ASTHMA, ALLERGIC AND IMMUNOLOGIC DISEASES COOP RES CTR

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Description (adapted from the applicant's Abstract): Cytokines act to modulate the activities of immune and inflammatory cells during all stages of the immune response. The overall goal of the investigators is to understand the mechanisms by which proinflammatory and atopic cytokines modulate the host response to pathogens and environmental antigens. This project focuses particularly on two areas of cytokine regulation as they relate to development and expression of hypersensitivity responses. The first concerns the initial induction of hypersensitivity responses in the epidermis and the role of the proinflammatory cytokines IL-1-beta (IL-1b) and lymphotoxin-alpha (LTa) as mediators of sensitization. The second concerns the mechanism by which Th1 and Th2 cells synergize to establish eosinophilic inflammatory responses in experimental murine airway hypersensitivity. These investigations build on the Principal Investigator's long standing productive investigations of the molecular genetics and cellular physiology of IL-1 and LT, and on his strong clinical interest in asthma and hypersensitivity diseases as Director of the Division of Allergy and Immunology at Washington University. Aim 1 builds on preliminary data indicating that the contact hypersensitivity response is ablated in mice carrying targeted null mutations in the IL-1b and LTa genes and investigates the expression of these cytokines during activation of contact hypersensitivity and how they in turn modulate additional downstream effector mechanisms in the response. It is particularly oriented to understanding the role of epidermal cell apoptosis as a trigger for the release of IL-1b following exposure to sensitizing agents. Aim 2 follows from the applicants initial data using the murine model of ovalbumin (OVA)-induced airway hypersensitivity which have demonstrated that both Th1 and Th2 cells enter the lung early in this hypersensitivity response, and suggest that these cell types synergize in the recruitment of the pathological eosinophilic inflammatory response in the airway. The Th1 and Th2 have traditionally been thought to be counter-regulatory and antagonistic. The applicants propose to investigate the mechanisms by which these two types of cells synergize in the development of the hypersensitivity response. Program Interactions: These Aims will be facilitated by sustained interactions with other members of the AAIDCRC. In particular, Dr. Murphy (Project 2) is an internationally recognized scholar in the field of Th1 and Th2 phenotype development. His experience in this area and the many reagents and methods he has developed will prove phenotype development. His experience in this area and the many reagents and methods he has developed will prove exceptionally useful for Aim 2. Dr. Unanue (Project 3) and Dr. Chaplin have worked together for nearly 10 years studying the physiology of IL-1, and Dr. Unanue's experience in the use of neutralizing anti-cytokine antibodies to study physiological functions in vivo will strengthen the application of these types of experiments. The addition of Dr. Yokoyama (Project 4) to the AAIDCRC will support efforts to determine the role of NK cells as regulators of these hypersensitivity responses.