IMMUNOSUPPRESSIVE EFFECTS OF ANTI-T CELL MABS

抗 T 细胞 MABS 的免疫抑制作用

• 批准号: 5205409
• 负责人: JEFFREY A BLUESTONE
• 金额: --
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5205409
• 关键词: CD antigens; CD3 molecule; T lymphocyte; anergy; antireceptor antibody; apoptosis; artificial immunosuppression; biological signal transduction; cell cycle proteins; cell migration; cyclosporines; etoposide; interleukin 2; isoantigen; laboratory mouse; monoclonal antibody; pancreatic islet transplantation; sirolimus; skin transplantation; surface antigens; tissue /cell culture; transplant rejection

OKT3 is a murine monoclonal antibody directed against the CD3epsilon chain of the T cell receptor complex on human T-cells. OKT3 has been widely used over the past decade in transplantation to treat corticosteroid- resistant organ graft rejections, and more recently, as prophylaxis of rejection. This mAb induces an efficient and rapid immunosuppression, at least in part due to, the prevention of allorecognition as a result of modulation of the T cell receptor (TCR) from the surface of T lymphocytes and clearance of T cells from the circulation. However, there are several clinical and scientific issues that remain unresolved regarding anti-CD3 therapy. First, a variety of side effects are associated with OKT3 that limits its usefulness in other diseases such as autoimmunity and bone marrow transplantation. These limitations are, in large part, a result of the first dose toxicity as a consequence of T cell activation and the subsequent massive cytokine release. In addition, the therapy has been limited by the generation of a potent humoral antibody response against the murine mAb limiting the potential for retreatment. During the past 4 years, Dr. Bluestone's laboratory has systematically evaluated the use of anti-CD3 to suppress transplantation responses in vivo first in a well- defined, small animal model and then in the hu-SPL-SCID model in collaboration with Dr. Thistlethwaite. The toxic effects of the mAb were defined and largely eliminated, immunosuppressive agents such as deoxyspergualin and CTLA4Ig were used in conjunction with anti-CD3 to potentiate immunosuppression and block the humoral response, and genetically-engineered monoclonal anti-CD3 antibodies were developed to examine the role of T cell activation and Co-stimulation in immune suppression. However, many questions remain including: the relative efficacy of "activating" and "non-activating" anti-CD3 mAbs; the signal transducing ability of "non-activating" anti-CD3 mAbs and how it regulates T cell activation; the role of co-stimulatory in the activating and toleragenic effects of anti-CD3; and the role of other inhibitors of T cell signalling, such as cyclosporin A in the efficacy of anti-CD3 therapy. In order to answer these questions the following specific aims are proposed: 1. To study the in vivo effects of non-mitogenic anti-CD3 mAbs alone and in conjunction with donor antigen; 2. To determine the role of CD28/B7 interactions in anti-CD3-mediated immunosuppression; 3. To determine the molecular mechanism(s) controlling apoptosis and anergy in mice treated with mitogenic anti-CD3. The results of these studies will provide important insights into the effects of anti-CD3 and the CD28/B7 family of cell surface molecules in the regulation of transplant rejection that may translate into clinical application.

OKT3是针对CD3EPSILON链的鼠单克隆抗体 人类T细胞的T细胞受体复合物的。 OKT3广泛 在过去十年中，用于治疗皮质类固醇 抗性器官移植拒绝，最近作为预防 拒绝。该mAb诱导有效且快速的免疫抑制 至少部分原因是，由于 从T淋巴细胞表面调节T细胞受体（TCR） 和从循环中清除T细胞。但是，有几个 关于抗CD3尚未解决的临床和科学问题 治疗。首先，多种副作用与OKT3相关 限制其在自身免疫和骨骼等其他疾病中的有用性 骨髓移植。这些限制在很大程度上是 由于T细胞激活和 随后的大规模细胞因子释放。此外，该疗法已经 受到有效的体液抗体反应的限制 鼠mab限制了撤退的潜力。在过去的4个 多年，Bluestone博士的实验室已系统地评估了 抗CD3首先在体内抑制移植反应 定义的小动物模型，然后在HU-SPL-SCID模型中 与Thintlethwaite博士的合作。 mAb的毒性作用是 定义并在很大程度上消除了免疫抑制剂，例如 Deoxyspergualin和ctla4ig与抗CD3一起使用 增强免疫抑制并阻止体液反应，并 开发了基因工程的单克隆抗CD3抗体 检查T细胞激活和共刺激在免疫中的作用 抑制。 但是，仍然存在许多问题，包括：亲戚 “激活”和“非激活”抗CD3 mAb的功效；信号 “非激活”抗CD3 mAb的转导能力及其如何调节能力 T细胞激活；共刺激性在激活和 抗CD3的阳性作用；以及T的其他抑制剂的作用 细胞信号传导，例如抗CD3疗效的环孢菌素A 治疗。为了回答这些问题，以下具体目标 提出：1。 单独单独使用mab，并与供体抗原结合； 2。确定角色 抗CD3介导的免疫抑制中的CD28/B7相互作用； 3 确定控制凋亡和反感的分子机制 用有丝分裂抗CD3处理的小鼠。 这些研究的结果将为您提供重要的见解 抗CD3和CD28/B7细胞表面分子家族的影响 可以转化为临床的移植排斥反应的调节 应用。