Mechanism of anti-CD45 induced transplantation tolerance

抗CD45诱导移植耐受的机制

基本信息

批准号：
7557931
负责人：
JAMES FRANCIS MARKMANN
金额：
$ 18.57万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-01-01 至 2010-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7557931
关键词：
Adult Allografting Animals Antibodies Antibody Formation Antigens B-Cell Activation B-Lymphocytes Cell physiology Cells Data Development Doctor of Philosophy Equilibrium Generations Graft Survival Human Immune system Immunosuppression Immunosuppressive Agents In Vitro Investigation Life Link Lymphocyte Mediating Modeling Nature Numbers PTPRC gene Pathway interactions Peripheral Preclinical Testing Primates Process Production Property Reagent Reporting Research Personnel Role Series Signal Transduction T-Cell Activation T-Lymphocyte Therapeutic immunosuppression Thymus Gland Time Transcriptional Activation Transgenic Model Translating Transplantation Transplantation Tolerance Treatment Protocols Up-Regulation base cell motility clinical application clinically relevant day design in vivo insight interest novel programs reconstitution tool trafficking

项目摘要

In the current proposal, we investigate the mechanisms underlying transplantation tolerance induced by treatment with anti-CD45RB antibody. This agent is of considerable interest based on a number of attractive properties, including: 1) that a short course of anti-CD45RB results in long-lived transplantation tolerance in experimental animals, 2) that it may be unique in its ability to reverse ongoing rejection and still result in tolerance, 3) that it may synergize with costimulatory blockade, and 4) that it may exert a negative regulatory signal to T cells through up regulation of CTLA-4. Because of these unique attributes, recently there has developed a renewed enthusiasm for evaluating humanized or human anti-CD45 reagents in primate preclinical testing as a component of a regimen to induce transplant tolerance. Despite extensive study at the cellular level on the CD45's role in T cell activation, the mechanism of tolerance induced by anti CD45RB antibody in vivo is poorly understood. This fact is underscored by two novel and unexpected observations we recently made regarding its in vivo action: first is that tolerance induced by anti-CD45RB is thymus dependent and acts through generation of antigen specific thymus derived T-regs; and second is that tolerance depends on the presence of host B lymphocytes. These findings may make this agent unique among tolerance inducing antibody regimens. Moreover, the fact that anti-CD45RB induced tolerance is centrally mediated further heightens interest in its potential as a unique agent for clinical application. To integrate our preliminary findings into a cohesive model explaining the tolerogenic property of anti-CD45RB, we develop a model to explain the B cell dependent state of central tolerance induced by this agent. Studies in the proposal that dissect the immunological mechanism by which anti-CD45RB therapy leads to transplantation tolerance are facilitated by use of a TcR transgenic model of allograft rejection developed in our lab. This approach allows precise definition of the activity of graft specific T cells and antigen specific T-regs in vivo. Further understanding of the tolerogenic properties of anti-CD45RB therapy in the context of our preliminary data will not only provide insight into the action of this potentially clinically relevant agent, but also may define novel pathways of tolerance induction in vivo.

在当前的提案中，我们研究了由以下因素引起的移植耐受的机制：用抗CD45RB抗体治疗。基于许多方面，该代理引起了相当大的兴趣有吸引力的特性，包括：1) 短期抗 CD45RB 疗程可实现长寿命移植实验动物的耐受性，2）它可能具有独特的逆转持续排斥反应的能力，并且仍然导致耐受性，3）它可能与共刺激阻断产生协同作用，4）它可能产生负面影响通过上调 CTLA-4 向 T 细胞发出调节信号。由于这些独特的属性，最近人们对评估人源化或人类抗 CD45 试剂产生了新的热情灵长类动物临床前测试作为诱导移植耐受方案的一部分。尽管在细胞水平上对 CD45 在 T 细胞激活中的作用进行了广泛的研究，但其机制抗CD45RB抗体在体内诱导的耐受性尚不清楚。两个事实都强调了这一事实我们最近对其体内作用进行了新颖且意想不到的观察：首先是耐受性抗 CD45RB 诱导的胸腺依赖性，通过产生抗原特异性胸腺发挥作用派生 T 规则；其次，耐受性取决于宿主 B 淋巴细胞的存在。这些研究结果可能使该药物在耐受诱导抗体治疗方案中独一无二。此外，事实是抗 CD45RB 诱导的耐受性是集中介导的，进一步提高了人们对其作为独特药物的潜力的兴趣临床应用剂。将我们的初步发现整合到一个内聚模型中，解释抗 CD45RB，我们开发了一个模型来解释由此引起的 B 细胞依赖性中枢耐受状态代理人。解析抗CD45RB治疗免疫学机制提案的研究通过使用同种异体移植排斥的 TcR 转基因模型促进移植耐受我们实验室开发的。这种方法可以精确定义移植物特异性 T 细胞的活性体内抗原特异性T-regs。进一步了解抗 CD45RB 疗法的耐受特性在我们的初步数据背景下，不仅可以深入了解这种潜在的临床作用相关药物，而且还可能定义体内耐受诱导的新途径。