± 0.3 Hz). The maximum tension/contractility curves in response to MCh were similar in both strains of mice. These experiments show that the sensitized EL- 10-deficient mice fail to develop altered airway reactivity to EFS as well as to inhaled MCh. Example 5 The following example demonstrates that adenovirus-mediated transfer of the EL-10 gene reconstitutes airway hyperresponsiveness in EL-10-/- mice. To address whether the absence of EL-10 was solely responsible for the failure to respond to inhaled MCh or EFS following allergen sensitization and challenge, genetically- deficient animals were reconstituted with EL-10 using adenovirus-mediated gene transfer. Briefly, replication-deficient human type 5 adenoviral (Ad) constructs carrying the transgene for murine EL- 10 in the E 1 region of the viral genome 17 (Ad JL- 10)were delivered intranasally (i.n.). An El-deleted replication-deficient human type 5 adenoviral construct carrying no transgene was used as a control vector (Ad/C). 24 hours before the first aerosolized challenge (5 days before measurement of airway function), mice were anaesthetized with an intraperitoneal (i.p.) injection of tribromoethanol (Avertin, 250 mg/kg of 2.5% solution in PBS), after which 1 x 10 8 PFU of either construct was applied in the nostril with a micropipette in a total volume of 30 ul of PBS vehicle (two 15 μl administrations, 2 min. apart). Airway responsiveness was monitored, following OVA sensitization and challenge, by measuring lung resistance (RL; Fig. 5A) and dynamic compliance (Cdyn; Fig. 5B) as described in Example 1. Results showed that the expression of EL-10 was transient in the airways, but there were still detectable concentrations of the cytokine in the BALF 5 days after the administration of this concentration of the viral construct (33 ± 25 pg/ml). Active gene transfer (Figs. 5A and 5B, squares) reconstituted both lung resistance (Fig. 5A) and dynamic compliance (Fig. 5B) in the EL- 10-deficient mice (EL-10 -/-, open square) to the levels observed in WT mice (black symbols) in response to inhaled MCh. Ad EL-10 alone did not cause AHR either in the naive EL-10-/- or the WT mice (RL at 100 mg/ml MCh 1.8 and 1.7, respectively). The control adenovirus construct (Ad/C; Figs. 5A and 5B, circles) induced a low level, but not significant, increase in airway resistance in the sensitized and challenged EL-10-/- mice (open circle) compared to those mice receiving no construct (triangle). Significant differences between Ad/EL- 10 (open square) and Ad/C (open circle) treated EL- 10 -/- mice were observed for both airway resistance and dynamic compliance in response to all MCh doses. WT mice administered the Ad/EL-10 (Fig. 5 A, black square) showed a minor further increase in airway resistance compared to the WT mice administered the Ad/C (Fig. 5 A, black circle). The results for each group are expressed as means ± SEM (n=8 per group). Significant differences between the groups (ANOVA and Tukey-Kramer, p<0.05) are designated (*). Reconstitution of the mice with the Ad/EL- 10 construct, 24 h before the initial airway challenge also increased mucus production both in the EL-10-/- and WT mice as was seen in PAS-stained sections (data not shown). As discussed above, allergen sensitized EL-10-/- mice had fewer eosinophils but more neutrophils in the BALF than in the WT mice. After reconstitution, the neutrophils decreased from 16% in mice administered the empty control vector to 8% in mice receiving Ad/EL-10 vector (p<0.05)(data not shown). Correspondingly, the percentage of eosinophils increased from 52% to 65% (p<0.05). To define whether EL-10-mediated reconstitution of AHR was EL-5/ eosinophil-dependent, since AHR has been shown to be EL-5/eosinophil dependent in other related models using a similar sensitization and challenge protocol 16 ' 21 , EL-10 -/- mice sensitized to OVA and administered Ad/EL-10 were treated with anti-EL-5 antibody 2 hours before the first airway challenge with OVA. Anti-mouse EL-5 mAb, TRFK-5 (IgG2b) was used in this study for studying effects on AHR 16 . One hundred μg of the stock mAb was diluted with PBS in a total volume of 100 μl, which was then given to i.p. sensitized mice as a single intravenous injection 2 hours before the first airway