NOVEL IMMUNOTHERAPEUTIC APPROACHES FOR THE TREATMENT OF ALLERGIC DISEASES

Advances in the knowledge of the cellular and molecular basis of immunity have led to an enhanced thorough understanding of the immunologic features that characterize an allergic response. A hallmark of an allergic response is a persistently elevated level of specific IgE antibodies to a variety of antigens, also referred to as allergens, to which the affected individual is regularly exposed by inhalation, ingestion, or contact with the skin. 48 Allergic sensitization involves processing of the antigen by an antigen-presenting cell (APC) and presentation, in association with a class II major histocompatibility complex (MHC) protein, to a T-cell receptor. Whereas dendritic cells (and macrophages) predominantly act as APCs in primary immunization, B cells may also participate in secondary immune responses to allergens. Activation of T cells requires the first signal from this trimolecular interaction and an additional costimulatory signal involving the ligation of B-7 on an APC (CD80/86) with CD28 or CTLA4 on a T cell. 27 When stimulated by antigens, helper T cells produce an array of specific cytokines, all of which have been designated as either T H 1 cytokines (interleukin [IL]-2, interferon [IFN]-γ, and tumor necrosis factor [TNF]-β) or T H 2 cytokines (IL-4, IL-5, IL-9, IL-10, and IL-13). The state of T-cell activation depends on several factors. 27,85 The first of these factors is the affinity of the interaction between the antigen and the T cell. The site of the antigen recognized by the T cell is termed the epitope. The affinity of epitope–T cell interaction is affected by the concentration of the antigen and the type of APC. 80 It also depends on the cytokine milieu of the T cell during antigen interaction. Thus, IFN-γ and IL-12 promote a T H 1-like response, whereas IL-4 promotes a T H 2-like response. 12 Additionally, host immune response genes may bias the overall immune responsiveness of an individual to favor a T H 1- or T H 2-like response. A T H 2-like cytokine profile is associated with the induction of IgE antibody (Ab) production in vitro and in vivo. 73 Specifically, IL-4 favors the development of T H 2-like cells from uncommitted T cells, and both IL-4 and IL-13 play a role in IgE antibody production. Manifestation of an allergic reaction depends on the specific IgE levels and the amount of exposure at the time of the reaction. Although an allergic condition is a risk factor for asthma, about 20% to 30% of asthmatics do not show positive skin tests to allergens. In general terms, asthma is defined as an inflammatory disease where not only lymphocytes, but also other cells, such as mast cells, basophils, eosinophils, and epithelial cells, play a role. Studies to date suggest that T H 2-like cytokines, such as IL-4 and IL-5, also play an important role in nonatopic asthma. 3,85 Developing immunotherapeutic approaches against allergic diseases, including asthma, may be pragmatically divided into two categories based on how soon they may make an inroad to the clinic, as shown in Figure 1. The first category includes therapies that are already in phase II/phase III clinical trials and are expected to be available in clinics within the next 1 to 3 years; such therapies include antihuman IgE antibodies and the soluble IL-4 receptor. The second category includes experimental approaches that are mainly at the stage of preclinical research in model systems and may proceed to clinical trials and the clinic within the next 5 to 10 years; these therapies include various allergen-specific and allergen-nonspecific approaches.