bluuebunny/crossref_metadata_2025 huggingface dataset:
Endogenous Retroviruses: A Potential Problem for Xenotransplantation?a
Authors: STOYE JONATHAN P. , Le TISSIER PAUL , TAKEUCHI YASUHIRO , PATIENCE CLIVE , WEISS ROBIN A.
Published: February 2006

ABSTRACT: To overcome the shortage of suitable human donors for transplantation attention has recently turned to the possibility of using genetically modified pigs as a source of cells and organs. It has been suggested that such procedures might facilitate the introduction of novel retroviruses, normally resident in the pig germ line, into the human population (Stoye and Coffin, Nature Medicine 1: 1100, l995). The consequences of such a transfer remain unclear; however, the demonstration that certain porcine cell lines express infectious retroviruses which can infect human cells (Patience et al., Nature Medicine 3: 282–286, 1997) emphasizes that there are grounds for practical concern. We have now cloned the envelope genes of the expressed viruses and are using these clones in studies of the interaction of the porcine viruses with their cellular receptors. We have also initiated studies of the inheritance and expression of human‐tropic endogenous proviruses present in different pig populations. These studies reveal that at least two classes of human‐tropic endogenous porcine retrovirus are widely distributed in pigs (Le Tissier et al., Nature 389: 681–681, 1997). The implications of our results for assessing the potential risks of retroviral transfer during xenotransplantation are discussed.
Immunosuppression by Retroviruses: Implications for Xenotransplantation
Authors: DENNER JOACHIM
Published: February 2006

ABSTRACT: Retroviruses induce in the infected host an immunosuppression the severity of which depends on the viral load. A pronounced immunosuppression is induced by human and simian immunodeficiency viruses (HIV and SIV) ultimately leading to AIDS. It is very likely that HIV originated by trans‐species transmission from primates. In contrast, SlVs are not pathogenic for their natural hosts probably as the result of virus‐host coevolution We have shown that a retroviral protein, the transmembrane envelope protein, may play an important role in retrovirus‐induced immunosuppression and that all retroviruses share an evolutionarily highly conserved domain in this protein. We demonstrate that synthetic peptides corresponding to this domain of different retroviruses, including HlV, the baboon endogenous virus (BaEV), and different porcine endogenous retroviruses (PERVs), are immunosuppressive. We provide evidence that BaEV and different PERVs, including those able to grow in human cells, are immunosuppressive for lymphocytes of different species including human. This implies that xenotransplantation may result in a trans‐species transmission of endogenous retroviruses derived from the donor animal. In analogy to HIV and SIV high‐titer virus replication may cause an AlDS‐like disease in the immunosuppressed human transplant recipient. Two additional points have to be considered: First, human anti‐complement proteins produced by transgenic animals will also protect the virus and, second, the virus may be transmitted to other humans and thus increase its pathogenic potential.
The Risk of Using Baboons as Transplant Donors: Exogenous and Endogenous Viruses
Authors: ALLAN JONATHAN S.
Published: February 2006

ABSTRACT: African nonhuman primates harbor several exogenous and endogenous retroviruses which deserve further consideration in the transplant setting. In particular, simian foamy viruses (SFV), simian T‐cell lymphotropic virus (STLV), baboon endogenous virus (BaEV), and simian endogenous retrovirus (SERV) are all carried by baboons and may be transmitted to humans by transplantation. We have found baboons to have high seroprevalence rates to both SFV and STLV, and molecular and serologic methods have been developed to detect such agents. In addition, current nonhuman primate breeding programs have thus far not focused on eliminating these viruses. In summary, the close genetic relationship with humans and number of persistent viral infections in baboons translates into a much greater infectious disease risk when compared to that of other domesticated species.
Xenozoonoses and the Xenotransplant Recipient
Authors: Michaels Marian
Published: February 2006

The use of animal cells, tissues, or organs for humans is being investigated as an alternative to allotransplantation and as therapy for a broad range of disease states including diabetes, Parkinson's disease, and neurologic pain control. The risk of transmitting novel infections with these tissues, xenozoonoses, has led to much debate. It is well recognized that infections are a hazard with the use of all biologic agents. In addition, infections from human donors remain a major cause of morbidity and mortality after allotransplantation. Accordingly the potential for animal microbial agents to be pathogenic in the human recipient after xenotransplantation and be transmissible to others must be critically examined. Along with laboratory‐based research, clinical trials must be conducted in a manner to evaluate the transmission of potential animal infections. Pretransplant evaluation should include discussions with the candidate and, if possible, with close contacts. Information must be provided as to the potential risks of infection and transmission to others. Behavioral modifications which can decrease spread of infections should be emphasized. Serial samples should be obtained from the patients at defined intervals and if recipients become ill. In addition, archiving samples for future evaluation is critical. Prospective evaluation will enhance the ability to define and understand the spectrum of xenogeneic infections.
Definition of a Production Specification for Xenotransplantation: A European Perspective
Authors: IVERSON WILLIAM O. , TALBOT TONY
Published: February 2006