challenge. As a control, purified rat IgG2b at the same dose and volume was given. Following administration with Ad/EL-10 and treatment with control IgG (C/Ig)(Fig. 6, circle) or a monoclonal antibody against EL-5 (anti-EL-5)(Fig. 6, square), airway responsiveness was monitored by measuring lung resistance as described in Example 1. Fig. 6 shows that treatment of sensitized EL-10 -/- mice with EL-5 prior to airway challenge resulted in a dramatic decrease in airway eosinophil numbers (from 55% to 6%) and a concomitant normalization of lung function. Thus, the effects of EL-10 on airway function are dependent, at least in part, on allergen-induced eosinophilic inflammation. Adenovirus-mediated EL-10 reconstitution was also assessed by in vitro measurements of airway function following 10 consecutive days of OVA exposure. In this experiment, the constructs were administered 4 days before measurement of the response to electrical field stimulation (day 12) as described in Example 4. As in the in vivo system, Ad EL-10, but not Ad C, reconstituted the response to EFS (ES 50 2.1 ± 0.2 Hz and 3.8 ± 0.2 Hz, respectively) (Fig. 4). References noted: 1. Gelfand & Irvin, (1997) Nat. Med. 3, 382-384 2. Wills-Karp, (1999) Ann. Rev. Immunol. 17, 255-281 3. Grunig et al.,(1998) Science 282, 2261-2263 4. Fiorentino et al.,(1989) J. Exp. Med. 170, 2081-2095 5. Borish, (1998) J. Allergy Clin. Immunol. 101, 293-297 6. Moore et al.,(1993) Ann. Rev. Immunol. 11, 165-190 7. Lelievre et al., (1998) Cytokine 10, 831-840 8. Rennick et al., (1997) J. Leukoc. Biol. 61, 389-96 9. Robinson et al., (1996) Am. J. Respir. Cell. Mol. Biol. 14, 113-117 10. Tillie-Leblond et al., (1999) Am. J. Respir. Crit. Care Med. 159, 487-494 11. Magnan et al., (1998) Allergy. 53, 1092-1095 12. Pretolani & Goldman, (1997) Immunol. Today 18, 277-280 13. Kuhn et al., (1993) Cell 75, 263-274 14. Takeda et al., (1997). J. Exp. Med. 186, 449-454 15. Larsen et al, (1992) J. Clin. Invest. 89, 747-752 16. Hamelmann et al., (1997) Am. J. Respir. Crit. Care Med. 155, 819-825 17. Xing et al., (1997) Gene Therapy 4, 140-149 18. Oshiba et al., (1996) J. Clin. Invest. 97, 1398-1408 19. Haczku et al., (1999) Am. J. Respir. Crit. Care Med. 159, 1638-1643 20. Hamelmann et al., (1997) Amer. J. Resp. Cell. Molec. Biol. 16, 674-682 21. Foster et al., (1996) J. Exp. Med. 183, 195-201 22. Larsen et al., (1994) Amer. J. Physiol. 266, L263-L270 23. Evans et al., (1997) J. Clin. Invest. 100, 2254-2262 24. Hakonarson et al., (1999) J Clin. Invest 104, 657-667 While various embodiments of the present invention have been described in detail, it is apparent that modifications and adaptations of those embodiments will occur to those skilled in the art. It is to be expressly understood, however, that such modifications and adaptations are within the scope of the present invention, as set forth in the following claims:

Claims: What is claimed is: I. A method to reduce or prevent airway hyperresponsiveness in an animal, comprising inhibiting interleukin- 10 (EL- 10) in an animal that has, or is at risk of developing, airway hyperresponsiveness associated with inflammation. 2. The method of Claim 1, wherein said airway hyperresponsiveness is associated with allergic inflammation. 3. The method of Claim 1, wherein said airway hyperresponsiveness is associated with viral-induced inflammation. 4. The method of Claim 1, wherein said step of inhibiting comprises administering to said animal an agent effective to inhibit interleukin-10 (EL-10). 5. The method of Claim 4, wherein said agent is an inhibitor of EL- 10 expression. 6. The method of Claim 5, wherein said agent is an isolated nucleic acid molecule that reduces expression of EL-10 by selectively hybridizing to a nucleic acid molecule encoding EL-10. 7. The method of Claim 5, wherein said agent is a ribozyme specific for EL-10 RNA. 8. The method of Claim 4, wherein said agent is an inhibitor of EL- 10 biological activity. 9. The method of Claim 8, wherein said agent is an EL-10 antagonist. 10. The method of Claim 8, wherein said agent is an antibody that selectively binds to EL-10. I I . The method of Claim 8, wherein said agent is a soluble EL-10 receptor. 12. The method of Claim 8, wherein said agent is an EL-10 receptor antagonist. 