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，我们研究了由用抗CD45RB抗体治疗。根据许多有吸引力的特性，包括：1）抗CD45RB的短暂过程会导致长期移植在实验动物中的耐受性，2）它在逆转持续拒绝的能力上可能是独一无二的耐受性，3）它可能与cost刺激性封锁协同作用，4）可能发出负面通过加强CTLA-4的调节对T细胞的调节信号。由于这些独特的属性，最近在评估人性化或人类抗CD45试剂中，有一种新的热情灵长类动物临床前测试是诱导移植耐受性的方案的组成部分。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研究，但抗CD45RB抗体在体内诱导的耐受性知之甚少。这个事实被两个我们最近就其体内作用进行了新颖和意外的观察：首先是公差由抗CD45RB诱导的是胸腺依赖性，并通过产生抗原特异性胸腺起作用派生的t-regs;其次是公差取决于宿主B淋巴细胞的存在。这些发现可能会使该药物在诱导抗体方案的耐受性中与众不同。而且，事实抗CD45RB诱导的公差被集中介导，进一步提高了其作为独特的潜力的兴趣临床应用的代理。将我们的初步发现整合到一个结合模型中，以解释抗CD45RB，我们开发了一个模型来解释由此引起的中心耐受性的B细胞依赖性状态代理人。在剖析抗CD45RB治疗的免疫机制的提案中的研究通过使用同种异体移植排斥的TCR转基因模型，可以促进移植耐受性在我们的实验室中开发。这种方法允许精确定义移植物特异性T细胞的活性和体内抗原特异性T-REG。进一步了解抗CD45RB治疗的耐受性特性在我们的初步数据的背景下相关的药物，但也可能定义了体内耐受性诱导的新途径。