ABSTRACT: In the absence of regulatory guidance on animal production for xenotransplantation and the need to conform to European, U.K. and international standards of animal health and welfare, Imutran set up a forum of experts in 1994 to assess the risks associated with the possible transmission of diseases from pig to man after transplantation of porcine tissue. This risk assessment set the specification for Qualified Pathogen‐Free pig production and the animal testing required to demonstrate that the specification has been achieved. The invasive sampling required for detailed health monitoring of individual source animals is in conflict with the aim of producing healthy, normal animals that are not subject to undue stress, and produces predominantly retrospective data on a donor. Imutran has developed a sampling regime that qualifies age‐class cohorts and the whole herd by the routine testing of representative sentinel animals. Imutran set up a pilot production unit in 1995 and this unit has remained populated beyond a 30‐month period and has received in excess of 20 cohorts of animals by hysterectomy re‐derivation. Rigorous testing of sentinels and noninvasive testing of individuals have demonstrated that this pilot unit has achieved the required specification on a routine basis in a system that has been designed to meet European ethical and animal welfare concerns, within the constraints of the strict U.K. animal research laws and an ISO 9001 quality environment.
International Issues in Transplantation: Setting the Scene and Flagging the Most Urgent and Controversial Issues
Authors: MIRANDA B. , MATESANZ R.
Published: February 2006

ABSTRACT:Organ transplantation is the primary technique for treatment of end‐stage organ failure and has benefited more than one million persons world wide. A number of patients have survived for well over 25 years and survival rates at 5 years can be 70% or higher for many organ transplant programs. However, currently more than 40,000 patients are waiting for a kidney, and in western Europe mortality rates for patients waiting for a heart, liver, or lung range from 15 to 30%. The potential need for transplants is even greater and this imbalance between supply and demand creates technical and ethical problems including the risk of organ trafficking. Consequently the number of available organs must be increased. In some cases the organ shortage reflects a true lack of donors, but more often it results from the failure to turn potential into actual donors. The transplant commission of the Council of Europe has just approved a document recommending that member states ensure that all potential donors are identified and as many as possible converted to actual donors. Even with the highest organ donation rate, the indications for organ and tissue transplantation will continue to increase, perpetuating the gap between supply and demand. Organ transplantation, whether living or cadaveric, might be supplemented or replaced by the use of artificial organs, although problems such as power supply, thrombosis, infection, and biocompatibility pose obstacles to long‐term function. The use of animals as an alternative source is considered, but so many problems still remain unresolved that xenotransplantation cannot be put forth as a solution at this time. This paper reviews these issues and, citing the Spanish experience, offers strategies to improve the organ donation rate.
The Research‐Policy Continuum: Comparing Allo‐ and Xenotransplantation
Authors: BATTISTA RENALDO N.
Published: February 2006

ABSTRACT: Where are we on the continuum leading from research to policy decisions in allo‐ and xenotransplantation? In the case of allotransplantation all the activities needed in achieving an effective research policy transfer are ongoing. Research is vibrant and several technology assessment reports have been produced and translated into decisions at the policy, institutional, and practice levels, and quality monitoring activities are an integral part of transplant programs. The field of xenotransplantation is young and so the major emphasis in xenotransplantation will remain knowledge production for the coming years. Exploring the intricacies of the physiology of xenotransplantation, the associated risks of infection, and the complexity of the immunological response will remain research priorities. The social and ethical debate, necessary to the formulation of sound health policy, will intensify and be focused on whether to allow human experimentation and under what conditions.
The Swiss Technology Assessment Project on Xenotransplantation
Authors: BELLUCCI SERGIO , BONDOLFI ALBERTO , HÜSING BÄRBEL , RÜEGSEGGER ADRIAN
Published: February 2006

ABSTRACT: The Swiss Technology Assessment (TA) project on xenotransplantation is intended to study the opportunities and risks of this technique, recognizing the input of those involved in and those affected by it. This also implies taking into account the clinicoscientific, social, ethical, economic, and legal aspects. The situation in Switzerland is analyzed in depth, with reference to the acceptance, ethics, and existing federal legislation pertinent to xenotransplantation. Apart from consultation with experts from various specialized areas, a written questionnaire was sent to more than 100 organizations, institutions, companies, and individuals. The resulting assessments range from clear approval to complete rejection of the notion of xenotransplantation. Even acceptance was granted only on condition that criteria such as security (minimum risk of infection) and respect for human dignity and animal protection issues are respected. Such criteria are generally accepted, but if concrete conclusions must be drawn, we must recognize that opinions vary in today's discussions on ethics in Switzerland. It is commonly agreed that animals are not objects, but their precise status is not clear. Moreover, there are no patented ethical “recipes” for handling risks.
Xenotransplantation: Perspectives from the Netherlands
Authors: VAN RONGEN ERIC
Published: February 2006

ABSTRACT: Recently, the Health Council of the Netherlands published a report on xenotransplantation. The technique is considered ethically acceptable, both from a human and from an animal point of view. Clinical application should not yet be permitted, however, because of continuing rejection problems and growing concerns on safety aspects associated with possible transfer of pathogens from the xenotransplant to the host. More research is necessary. Mainly because of the risk for infection, non‐human primates are not considered acceptable as source animals; the genetically engineered pig is at present the source animal of choice. Legally, import in the Netherlands of (organs from) source animals from within Europe is difficult to prevent. Therefore experiments with such material are not subjected to licensing by the government, which is the case for experiments involving genetic engineering with animals in the Netherlands, but only by local review boards. This situation is considered unwanted and adjustment of the pertinent law is suggested. Also, both genetically engineered animals and patients carrying organs from such animals fall under the European Genetically Modified Organisms regulations. These regulations are not designed for this case and conflicts may arise. Agreements on how to handle this situation have to be made at the European level. It is proposed to draft a national law on “biologicals,” medical products consisting at least partly of living materials. Pending such regulations, it is suggested, also on a European level, that xenotransplants be considered as medicines, which would allow adequate control of safety aspects.
Experience of Gene Therapy in the United Kingdom
Authors: NEVIN NORMAN C.
Published: February 2006

