: The long-term objective of this proposal is to gain insight into mechanisms of cell-mediated immunity and unresponsiveness to intracellular pathogens in humans. Leprosy provides an extraordinary model to investigate these immunoregulatory processes. First, the disease primarily affects skin and is therefore accessible for study, proving a unique opportunity for investigating the nature of the local inflammatory response in human infectious disease. Secondly, the disease represents a spectrum of clinical manifestations that correlate with the pattern of cytokines produced at the site of infection. Patients with the resistant tuberculoid form (T-lep) express type 1 cytokines in lesions; whereas patients with progressive lepromatous form (L-lep) manifest type 2 cytokines in lesions. Our approach has been to study immune responses in lesions at the site of disease activity. Such studies have provided insight that cannot be obtained from the study of the peripheral blood from these patients. We hypothesize that the outcome of the host response to M. leprae is determined by the nature of the innate and adaptive immune response in lesions. We now propose to: 1) elucidate the gene expression profiles associated with resistance versus susceptibility in the human immune response to an intracellular pathogen, 2) determine the role of leukocyte immunoglobulin-like receptor (LIR) family members in contributing to immune unresponsiveness in leprosy; and, 3) elucidate the mechanism by which T-cell recognition of a major microbial antigen contributes to host defense in leprosy. The studies we propose are intended to provide a comprehensive analysis of the immune response in leprosy, comparing host responses in patients that are resistant to infection vs. susceptible to progressive disease. Such studies should provide new insights into mechanisms of immunoregulation in humans, and, we would hope, would provide the ability to predict disease outcome and also lead to the development of new immunomodulatory treatments for a variety of human infectious diseases. These issues are timely, given the rise in emerging infections and the threat of bioterrorist attacks.
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