Jo-1-specific T Cell Responses in Polymyositis

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

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Abstract

DESCRIPTION (provided by applicant): Polymyositis represents an autoimmune disease in which muscle is inappropriately targeted for T cell-mediated destruction. Because the antigenic trigger(s) remain unknown, current therapies are non-specific and rely on global immunosuppression. Distinct clinical subsets of polymyositis exist that are defined by antibodies directed against specific nuclear and cytoplasmic antigens including Jo-1 (histidyl-tRNA synthetase). Based on a range of genetic, serologic, and histomorphologic data, the underlying hypothesis of this proposal is that antigen-specific T cell responses directed against Jo-1 promote anti-Jo-1 antibody formation as well as T cell-mediated cytolysis/dysfunction of muscle cells in Jo-1+ polymyositis. , The initial phase of this study will define the in vitro T cell proliferative and cytokine responses to Jo-1. Subsequent experiments will involve cloning of Jo-1-specific T cells derived from the peripheral blood of patients with Jo-1 + polymyositis and healthy controls. TCR sequencing as well as epitope mapping studies using both Jo-1 fragments and linear peptides will then permit further characterization of the Jo-1-specific T cell repertoire and facilitate comparison of Jo-1-specific T cells derived from polymyositis patients and healthy controls. Localization of these Jo-1-specific T cell subsets to lymphocytic infiltrates of diseased muscle in vivo will be investigated through RT-PCR and immunohistochemistry techniques. Cloning of muscle-infiltrating lymphocytes will provide a pool of antigen-specific cells to be analyzed for responses to Jo-1 as well as other putative autoantigens derived from muscle protein extracts. Assessment of myocyte destruction after the application of Jo-1-specific T ceils to autologous myotube cultures in vitro will further define the role of such T cells in Jo-1+ polymyositis. These studies are intended to also provide insight concerning the relative roles of altered T cell repertoire and antigen presentation in the expression of Jo-1+ polymyositis.