ABSTRACT: The UK Committee on the Ethics of Gene Therapy recommended the establishment of a supervisory body with collective expertise, experience, and authority to regulate gene therapy. In November 1993, the supervisory body, known as the Gene Therapy Advisory Committee (GTAC), was established. It interacts with other bodies, including the Medicines Control Agency, local research ethics committees, the Health and Safety Executive, and the Hospital Trust. When proposals for gene therapy are reviewed, there is careful assessment of the scientific merits, the competence of those undertaking the research, and the risks involved. Each proposal is assessed by several independent expert advisors, in specific aspects of the research. The researchers are apprised of the issues raised by the assessors and given the opportunity to modify their proposals. The research team is then given the opportunity to make a brief presentation to the GTAC. The proposals may be approved subject to conditions, deferred until further issues are resolved, or rejected on the basis that the proposal is unethical or the science unsound. Researchers are expected to provide the committee with regular progress reports. This paper discusses the experience of gene regulation in the United Kingdom.
Development of Databases and Registries: International Issues
Authors: WHITEHEAD JAMES M. , PATTERSON AMY P. , MOULTON AUSTINE
Published: February 2006

ABSTRACT: This paper describes the U.S. Public Health Service (PHS) efforts to develop a National Xenotransplantation Registry (NXR). The function of the registry is discussed, paying particular attention to data collection and harmonization issues. The need for standardization and coordination on an international scale is presented and the benefits of such efforts are discussed. Finally, a recommendation for an international effort aimed at harmonization is made.
Analysis of Factors for the Prediction of the Response to Xenotransplantation
Authors: DAAR A. S.
Published: February 2006

ABSTRACT: Predicting the response to xenotransplantation is difficult, but can be based upon (i) past clinical experience, (ii) opinion surveys and focus groups, (iii) predictable variables, and (iv) the allotransplant experience. Baby Fae, the Pittsburgh baboon liver transplant, and the Jeff Getty baboon marrow transplant have taught us (a) not to underestimate hurdles, (b) to communicate professionally, (c) not to promise too much, (d) that lobbying can be effective, (e) that “being the first” is important, and (f) that the media can be fickle. The Swedish isle cell and the U.S. neural tissue transplant suggest that patients without immediately life‐threatening illnesses will accept xenogeneic tissue and that the public/media will not respond negatively when there is little fanfare. Limited opinion surveys/focus groups suggest a degree of reluctance/revulsion that is more common is women, minorities, and the less‐educated, and when the likely donor is a subhuman primate. Predictable positive public‐response variables include perceptions of (a) adequacy of the scientific base, (b) adherence to globally agreed upon guileines, (c) legitimacy/competence of regulatory bodies, and (b) adequate infectious risk assessment and management. A likely negative predictor is the role of animal rights activists (more in Europe, less in the U.S. and the developing world). Less predictable is the response of the media and what other societal concerns dominate the news at the time. Cultural concerns will need careful study. Allotransplant experience suggests that informed religious opinion can be accommodating to new technology. Psychological factors will be important and will need professional management.
Introduction: Overview of the Conference and the Field
Authors: STERNBERG ESTHER M.
Published: February 2006

Abstract: The field of neuroimmune interactions is a prime example of interdisciplinary research spanning immunology, neurobiology, neuroen‐docrinology, and behavioral sciences. It also exemplifies research from the molecular to the clinical domain. The greatest challenge of the field, which this conference seeks to stimulate, is research that is at the same time precise, focused, and integrative. Several levels of interdisciplinary overlap will be highlighted. At the molecular level, neuro‐ and immune mediator molecules or their receptors may be members of the same superfamily or may regulate each other's expression or function. Most extensively studied are cytokine‐neuropeptide/neurotransmitter interactions, including expression of cytokines within the central nervous system and production of neuropeptides by immune cells or at inflammatory sites. Advances relating cytokine‐neurohormone interactions to mechanisms of apoptosis will ultimately shed light on the role of neuroimmune interactions in neuronal cell death and survival and immune cell selection, processes important in neuronal plasticity and immune specificity. At a systems level, advances have been made in cross‐disciplinary application of modes of thinking. Incorporation of neurobiology's appreciation of anatomical organization, endocrinology's temporal dimension of neurohormonal secretion, and immunology's understanding of stimulus specificity all contribute to a more precise definition of how these complex systems interact at multiple levels. More precise understanding of effects of disruptions of these communications on disease susceptibility and expression will clarify how perturbations of one system, such as stimulation of the neuroendocrine stress response, might affect expression of disease in the other, such as autoimmune/inflammatory or infectious diseases.
Opiate Inhibition of Chemokine‐Induced Chemotaxis
Authors: GRIMM M. C. , BEN‐BARUCH A. , TAUB D. D. , HOWARD O. M. Z. , WANG J. M. , OPPENHEIM J. J.
Published: February 2006

