Mechanism of anti-CD45 induced transplantation tolerance

在目前的建议中，我们研究了诱导移植耐受的机制 用抗CD45Rb抗体治疗。该代理基于多个 诱人的特性，包括：1)短程抗CD45RB可导致长期移植 实验动物的耐受性，2)它可能在逆转持续排斥和静止的能力上是独一无二的 导致耐受，3)它可能与共刺激阻断协同作用，4)它可能产生负面影响 通过上调CTLA-4对T细胞的调节信号。由于这些独特的属性，最近 人们对人源化或人源性抗CD45试剂的评价重新燃起了热情 作为诱导移植耐受方案的组成部分的灵长类临床前试验。 尽管在细胞水平上对CD45‘S在T细胞活化中的作用进行了广泛的研究，但其机制 抗CD45RB抗体在体内诱导耐受的机制尚不清楚。两个事实突显了这一事实 我们最近对其在体内的作用进行了新颖和意想不到的观察：首先是耐受性 抗CD45RB诱导的胸腺依赖，通过产生抗原特异性胸腺起作用 第二，耐受性取决于宿主B淋巴细胞的存在。这些 这一发现可能会使该制剂在诱导耐受的抗体方案中独一无二。此外，事实是 抗CD45RB诱导的耐受是集中介导的，进一步增强了人们对其作为一种独特的 临床用药。 将我们的初步发现整合到一个连贯的模型中，解释 抗CD45RB，我们建立了一个模型来解释由此导致的中枢耐受的B细胞依赖状态 探员。关于剖析抗CD45Rb治疗的免疫学机制的提案中的研究 通过使用同种异体移植排斥反应的TCR转基因模型来促进移植耐受 这是我们实验室研发的。这一方法允许准确定义移植物特异性T细胞的活性和 体内抗原特异性T-regs。对抗CD45Rb治疗耐受性的再认识 在我们的初步数据的背景下，不仅将提供对这一潜在临床行为的洞察 相关试剂，但也可能定义体内耐受诱导的新途径。

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.