Immune and inflammatory reactions in human allergic asthma has become a focus of intense interest over the past few years. The interaction of allergen with immune cells, in particular thymus derived lymphocytes (T cells) and antigen-presenting cells (APC) is critical to the development of allergy in humans. The development of this allergic inflammation is associated with the late phase of asthmatic responses, seen in human allergic asthma. The goals of the specific aims outlined in this proposal involve an in-depth examination of the specificity of the interaction between antigenic epitopes of allergens derived from rodent tissues, APC and specific immune T cells from individuals allergic to rodents. In the first specific aim we will examine the potential function of airway alveolar macrophages as APCs for allergen induced T cell activation in an Fc receptor dependent manner. We will assess the capacity of AM to function as APCs by a number of criteria. We will directly explore the capacity of Fc receptor bearing AM to support IL-1 production and augment APC dependent allergen presentation as evaluated by T cell proliferation and activation. The second specific aim involves the examination of the nature of recognition of allergenic epitopes by airway T cells in asthma. These experiments will examine in detail the nature and regulation of T cell recognition in the airways of asthmatics and normals. Whole population T cells, T cell lines and T cell clones from challenged airways will be evaluated for a) epitope specificity in terms of the nature of the antigenic determinant recognized by allergic and asthmatic T cells. We have previously identified a short 29 amino acid stretch of the overall 162 amino acid rodent allergen rat alpha 2 u globulin (RA2UG) that seems to be the target for most T cell reactivity. b) An evaluation of the V region gene usage for T cell receptors in whole population T cells, T cell lines, and T cell clones derived from challenged airways revealed by bronchoalveolar lavage. c) T cells will also be analyzed for cytokine expression after stimulation. In the final specific aim, the effect of in vivo immunotherapy with a fragment of the overall rodent allergen, peptide RA2UG 80-108 as well as whole allergen, Mus m 1, will be evaluated in an attempt to identify any potential benefit accrued to a course of immunotherapy with an epitope that seems to preferentially interact with the T cell compartment rather than with the B cell or IgE compartment. This immunotherapy trial will involve weekly injections of allergen administered over 4 months with evaluation in terms of breath units of Mus m 1 required to cause a 20% drop in FEV1 on three successive occasions prior to the immunotherapy trial and after the immunotherapy trial. This intervention and its immunologic manifestations should provide unusual insight into the mechanisms of immunotherapy and by implication, immune contributions to asthma.
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