Abstract: Chemokines consist of a family of 8‐16‐kDa cytokines that are generated very early in a wide variety of inflammatory responses and attract leukocytes to local sites. At nanomolar concentrations chemokines initiate signal transduction and activate leukocytes through seven transmembrane receptors (STM), but higher micromolar doses result in homologous desensitizing effects. On the basis of reports that opiates have anti‐inflammatory effects and also use STM, we have investigated the possibility that they may cross‐desensitize the response of leukocytes to chemokines. We have confirmed previous observations that met‐enkephalin (MET) is chemotactic for human peripheral blood mono‐cytes. Furthermore, we observed that preincubation of monocytes or neutrophils with MET or morphine prevented their subsequent chemotaxis in response to chemokines (MIP1α or IL‐8). However, MET did not inhibit the chemotactic response of PMN to NAP‐2, a homologous chemokine that is less potent than IL‐8 but cannot be desensitized. The inhibitory effect of opiates on chemokine‐induced chemotaxis was antagonized by naloxone. Since MIP‐1α and IL‐8, unlike NAP‐2, have the capacity to desensitize leukocytes, it is possible that opiates, by desensitizing some chemokine responses, can suppress inflammatory reactions.
Corticotropin‐Releasing Hormone and Inflammation
Authors: WEBSTER ELIZABETH L. , TORPY DAVID J. , ELENKOV ILIA J. , CHROUSOS GEORGE P.
Published: February 2006

Abstract: Cortic otropin‐releasing hormone (CRH) is a major regulator of the hypothalamic‐pituitary‐adrenal axis (HPA) and principal coordinator of the stress response. As in stress, intracerebroventricular administration of CRH suppresses the immune system indirectly, via glucocorticoid and/or sympathetic system‐mediated mechanisms. Also, during inflammatory stress, the cytokines TNFα, IL‐1, and IL‐6 stimulate hypothalamic CRH and/or vasopressin secretion as a way of preventing the inflammatory reaction from overreacting. Recently, CRH receptors were described in peripheral sites of the immune system, and CRH was found to promote several immune functions in vitro. We demonstrated a direct role of CRH in the inflammatory immune process in vivo, by first studying the effect of systemic CRH immunoneutralization in an experimental model of carrageenin‐induced aseptic inflammation in Spague‐Dawley rats. We extended these observations to other forms of experimental inflammation, including streptococcal cell wall polysaccharide‐ and adjuvant‐induced arthritides and peptide R16 (epitope of the interphotoreceptor retinoid‐binding protein)‐induced uveitis in Lewis rats. We also studied human disease states, including rheumatoid arthritis, Hashimoto thyroiditis, and ulcerative colitis. Inflamed tissues contained large amounts of IR CRH, reaching levels similar to those observed in the hypophyseal portal system. We also demonstrated the presence of CRH mRNA and CRH receptors in inflammatory cells and identified the mast cells as a major immune target for CRH. In addition to production by immune cells, the peripheral nervous system, including the postganglionic sympathetic neurons and the sensory fibers type C, appears to contribute to IR CRH production in inflammatory sites. The production of CRH from the post‐ganglionic sympathetic neurons may be responsible for the stress‐induced activation of allergic/autoimmune phenomena, such as asthma and eczema, via mast cell degranulation. Antalarmin, a novel nonpeptide CRH receptor antagonist, displaced 125I‐labeled ovine CRH binding in rat pituitary, frontal cortex, and cerebellum, but not heart, consistent with antagonism at the CRHR1 receptor. In vivo antalarmin significantly inhibited CRH‐stimulated ACTH release and carrageenin‐induced subcutaneous inflammation in rats. Thus, antalarmin and other related compounds that antagonize CRH at the level of its own receptor have therapeutic potential in some forms of inflammation directly mediated by type 1 CRH receptors and promise to enhance our understanding of the many roles of CRH in immune/inflammatory reactions.
Neuroimmunomodulation by Macrophage Migration Inhibitory Factor (MIF)
Authors: BUCALA RICHARD
Published: February 2006

Abstract: Recent studies have led to the discovery of a mediator that appears to act as an endogenous hormone to counterregulate glucocorticoid action within the immune system. Isolated as a product of anterior pituitary cells, the structure of this protein was found to be that of macrophage migration inhibitory factor (MIF)‐one of the first cytokines to be identified and described originally as a T lymphocyte factor that inhibited the random migration of macrophages. Macrophages and T cells release MIF in response to glucocorticoids, as well as upon activation by various proinflammatory stimuli. Once secreted MIF “overrides” the immunosuppressive effects of steroids on macrophage and T‐cell cytokine production. MIF appears to fill an important gap in our understanding of how the host initiates and controls the immune response. Because glucocorticoids are an integral part of the host's metabolic “stress” response to infection or tissue invasion, the role of MIF is to act at an inflammatory site or lymph node to counterbalance the inhibitory effects of steroids on the immune response. Anti‐MIF therapeutic strategies are under development and may prove to be a means to increase the immunosuppressive and anti‐inflammatory properties of endogenously released glucocorticoids, thereby reducing the requirement for steroid therapy in a variety of autoimmune and inflammatory conditions.
Structural and Functional Impact of the Transgenic Expression of Cytokines in the CNSa
Authors: CAMPBELL I. L.
Published: February 2006

