Normal/Pathologic Mechanisms Of Inflammation &Immunity

Dental &Craniofacial Research

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Abstract

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 pathogens. 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 longterm development of strategies for modulating chronic pathogenic inflammatory diseases. In experimental animal models, we have characterized immunopathology through phenotypic, functional and morphologic parameters, in addition to DNA microarrays and proteomic analyses, to identify targets for therapeutic intervention. New insights into the regulation of immune function involving CD4+CD25+ regulatory T cells, TGF-beta, and SLPI raise the prospect of novel approaches to controlling immunological tolerance, asthma, autoimmunity, and tumor immunity. Secretory Leukocyte Protease Inhibitor - an Innate Immunomodulatory Molecule: Effective host defense against intracellular pathogens relies upon activation of both innate and adaptive immune responses to contain or eliminate the infectious microbe. Equally important are regulatory mechanisms to terminate exuberant responses to restore homeostasis in the immune system. SLPI is a potent serine protease inhibitor with both anti-microbial and anti-inflammatory functions and is found in fluids associated with mucosal surfaces of the oral, nasal, respiratory, and reproductive tracts. Furthermore, SLPI is produced by mouse macrophages but also inhibits macrophage activation by suppressing NFkB-dependent signaling pathways. The combination of SLPI?s microbicidal activity and suppressive activity on bacterial-mediated immune responses implicate this molecule in innate host defense and the SLPI -/- mouse provides a model to explore the in vivo role for SLPI in inflammatory responses and host defense. To determine whether SLPI plays a role in host defense, SLPI -/- and +/+ mice were infected with the intracellular parasite Leishmania major in a model of cutaneous leishmaniasis. In contrast to C57Bl/6 SLPI +/+ littermates which develop self-healing skin lesions at the site of L. major inoculation, SLPI -/- mice are initially resistant to cutaneous infection by L. major but develop an exacerbated chronic infection with increased lesion size and parasite numbers (3 to 5 log increase as compared to SLPI +/+ mice) that results in systemic spread of parasites. Whereas spontaneous healing of lesions in SLPI +/+ mice involves a Th1-dominant cytokine response, elevated suppressive Th2 cytokines IL-4, IL-10 and TGF-beta in SLPI -/- mice likely contribute to the failed host response, despite persistently elevated levels of IFN-g. These studies highlight a protective role for SLPI in the chronic infective phase of leishmaniasis and its potential as a therapeutic agent for the treatment of inflammatory and infectious disease. Importantly, administration of exogenous SLPI (adenoviral construct containing SLPI) to L. major-infected SLPI -/- mice reduces lesion size and parasite numbers, thus providing definitive evidence of the crucial role of SLPI in the regulation of the host response to leishmania infection. TGF-beta and regulatory T cells in the control of infectious, immune and neoplastic diseases: 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, GITR, CTLA-4, TGF-beta and TGF-beta receptor type II, all of which contribute to their unique functional repertoire, Treg specifically express Foxp3, a member of the forkhead-winged helix family of transcription factors. We have previously shown that generation of these cells in vitro and adoptive transfer into experimental animals with immune-mediated mucosal pathology alleviates the symptoms of disease. It is also evident that whereas an increase in Treg is beneficial in autoimmune and antigen-driven pathologies where insufficient numbers are contributory, an over-representation of these cells can also be detrimental, especially evident in infectious and neoplastic diseases. In this regard, we have identified a high level of expression of TGF-beta in cells infiltrating tumor tissues, in addition to an abundance of Foxp3+ cells in association with these tumors. These Treg may contribute to the failure of immune surveillance to detect and/or eliminate such tumors and be a potential target in promoting immune-mediated tumor therapy.