13. The method of Claim 8 , wherein agent is an antibody which binds to an EL- 10 receptor and blocks EL-10 from binding to said receptor. 14. The method of Claim 4, wherein said agent is administered by a route selected from the group consisting of oral, nasal, topical, inhaled, intratracheal, transdermal, rectal and parenteral routes. 15. The method of Claim 4, wherein said agent is administered to said animal in an amount effective to measurably reduce airway hyperresponsiveness in said animal as compared to prior to administration of said agent. 16. The method of Claim 4, wherein said agent is administered to said animal in an amount effective to measurably reduce airway hyperresponsiveness in said animal as compared to a level of airway hyperresponsiveness in a population of animals having allergic inflammation wherein said agent was not administered. 17. The method of Claim 4, wherein administration of said agent decreases methacholine responsiveness in said animal. 18. The method of Claim 4, wherein administration of said agent reduces the airway hyperresponsiveness of said animal such that the FEV, value of said animal is improved by at least about 5%. 19. The method of Claim 4, wherein administration of said agent results in an improvement in saidanimal's PC 2 o methacho ι ine FEV 1 value such that the PC 20methachoIine FEV, value obtained before administration of the agent when the animal is provoked with a first concentration of methacholine is the substantially the same as the PC 20methacholine FEV, value obtained after administration of the agent when the animal is provoked with double the amount of the first concentration of methacholine. 20. The method of Claim 19, wherein said first concentration of methacholine is between about 0.01 mg/ml and about 8 mg/ml. 21. The method of Claim 4, wherein said agent is administered in a pharmaceutically acceptable excipient. 22. The method of Claim 1 , wherein said inflammation is associated with chronic obstructive disease of the airways. 23. The method of Claim 1 , wherein said allergic inflammation is associated with a disease selected from the group consisting of asthma, chronic obstructive pulmonary disease, allergic bronchopulmonary aspergillosis, hypersensitivity pneumonia, eosinophilic pneumonia, emphysema, bronchitis, allergic bronchitis bronchiectasis, cystic fibrosis, tuberculosis, hypersensitivity pneumonitis, occupational asthma, sarcoid, reactive airway disease syndrome, interstitial lung disease, hyper-eosinophilic syndrome, rhinitis, sinusitis, exercise-induced asthma, pollution-induced asthma and parasitic lung disease. 24. The method of Claim 1 , wherein said allergic inflammation is associated with a disease selected from the group consisting of asthma, occupational asthma and reactive airway disease syndrome. 25. The method of Claim 1, wherein the method reduces airway hyperresponsiveness in the animal. 26. The method of Claim 1 , wherein the animal has airway hyperresponsiveness. 27. The method of Claim 1 , wherein said animal is a mammal. 28. A method to reduce airway hyperresponsiveness in an animal that has airway hyperresponsiveness associated with inflammation, comprising administering to said animal an agent that inhibits interleukin-10 (EL-10) in said animal; wherein said agent is selected from the group consisting of: an isolated nucleic acid molecule that reduces expression of EL-10 by selectively hybridizing to a nucleic acid molecule encoding EL-10; a ribozyme specific for EL-10 RNA; an EL-10 antagonist; an antibody that selectively binds to EL-10; a soluble EL-10 receptor; an EL-10 receptor antagonist; and an antibody which binds to an EL- 10 receptor and blocks EL- 10 from binding to said receptor; and, wherein said agent is administered in an amount effective to measurably reduce methacholine responsiveness in said animal. 29. A formulation that reduces or prevents airway hyperresponsiveness associated with inflammation, comprising: a. an inhibitor of EL- 10 selected from the group consisting of: an isolated nucleic acid molecule that reduces expression of EL- 10 by selectively hybridizing to a nucleic acid molecule encoding EL- 10; a ribozyme specific for EL- 10 RNA; an EL- 10 antagonist; an antibody that selectively binds to EL-10; a soluble EL-10 receptor; an EL-10 receptor antagonist; and an antibody which binds to an EL-10 receptor and blocks EL-10 from binding to said receptor; and, b. an anti-inflammatory agent suitable for reducing inflammation in an animal that has, or is at risk of developing, airway hyperresponsiveness associated with inflammation. 