Abstract: Cytokines are powerfu1 mediators of biologic responses in the CNS and may contribute to cellular injury in pathophysiologic states. In order to better understand the actions of cytokines in the intact mammalian CNS, a transgenic approach was employed that targeted the expression of different cytokines to astrocytes in mice. Fusion gene constructs consisting of a GFAP expression vector into which was inserted the DNA encoding the cytokines interleukin‐6 (IL‐6), IL‐3, or TNF‐α were used to generate transgenic mice. Expression of the transgene‐encoded cytokines in astrocytes was confirmed at both the RNA and protein levels. Transgenic mice were subject to multilevel analysis to determine the extent of structural and functional CNS alterations. Transgenic mice exhibited distinct adult‐onset, chronic‐progressive neurological disorders that correlated with the level and anatomic distribution of transgene‐encoded cytokine expression. The principal findings were neurodegeneration and cognitive decline due to IL‐6 expression, macrophage/microglial‐mediated primary demyelination with motor disease resulting from IL‐3 expression, and lymphocytic meningoencephalomyelitis with paralysis induced by TNF‐α expression. These transgenic models (1) indicate that expression of cytokines per se in the intact CNS is pathogenic, with cytokine‐specific neural cell injury leading to unique functional deficits; (2) recapitulate many of the structural and functional changes seen in human inflammatory neurological disorders; (3) provide a valuable tool for advancing our understanding of the CNS pathobiology of cytokines; and (4) offer a unique resource for the development and testing of therapies aimed at abrogating the harmful actions of these important mediators.
The Neurotrophins and Neuropoietic Cytokines: Two Families of Growth Factors Acting on Neural and Hematopoietic Cells
Authors: IP NANCY Y.
Published: February 2006

Abstract: Recent progress has revealed similarities between the receptors and signaling systems used by neurotrophic factors as compared to other growth factors and cytokines. The neurotrophins use a family of receptor tyrosine kinases known as the Trk receptors, whereas ciliary neurotrophic factor (CNTF) uses a “cytokine receptor” system that shares receptor components with a number of distantly related cytokines. We have used a human embryonal carcinoma cell line and human leukemia cell lines to examine the actions of the neurotrophins and CNTF on cellular differentiation. Our findings demonstrate that specific combinations of neurotrophic factors are required to influence the neuronal progenitor cells to become postmitotic mature CNS neurons. Such synergistic interactions may play an important role in modulating the differentiation of a wide assortment of neuronal precursors in the developing nervous system. Furthermore, our studies with leukemia cells suggest that neurotrophic factors may play a similar role in hematopoietic differentiation and that these factors may have therapeutic application in leukemia differentiation.
Interleukin‐3 and Interleukin‐3 Receptors in the Braina
Authors: TABIRA TAKESHI , CHUI DE‐HUA , FAN JI‐PING , SHIRABE TERUO , KONISHI YOSHIHIRO
Published: February 2006

We have previously demonstrated that interleukin 3 (IL‐3) has a neurotrophic effect on central cholinergic neurons and have demonstrated the presence of IL‐3 receptor (IL‐3R)β subunits in septal cholinergic neurons by reverse‐transcribed polymerase chain reaction (RT‐PCR) and immunohistochemistry. In order to confirm that the expressed IL‐3R is functional, we conducted experiments to show an a subunit of IL‐3R. The α subunit was clearly demonstrated by RT‐PCR in the central cholinergic neuronal hybrid cell line SN6, but not in its mother cell line N18TG2, and the expression was slightly upregulated after IL‐3 treatment. Choline acetyltransferase and vesicular acetylcholine transporter mRNAs were significantly increased in SN6 after treatment with IL‐3. Immunohistochemically, IL‐3Rα‐positive cells were mainly present in the medial septal and basal forebrain region, and the stained cells were similar to choline acetyltransferase‐positive cells in shape and distribution. The IL‐3Rα‐positive cells slightly increased two days after fimbria‐fornix transection and decreased seven days after. These findings suggest that functional IL‐3 receptors are expressed in the central cholinergic neurons and contribute to some physiological roles such as the differentiation and maintenance of these neurons.
Interleukin‐1, but Not Stress, Stimulates Glucocorticoid Output during Early Postnatal Life in Micea
Authors: FURUKAWA HIROMU , DEL REY ADRIANA , MONGE‐ARDITI GABRIELA , BESEDOVSKY HUGO O.
Published: February 2006

Abstract: The development of neuroendocrine functions depends not only on genetically determined mechanisms but also on phenotypic signals. Some of these signals may derive from the immune system. For example, interleukin‐1β (IL‐1β) stimulates glucocorticoid output during the early postnatal period, and administration of this cytokine at birth induces permanent alterations in the HPA axis in adulthood. We have extended these studies and found that the glucocorticoid response elicited in 5‐day‐old mice by a low dose of IL‐1β is not desensitized by previous exposure to the cytokine. We have also compared the magnitude of the increase in corticosterone levels induced by IL‐1 in 3‐day‐old and adult mice to that caused by acute stress. IL‐1β and acute stress caused a comparable increase in corticosterone levels in adult mice. In newborn mice, however, IL‐1β, but not restraint or cold stress, stimulated corticosterone output. Thus, IL‐1β can elicit a corticosterone response during the postnatal stress‐hyporesponsive period. Furthermore, when the corticosterone levels attained following IL‐1β administration were compared to the basal levels of the hormone at a given age, the increase in plamsa corticosterone levels was several fold higher in newborn than in adult animals. These data, together with the long‐lasting endocrine effects of cytokine exposure at birth, suggest an important role of immune cytokines in the programming of neuroendocrine functions during ontogeny.
Administration of Interleukin‐1 at Birth Affects Dopaminergic Neurons in Adult Micea
Authors: KABIERSCH ALEXA , FURUKAWA HIROMU , DEL REY ADRIANA , BESEDOVSKY H. O.
Published: February 2006

