Research in this program is focused on the basic mechanisms by which the host mobilizes and modulates cellular inflammatory reactions in defense against foreign antigens and infectious agents. In a multi-disciplinary approach, mechanisms of integrin adhesion, chemotaxis, signaling, mediator synthesis and apoptosis are explored in vitro and extended into experimental animal models (knockout and transgenic mice) for in vivo analysis. In addition, human conditions of chronic inflammatory disease in response to trauma, tumors, infectious pathogens, or of unknown etiology are explored at the cellular, molecular and biochemical levels. Understanding the mechanisms which control normal immune cell recruitment, activation and/or deletion and the switch to pathogenesis underlies our long term development of strategies for modulating chronic pathogenic inflammatory diseases. In experimental animal models, we have characterized the immunopathology through phenotypic, functional and morphologic parameters, in addition to DNA microarrays and ribonuclease protection assays, to identify targets for therapeutic intervention. New insights into the regulation of immune function through CD4+CD25+ regulatory T cells, which express TGF-beta on their surface and mediate contact-dependent suppression of responder T cells, raise the prospect of novel approaches to controlling immunological tolerance, asthma, autoimmunity, and tumor immunity. The failure to successfully resolve an allergic response has been attributed to a failure to shift the antigen response from a prevailing Th2 phenotype towards an antagonistic Th1 healing response, but provocative new evidence also implicates an insufficiency in specialized regulatory T cells. Naturally occurring regulatory T cells, identified as CD4+CD25+ Treg, in addition to inducible/adaptive Tr1 and Th3 cells, are fundamental in the control of immune responsiveness to self and nonself antigens. Intense interest has focused on Treg, which represent 5-10% of CD4+ T cells, because they possess potent immunoregulatory functions essential to peripheral self-tolerance and to reining in infectious and noninfectious immune responses. Characterized by membrane expression of CD4, CD25, glucocorticoid-induced TNF receptor (GITR), CTLA-4, TGF-b and TGF-b receptor type II (TbRII), all of which contribute to their unique functional repertoire, Treg specifically express Foxp3, a member of the forkhead-winged helix family of transcription factors, which possesses a C-terminus winged helix domain involved in nuclear localization and DNA binding. Foxp3 has emerged as a master control gene for this population, and identifies Treg as a distinct T cell subset. Genetic insufficiency of Foxp3 derails immune control into an autoimmune and inflammatory disease in scurfy mice, whereas in humans, defects of the highly homologous Foxp3 gene underlie loss of tolerance and immune dysregulation. Another endogenous immunoregulatory molecule, SLPI, was found to be instrumental in host defense to an intracellular parasite, Leishmania major, and in protection from allergen-induced bronchial asthma. This multifunctional host defense molecule, found in mucosal fluids and produced by inflammatory cells in rodents, not only modulates innate immunity, but also adaptive immune sequelae by regulating T helper type I and type 2 immune responses. Airway exposure to otherwise innocuous environmental antigens (allergens) in genetically susceptible humans or in animal models initiates an inappropriate Th2 response characterized by airway hyperresponsiveness (AHR) to specific and nonspecific stimuli, obstructive airway mucus production, pulmonary eosinophilia and eelevated serum IgE. It is the Th2 cytokines IL-4, IL-5 and IL-13, which apparently set this scenario in motion, incorporating a plethora of additional contributing factors, including complement and other proteases, all of which are insttrumental in the ensuing pathogenesis. In this regard, many allergens are themselves proteases and the host inflammatory cells generate a battery of proteases that influence the Th1/Th2 shift. The absence of the endogenous protease inhibitor SLPI, normally found in the airways and produced by activated inflammatory cells, is associated with an exacerbated Th2 allergic response in a transgenic model of house dust mite (HDM)-induced allergic asthma. Thus, understanding the starting point, Th2 activation, is essential to ablating the downstream deleterious consequences. Delineation of the aberrant immune responses in SLPI deficent mice will help define the role of SLPI in innate and adaptive immunity and its potential as a therapeutic agent in the treatment of infectious, autoimmune and inflammatory diseases.
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