Immunoregulatory Mechanisms in the Rheumatic Disease

超出所提供的空间。系统性红斑狼疮是一种自身免疫性疾病，表现为多克隆B细胞活化，伴有大量自身抗体和许多T细胞缺陷。虽然所有人都认识到免疫调节在预防自身免疫中的重要性，并且某些T细胞具有这种能力，但在描述调节性T细胞的发育和作用机制方面进展缓慢。我们已经积累了大量的证据表明，转化生长因子- β (TGF-)在诱导调节性T细胞中起着至关重要的作用，并且在人类SLE中，这种细胞因子的淋巴细胞生成减少。本研究的主要目标是在体外产生有效的调节性T细胞，并证明这些细胞的过继转移可以改变小鼠狼疮的病程。我们还将确定用于过继转移的调节性T细胞的最佳组成，阐明SLE中调节性细胞分化的可逆缺陷，并了解这些调节性T细胞是否可以扩增。有五个具体目标。前两个将由加州大学洛杉矶分校的Bevra Hahn博士和她的团队进行。Hahn的实验室一直在比较狼疮（NZB x NZW） Fl小鼠与MHC相同的正常（BALB/c x NZW） Fl小鼠的T细胞反应。第一个目的是从正常的C/WF1小鼠体外产生CD4+和CD8+调节性T细胞，并证明这些细胞的过继性转移可减少肾炎，提高雌性B/WF1小鼠的存活率。第二个目标将是使用来自受影响的B/WF1小鼠的T细胞来实现这一目标。第三个目标是防止狼疮样综合征的发展，这种综合征可以在具有正常遗传背景的小鼠中引起。第四个目的是确定TGF-诱导幼稚T细胞产生有效调控活性的分子事件，并阐明这些细胞对疾病的作用机制。在目标5中，我们描述了小鼠和人类SLE中调节性T细胞产生的特定缺陷，确定这些缺陷是否可以通过暴露于适当的细胞因子来纠正，以及由此产生的抑制效应细胞是否可以扩增。这一建议将为slea患者和可能的其他自身免疫性疾病患者的新治疗奠定基础，如果成功，将避免当前一代治疗药物的毒副作用。网站性能 ======================================== 节结束 ===========================================

EXCEED THE SPACE PROVIDED. Systemic lupus erythematosus is an autoimmune disease manifested by polyclonal B cell activation with numerous autoantibodies and many T cell defects. While all recognize the importance of immune regulation in preventing autoimmunity, and that certain T cells develop this capacity, progress in delineating the development and mechanism of action of regulatory T cells has been slow. We have accumulated considerable evidence that transforming growth factor-beta (TGF- ) has a crucial role in the induction of regulatory T cells and that lymphocyte production of this cytokine is decreased in human SLE. The principal goal of this proposal is to generate potent regulatory T cells ex-vivo and demonstrate that the adoptive transfer of these cells can alter the course of mouse lupus. We will also determine the optimal composition of regulatory T cells for adoptive transfer, elucidate reversible defects of regulatory cell differentiation in SLE, and learn whether these regulatory T cells can be expanded. There are five specific aims. The first two will be performed with Dr. Bevra Hahn and her group at UCLA. Hahn's laboratory has been comparing the T cell response of the lupus (NZB x NZW) Fl mice with the MHC identical normal (BALB/c x NZW) Fl mice. The first aim is to generate CD4+ and CD8+ regulatory T cells ex-vivo from the normal C/WF1 mice and show that the adoptive transfer of these cells decreases nephritis and increases survival of female B/WF1 mice. The second aim will be to accomplish this goal using T cells from affected B/WF1 mice. The third aim is to prevent the development of a lupus-like syndrom which can be induced in mice with normal genetic background. The fourth aim is to determine the molecular events how TGF- induces naive T cells to develop potent regulatory activity and to elucidate the mechanism of action of these cells, disease. In aim five we characterize specific defects in the generation of regulatory T cells in mouse and human SLE, determine whether these defects can be corrected by exposure to the appropriate cytokines, and whether the resulting suppressor effector cells can be expanded. . This proposal will serve as the foundation for a novel treatment for patients with SLEand possibly other autoimmune diseases that, if successful, would avoid the toxic side effects of the present generation of therapeutic agents. PERFORMANCE SITE ========================================Section End===========================================