Abstract: Interleukin‐1β (IL‐1β), a cytokine that plays a relevant role during inflammatory and immune processes, can also affect brain neurotransmitters and the activity of peripheral sympathetic nerves. Because both brain and peripheral catecholaminergic systems in mice are not fully developed at birth, we speculated that the development of these systems may be susceptible to modifications when mice are exposed to IL‐1β early in life. Here we report that the administration to mice of a low dose of IL‐1β during the first days of life results in a decreased dopamine content in the hypothalamus in adulthood. We also show that the dopamine content of the superior cervical sympathetic ganglia was reduced in adult mice that were treated with IL‐1β at birth. No changes in noradrenaline content nor in its metabolite MHPG were detected in the brain and peripheral sympathetic ganglia of these animals. This indicates that central and probably also peripheral dopaminergic neurons are preferentially affected by IL‐1β treatment at birth. Collectively, these results indicate that an increased production of IL‐1β during infectious or inflammatory processes in the perinatal period may induce long‐lasting, probably permanent, alterations in central and peripheral neurotransmitter systems.
Effects of Peripheral Administration of LPS on the Expression of Immunoreactive Interleukin‐1α, β, and Receptor Antagonist in Rat Brain
Authors: VAN DAM ANNE‐MARIE , POOLE STEPHEN , SCHULTZBERG MARIANNE , ZAVALA FLORA , TILDERS FRED J. H.
Published: February 2006

Abstract: The cytokine interleukin‐1 (IL‐1) appears to play a pivotal role in the orchestration of brain‐mediated, nonspecific illness symptoms during an infection. In the present study, we examine the possibility that IL‐1 is produced in the central nervous system itself, which may be responsible for the induction of brain‐mediated responses. Using immunocytochemical techniques, we demonstrated that peripheral administration of bacterial endotoxin to rats caused a time‐ (1.5‐24 hr) and dose‐dependent (4μg/kg‐2.5 mg/kg) induction of IL 1β immunoreactivity in cells identified as macrophages in meninges and choroid plexus and microglial cells in various brain regions. At 8 hr after endotoxin (2.5 mg/kg), immunoreactive IL‐1α was observed in the same areas and cell types as IL‐1β. Although no quantitative measurements have been performed, it appears that fewer cells express immunoreactive IL‐1α than IL‐1β. Furthermore, IL‐1ra was found to be constitutively expressed in neurons in the paraventricular nucleus and supraoptic nucleus, which is in accordance with mRNA data. After administration of endotoxin, we observed no additional cells that expressed immunoreactive IL‐1ra. We conclude that IL‐lα and IL‐1β production in the brain is induced in the same cell types, whereas IL‐lra is expressed consititutively by a different cell type‐probably neurons.
Brain Neurotransmission during Peripheral Inflammationa
Authors: LINTHORST ASTRID C. E. , REUL JOHANNES M. H. M.
Published: February 2006

Abstract: It is now well established that an inflammatory challenge as evoked by bacterial endotoxin (LPS) induces autonomic, endocrine, and behavioral responses that are controlled by the brain. However, detailed information on the neuronal pathways and neurotransmitters involved is scarce. We used in vivo microdialysis and biotelemetry in rats to monitor hippocampal and preoptic serotonergic and noradrenergic neurotransmission, body temperature, and heart rate after an i.p. LPS injection. Moreover, free corticosterone levels were measured in the dialysates, and behavioral activity was scored by visual observation. Apart from a biphasic fever response, tachycardia, elevated free corticosterone levels, and sickness behavior, peripheral injection of LPS caused a dramatic increase in preoptic extracellular concentrations of noradrenaline, but no effect on serotonin in this structure. The increase in preoptic noradrenaline levels appears to underlie the first fever phase and may participate in hypothalamic‐pituitary‐drenocorticul axis activation. In contrast, whereas LPS had only a moderate effect on hippocampal noradrenaline, a marked increase in hippocampal extracellular serotonin levels was found. Use of the interleukin (IL)‐1 receptor antagonist and the cyclooxygenase inhibitor indomethacine learned that IL‐1 and prostaglandins are mediators in this response. Our data show that an endotoxin challenge results in highly differentiated changes in brain neurotransmission, probably subserving the coordinate processing of immune information in circuits involved in autonomic, neuroendocrine, and behavioral regulation.
Central and Peripheral Mechanisms Contribute to the Hypoglycemia Induced by Interleukin‐1a
Authors: DEL REY ADRIANA , MONGE‐ARDITI GABRIELA , BESEDOVSKY HUGO O.
Published: February 2006

