Immunoregulation in Cyclosporine-Induced Autoimmunity

Johns Hopkins University, Baltimore MD

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Abstract

DESCRIPTION (provided by applicant): Cyclosporine (CsA) is an effective immunosuppressive drug that paradoxically disrupts the mechanisms governing self-tolerance during reconstitution of the immune system. Administration of CsA after syngeneic or autologous bone marrow transplantation (BMT) elicits a T lymphocyte dependent autoimmune disease. The induction of this autoaggression syndrome requires the elimination of a peripheral regulatory mechanism providing a permissive environment for the autoreactive T cells that promiscuously recognize MHC class lI determinants. Promiscuous recognition of MHC class II antigens by the highly restricted repertoire of autoreactive T cells occurs at the clonal level and is dependent upon presentation of a peptide from the MHC class II invariant chain, termed CLIP. Furthermore, there appears to be a functional interaction between the T cell receptor and the flanking regions of CLIP (particularly the N-terminal flanking region that extends beyond the binding domain of the MHC class II molecule), which in part may explain the promiscuous specificity of the autoreactive T cells. At the clonal level, two distinct subsets of autoreactive T cells can be detected. The first subset requires the N-terminal flanking region of CLIP for activation, secretes type 1 cytokines and mediates pathology consistent with acute autoaggression. In addition, there is a reciprocal subset restricted by the C-terminal flanking region of CLIP. The C-terminal restricted T cells that secrete type 2 cytokines not only have "immunoregulatory" potential but can mediate pathology consistent with chronic autoaggression in the appropriate environment. The objectives of this proposal are to further characterize the interactions between the autoreactive and auto regulatory T cells, defining the underlying mechanisms of immunoregulation and define the pathogenic potential of the immunoregulatory subset. Additional studies plan to explore whether immunization with C- terminal variants of CLIP can accelerate the development of immunoregulation. These studies will be conducted in a well-established rat model of this autoaggression syndrome utilizing both cellular (clones) and molecular reagents. This unique model and the proposed studies will provide novel insights into systemic control of autoaggression.