30. The formulation of Claim 29, wherein said anti-inflammatory agent is selected from the group consisting of corticosteroids, (oral, inhaled and injected), β-agonists (long or short acting), leukotriene modifiers (inhibitors or receptor antagonists), cytokine or cytokine receptor antagonists, anti-IgE, phosphodiesterase inhibitors, sodium cromoglycate, nedocrimal, theophylline, inhibitors of T cell function. 31. A method to identify a compound that reduces or prevents airway hyperresponsiveness associated with inflammation, comprising: a. contacting a putative regulatory compound with a cell that expresses EL-10 wherein in the absence of said putative regulatory compound, said EL-10 can be expressed and is biologically active; b. detecting whether said putative regulatory compound inhibits EL-10 expression or activity in said cell; c. administering said putative regulatory compound to a non-human animal in which airway hyperresponsiveness can be induced, and identifying animals in which airway hyperresponsiveness is reduced or prevented as compared to in the absence of said putative regulatory compound; wherein a putative regulatory compound that inhibits EL- 10 expression or activity and that reduces or prevents airway hyperresponsiveness in said non-human animal is indicated to be a compound for reducing or preventing hyperresponsiveness associated with inflammation. 32. The method of Claim 31 , wherein said step (b) of detecting is selected from the group consisting of measurement of EL-10 transcription, measurement of EL-10 translation, measurement of EL- 10 receptor ligand binding activity, and measurement of EL- 10 biological activity associated with said cell. 33. The method of Claim 31 , wherein said step of contacting comprises contacting said putative regulatory compound with a cell containing transcripts of said EL-10, and wherein said step of detecting comprises detecting translational inhibition of said EL-10 transcript. 34. A method to identify a compound that reduces or prevents airway hyperresponsiveness associated with inflammation, comprising: a. contacting a cell or cell lysate which expresses an interleukin- 10 (EL- 10) receptor with a putative regulatory compound; b . detecting whether said putative regulatory compound inhibits an EL- 10 receptor function selected from the group consisting of EL- 10 receptor expression, EL- 10 receptor ligand binding or EL- 10 receptor biological activity; c. administering said putative regulatory compound to a non-human animal in which airway hyperresponsiveness can be induced, and identifying animals in which airway hyperresponsiveness is reduced or prevented as compared to in the absence of said putative regulatory compound; wherein a putative regulatory compound that inhibits EL-10 receptor expression, ligand binding or biological activity and that reduces or prevents airwayhyperresponsiveness in said non-human animal is indicated to be a compound for reducing or preventing hyperresponsiveness associated with inflammation. 35. The method of Claim 34, wherein said step of contacting comprises contacting said putative regulatory compound with a cell or cell lysate containing a reporter gene operatively associated with a regulatory element of said EL- 10 receptor, and wherein said step of detecting comprises detecting expression of the reporter gene product. 36. The method of Claim 34, wherein said step of contacting comprises contacting said putative regulatory compound with a cell or cell lysate containing transcripts of said EL- 10 receptor, and wherein said step of detecting comprises detecting translational inhibition of said EL-10 receptor transcript.

Inventors: GELFAND ERWIN W, MAEKELA MIKA, GELFAND, ERWIN, W., MAEKELA, MIKA
Applicants: NAT JEWISH MED & RES CENTER, NATIONAL JEWISH MEDICAL AND RESEARCH CENTER
Application year: 2001
Main classification: A61K39
IPC codes: A61K38, C07K14, C12N15