Abstract: The impact that neuroendocrine effects of cytokines have on general host homeostasis is reflected by the profound metabolic changes observed in parallel. The effect of interleukin‐1β (IL‐1β) on glucose blood levels serves as an example. Although IL‐1β stimulates glucocorticoid output and decreases hepatic glycogen content, hypoglycemia is concomitantly detected in adult and newborn mice. This effect is observed even during fasting and is probably due to increased glucose transport into tissues. Even after a glucose load, IL‐1‐treated animals remain hypoglycemic, suggesting that central mechanisms that control the set point of glucose homeostasis are affected. Low doses of IL‐1β injected i.c.v. can also induce hypoglycemia. Furthermore, central blockade of IL‐1 receptors partially inhibits the hypoglycemia induced by peripheral administration of IL‐1β. On the other hand, central depletion of catecholamines exacerbates IL‐1‐induced hypoglycemia. IL‐1‐mediated effects on glucose levels might be directed at providing more energy supply to tissues during processes with high metabolic demands.
Role of Nitric Oxide in the Neuroendocrine Responses to Cytokinesa
Authors: McCANN S. M. , KIMURA M. , KARANTH S. , YU W. H. , RETTORI V.
Published: February 2006

Abstract: During infection, bacterial and viral products, such as bacterial lipopolysaccharide (LPS), cause the release of cytokines from immune cells. These cytokines can reach the brain by several routes. Furthermore, cytokines, such as interleukin‐1 (IL‐1), are induced in neurons within the brain by systemic injection of LPS. These cytokines determine the pattern of hypothalamic‐pituitary secretion which characterizes infection. IL‐2, by stimulation of cholinergic neurons, activates neural nitric oxide synthase (nNOS). The nitric oxide (NO) released diffuses into corticotropin‐releasing hormone (CRH)‐secreting neurons and releases CRH. IL‐2 also acts in the pituitary to stimulate adrenocorticotropic hormone (ACTH) secretion. On the other hand, IL‐1α blocks the NO‐induced release of luteinizing hormone‐releasing hormone (LHRH) from LHRH neurons, thereby blocking pulsatile LH but not follicle‐stimulating hormone (FSH) release and also inhibiting sex behavior that is induced by LHRH. IL‐1α and granulocyte macrophage colony‐stimulating factor (GMCSF) block the response of the LHRH terminals to NO. The mechanism of action of GMCSF to inhibit LHRH release is as follows. It acts on its receptors on gamma‐aminobutyric acid (GABA)ergic neurons to stimulate GABA release. GABA acts on GABAa receptors on the LHRH neuronal terminal to block NOergic stimulation of LHRH release. This concept is supported by blockade of GMCSF‐induced suppression of LHRH release from medial basal hypothalamic explants by the GABAa receptor blocker, bicuculline. IL‐1α inhibits growth hormone (GH) release by inhibiting GH‐releasing hormone (GHRH) release, which is mediated by NO, and stimulating somatostatin release, also mediated by NO. IL‐1α‐induced stimulation of prolactin release is also mediated by intrahypothalamic action of NO, which inhibits release of the prolactin‐inhibiting hormone dopamine. The actions of NO are brought about by its combined activation of guanylate cyclase‐liberating cyclic guanosine monophosphate (cGMP) and activation of cyclooxygenase and lipoxygenase with liberation of prostaglandin E2 and leukotrienes, respectively. Thus, NO plays a key role in inducing the changes in release of hypothalamic peptides induced in infection by cytokines. Cytokines, such as IL‐1β, also act in the anterior pituitary gland, at least in part via induction of inducible NOS. The NO produced inhibits release of anterior pituitary hormones.
Acute and Subacute Effects of Endotoxin on Hypothalamic Gaseous Neuromodulators
Authors: KOSTOGLOU‐ATHANASSIOU I. , JACOBS R. A. , SATTA M. A. , DAHIA P. L. M. , COSTA A. , NAVARRA P. , CHEW S. L. , FORSLING M. L. , GROSSMAN A. B.
Published: February 2006

Abstract: Although two‐way communication between the hypothalamus and the immune system is now well established, particularly for the hypothalamo‐pituitary‐adrenal axis, the role of the gaseous neurotransmitters nitric oxide (NO) and carbon monoxide (CO) is much less well understood in terms of hypothalamic function. These agents are an important part of the peripheral inflammatory response; and their synthetic enzymes, NO synthase (NOS) and heme oxygenase (HO), respectively, have been localized to the hypothalamic PVN and SON. The induced generation of both NO and CO leads to the suppression of CRH and vasopressin, the major stimulators of the HPA. Thus, the addition of hemin to hypothalamic explants is maximally active at 1 μM in attenuating the release of CRH and vasopressin, and this dose is also most effective in generating biliverdin and associated CO. CO generation is also able to stimulate cyclooxygenase to produce prostaglandin E2, an established intermediary in the cytokine‐stimulated activation of the HPA. Finally, inducible NOS mRNA is specifically induced in the hypothalalmus in response to endotoxin, in parallel to interleukin‐1. These data provide increasing evidence in favor of NO and CO as counterregulatory agents in the HPA response to immune activation.
Pain Modulatory Actions of Cytokines and Prostaglandin E2 in the Brain
Authors: HORI T. , OKA T. , HOSOI M. , AOU S.
Published: February 2006

