The overall goal of this project is to define the mechanism of cell- mediated immunological unresponsiveness to Mycobacterium leprae seen in patients with lepromatous leprosy (LL). We have demonstrated that the T cell defectin LL patients is reversible invitro. The recovery of T cell function is specific for M. leprae and occurs at the level of CD4+ cells, and is not affected by monocytes or CD8+ suppressor T cells. Moreover, recovery of T cell reactivity is blocked by the presence of leprosy bacilli in the preculture medium. On the basis of these findings, we have postulated that the continued presence of M. leprae antigen(s) in LL patients may be responsible for immune paralysis, or alternatively may be responsible for chronic activation of CD4+ suppressor cells. To explore the regulatory role of M. leprae proteins in affecting the overall responses to the leprosy bacilli, we have isolated a major immunostimulating protein from M. leprae, designated MLP, with a MW of 35 KD. This protein contains epitope(s) recognized by the T cells of convalescent patients with leprosy and confers protection against infection with leprosy bacilli in mice. We now propose to 1) characterize this protein in detail and prepare a set of peptides encompassing the entire molecule; 2) define the repertoires of T helper cells directed against epitopes on this protein; 3) examine the ability of these peptides to block the functional recovery of CD4+ T cells derived from nonresponder LL patients; 4) assess the potential value of peptides derived form MLP in conferring protection in a murine model of leprosy; and 5) characterize the expression and structure of T cell receptors in M. leprae specific CD4+ helper T cell clones. Studies by other investigators indicate that some protein antigens contain epitope(s) which are able to nullify the positive effect induced by determinants from other regions of the molecule. Using the peptides derived from M. leprae-MLP as probes, significant advances in our understanding of the mechanism of cell-mediated immunological unresponsiveness to M. leprae can be anticipated, and such advances should eventually contribute to new approaches of intervention in this disease.
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