The main hypothesis of this proposal is that the spectrum of disease associated with L. braziliensis infectionis a reflection not only of whether an individual has mounted an effector immune response against theparasite, but, whether this effector response is appropriately modulated response. For over 25 years wehave conducted laboratory and field based studies in leishmaniasis and have shown that while a type 1immune response is critical for protection, an exaggerated inflammatory response as observed in cutaneousleishmaniasis (CL) and mucosal leishmaniasis (ML) determine patology. In contrast, up to 75% of L.braziliensis infected individuals, which have a modulated immune response, will remain without disease.The major aims are: 1) Determine whether individuals with subclinical L. braziliensis infection (SC) have anappropriately modulated immune response, and whether patients with clinically symptomatic disease havedefective regulatory mechanisms. We will evaluate the role of IL-27 and Treg cells in modulating theimmune response and determine the mechanisms responsible for the failure of IL-10 to down regulateimmune response in CL and ML. Leucocytes from SC, CL and ML will be used for these studies. We willuse techniques such as intracellular cytokine staining coupled with flow cytometer-based analyses oflymphocyte proliferation, and studies derived from sorted, purified cell populations, to determine, inpreviously unattainable detail, the function of these cell populations. 2) Determine the specific mechanismsof tissue destruction in CL and ML. The ulcerative lesions that develop in CL and ML are associated with astrong inflammatory response. We will measure TNF-a receptor expression, apoptosis chemokines involvedin the leukocyte recruitment, metalloproteinases, and IL-17. 3) Determine memory T cell responses afterspontaneous or drug induced cure of subclinical or symptomatic human tegumentary leishmaniasis. We willevaluate lymphocyte proliferation and cytokine production to selected recombinant leishmania antigens. Inindividuals with past history of SC L. braziliensis and L. chagasi infection as well as in patients cured of CL,ML, and VL. Futhermore the development of central memory and effector memory T cells will be evaluated.These studies will elucidate immune mechanisms that could inspire the development of novel immune basedstrategies to be used as immunotherapy.
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