Abstract: Proinflammatory cytokines such as IL‐1, IL‐6, and TNFα are known to enhance nociception at peripheral inflammatory tissues. These cytokines are also produced in the brain. We found that an intracerebroventricular injection of IL‐1β only at nonpyrogenic doses in rats reduced the paw‐withdrawal latency on a hot plate and enhanced the responses of the wide dynamic range neurons in the trigeminal nucleus caudalis to noxious stimuli. This hyperalgesia, as assessed by behavioral and neuronal responses, was blocked by pretreatment with IL‐1 receptor antagonist (IL‐lRa), Na salicylate, or α melanocyte‐stimulating hormone, indicating the involvement of IL‐1 receptors and the synthesis of prostanoids. IL‐6 and TNFα at nonpyrogenic doses also induced hyperalgesia in a prostanoid‐dependent way. Furthermore, the preoptic area (POA) was most sensitive to IL‐1β (5‐50 pg/kg) in the induction of behavioral hyperalgesia. The maximal response was obtained 30 min after injection of IL‐1β at 20 pg/kg. On the other hand, an injection of IL‐1β (20‐50 pg/kg) into the ventromedial hypothalamus (VMH) prolonged the paw‐withdrawal latency maximally 10 min after injection. This analgesia, as well as the intraPOA IL‐1β‐induced hyperalgesia, was completely blocked by IL‐1Ra or Na salicylate. Our previous study has revealed that i.c.v. injection of PGE2 induces hyperalgesia through EP3 receptors and analgesia through EP1 receptors by its central action. The results, taken together, suggest (1) that IL‐1β at lower doses in the brain induces hyperalgesia through EP3 receptors in the POA and (2) that the higher doses of brain IL‐1β produces analgesia through EP1 receptors, probably, in the VMH.
Endocrine and Vagal Controls of Sympathetically Dependent Neurogenic Inflammationa
Authors: GREEN PAUL G. , MIAO FREDERICK JIA‐PEI , STRAUSBAUGH HOLLY , HELLER PHILIP , JANIG WILFRID , LEVINE JON D.
Published: February 2006

Abstract: Recently the very significant role of the postganglionic sympathetic neuron (PGSN) terminal in the production of neurogenic inflammation has been appreciated. An important model of this sympathetically dependent inflammation is venular plasma extravasation (PE) and neutrophil attraction produced by local intra‐articular injection of the potent inflammatory mediator bradykinin (BK). Sympathetic‐dependent PE in the synovium has been proposed as a protective mechanism in arthritis. In a recent series of studies, a novel mechanism has been discovered by which activation of primary afferent nociceptors exerts a potent feedback inhibition of PGSN‐dependent PE. Activation of nociceptive afferents was shown to be involved in this feedback system. Such a negative feedback control of the acute inflammatory response would have survival value; the inflammatory response, as initiated by a high degree of positive feedback, and the inflammatory process itself when persisting can result in significant tissue injury. If indeed HPA axis activity plays a significant physiological role in the modulation of neurogenic inflammation, then physiological processes that modulate the HPA axis would be expected to influence neurogenic inflammation. A dramatic effect of this kind has been demonstrated, in the rat, for vagal afferent activity. In the presence of subdiaphragmatic (or celiac branch) vagotomy, the potency of nociceptive afferent activity to inhibit sympathetically dependent, BK‐induced PE was increased by four orders of magnitude compared to vagus‐intact animal. Hypoactivity or hyperactivity of these vagally mediated mechanisms could contribute to diseases characterized by either an inadequate or an exaggerated inflammatory response.
Cutaneous Immunomodulation and Coordination of Skin Stress Responses by α‐Melanocyte‐Stimulating Hormonea
Authors: LUGER THOMAS A. , SCHOLZEN THOMAS , BRZOSKA THOMAS , BECHER EVA , SLOMINSKI ANDRZEJ , PAUS RALF
Published: February 2006

Abstract: The capacity of the skin immune system to mount various types of immune responses is largely dependent on their ability to release and respond to different signals provided by immunoregulatory mediators such as cytokines. There is recent evidence that neuropeptides such as α‐melanocyte‐stimulating hormone (αMSH), upon stimulation, are released by epidermal cells including keratinocytes, Langerhans cells, and melanocytes as well as immunocompetent cells. Moreover, αMSH recently has been recognized as a potent immunomodulating agent, which inhibits the production and activity of immunoregulatory and proinflammatory cytokines such as IL‐1, IL‐2, interferon‐γ, downregulates the expression of costimulatory molecules (B7) on antigen‐presenting cells; and recently turned out to be a potent inducer of inhibitory mediators such as cytokine synthesis inhibitory factor interleukin‐10. Recently, it also was discovered that monocytes among the five known melanocortin (MC) receptors only express MC‐1, which is specific for αMSH. The expression of MC‐1 on monocytes is upregulated by mitogens, endotoxins, and proinflammatory cytokines. There is also recent evidence for the in vivo relevance of the immunosuppressing capacity of αMSH. Accordingly, in animals αMSH has been shown to inhibit the induction of contact hypersensitivity reactions and to induce hapten‐specific tolerance. These findings indicate that, in addition to the cytokine network, neurohormones within the cutaneous microenvironment are a crucial element for the induction, elicitation, and regulation of cutaneous immune and inflammatory responses.