Mechanism of anti-CD45 induced transplantation tolerance

描述（由申请人提供）：在目前的提案中，我们研究了抗cd45rb抗体治疗诱导移植耐受的机制。基于许多吸引人的特性，这种药物引起了相当大的兴趣，包括：1)抗cd45rb的短过程导致实验动物的长期移植耐受，2)它可能在逆转持续排斥的能力上是独一无二的，并且仍然导致耐受，3)它可能与共刺激阻断协同作用，4)它可能通过上调CTLA-4向T细胞施加负调节信号。由于这些独特的属性，最近在灵长类动物临床前试验中，评估人源化或人类抗cd45试剂作为诱导移植耐受方案的组成部分的热情重新燃起。尽管在细胞水平上对CD45在T细胞活化中的作用进行了广泛的研究，但抗CD45RB抗体在体内诱导耐受的机制尚不清楚。我们最近对其体内作用的两个新颖和意想不到的观察结果强调了这一事实：首先，抗cd45rb诱导的耐受性依赖于胸腺，并通过抗原特异性胸腺源性T-regs的产生起作用；第二，耐受性取决于宿主B淋巴细胞的存在。这些发现可能使这种药物在诱导耐受性的抗体方案中独一无二。此外，抗cd45rb诱导的耐受性是由中枢介导的，这一事实进一步提高了人们对其作为一种独特的临床应用药物的潜力的兴趣。为了将我们的初步发现整合到一个解释抗cd45rb耐受性的内聚模型中，我们建立了一个模型来解释该药物诱导的B细胞依赖性耐受状态。我们实验室开发了一种TcR转基因同种异体移植排斥模型，研究了抗cd45rb治疗导致移植耐受的免疫学机制。这种方法允许在体内精确定义移植物特异性T细胞和抗原特异性T-regs的活性。在我们的初步数据背景下，进一步了解抗cd45rb治疗的耐受性特性不仅可以深入了解这种潜在的临床相关药物的作用，还可以确定体内耐受性诱导的新途径。

DESCRIPTION (provided by applicant): 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.