Immunoregulation in Cyclosporine-Induced Autoimmunity

描述（由申请人提供）：环孢素（CsA）是一种有效的免疫抑制药物，在免疫系统重建过程中矛盾地破坏了控制自我耐受的机制。同源或自体骨髓移植（BMT）后给予CsA可引起T淋巴细胞依赖性自身免疫性疾病。这种自身攻击综合征的诱导需要消除外周调节机制，该机制为混杂识别MHC lI类决定因子的自身反应性T细胞提供了一个允许的环境。高度受限的自身反应性T细胞对MHC II类抗原的混杂识别发生在克隆水平，并依赖于MHC II类不变链中称为CLIP的肽的呈现。此外，T细胞受体和CLIP的侧翼区域（特别是延伸到MHC II类分子结合域之外的n端侧翼区域）之间似乎存在功能性相互作用，这在一定程度上可以解释自身反应性T细胞的混杂特异性。在克隆水平上，可以检测到两种不同的自身反应性T细胞亚群。第一个亚群需要CLIP的n端侧翼区域激活，分泌1型细胞因子并介导与急性自身攻击一致的病理。此外，还存在一个受CLIP c端侧翼区限制的互反子集。分泌2型细胞因子的c端限制性T细胞不仅具有“免疫调节”潜力，而且可以在适当的环境中介导与慢性自身攻击一致的病理。本提案的目的是进一步表征自身反应性和自身调节性T细胞之间的相互作用，定义免疫调节的潜在机制，并定义免疫调节亚群的致病潜力。进一步的研究计划探索是否使用CLIP的C端变体免疫可以加速免疫调节的发展。这些研究将在利用细胞（克隆）和分子试剂建立的自体攻击综合征大鼠模型中进行。这个独特的模型和提出的研究将为系统控制自我攻击提供新的见解。

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.