COSTIMULATORY MOLECULES IN TRANSPLANTATION TOLERANCE

现在人们认识到，T细胞需要2个信号来诱导 免疫反应。通过阻断来中断共刺激信号 CD28或其两个配体B7-1和B7-2可诱导移植 动物模型中的耐受性和预防或逆转自身免疫。 类似的数据也存在于阻止CD40配体：CD40相互作用，a 潜在的附加共刺激途径。这个项目的总体目标是 该项目旨在了解共刺激在移植排斥反应中的作用和 确定封锁的战略和机制 共刺激信号诱导移植耐受。我们的研究 阻断CD28或CD40L诱导移植耐受 已经显示出它们的配体B7-之间的一系列复杂的关系- 1、B7-2和CD40(均表达于抗原提呈细胞)，以及 引起排斥或容忍。具体目标1将重点放在以下几个方面 问题，使用选择性阻断试剂和基因敲除动物 小鼠同种异体心脏移植模型：研究B7-1的单独作用 和B7-2，检验(基于初步数据)B7-1的假设 在特定情况下，可以促进与 CTLA4，并检测B7-1的细胞和分子调控 通过CD40。我们的数据还表明，额外的捐赠者 在移植时，脾细胞形式的抗原是 需要与共刺激阻断协同作用才能诱导耐受。 在没有供体抗原的情况下，动物只是暂时的 免疫抑制，但有慢性排斥反应。具体目标#2将 确定捐赠者所需的细胞和MHC类型- 输血以诱导耐受性。然后我们将检验这一假设 免疫原性别肽可替代完整细胞诱导 宽容。最后，使用别肽，我们将检验假设 慢性排斥与不能容忍间接排斥有关 异种认同感。最后，基于协同刺激通过的数据 CD28诱导细胞生存基因bclx，该基因是 淋巴细胞存活，在特定目标#3中，我们将使用bcl-x转基因 小鼠测试通过CD28-免疫抑制的假设 BLOKADE通过诱导细胞死亡和bcl-x转基因来运作 通过这一动作，小鼠将抵抗耐受诱导。 这些研究将对……的发展产生重要影响 移植和自身免疫治疗的实施。

It is now recognized that T cells required 2 signals for induction of immune responses. Interruption of costimulatory signals by blocking CD28 or its two ligands B7-1 and B7-2 can induce transplantation tolerance and prevent or reverse autoimmunity in animal models. Similar data exists for blocking the CD40-ligand:CD40 interaction, a potential additional costimulatory pathway. The overall goal of this project is to understand the role of costimulation in graft rejection and determine the strategies and mechanisms by which blockade of costimulatory signals induces transplantation tolerance. Our studies of induction of transplant tolerance through blocking CD28 or CD40L have shown a complex series of relationships between their ligand, B7- 1, B7-2 and CD40 (all expressed on antigen-presenting cells), and the induction of rejection or tolerance. Specific aim #1 will focus on these questions, using selective blocking reagents and knockout animals in a murine cardiac allograft model to: examine the separate roles of B7-1 and B7-2, test the hypothesis (based on preliminary data) that B7-1 can, in select circumstances, promote tolerance interactions with CTLA4, and examine the cellular and molecular regulation B7-1 through CD40. Our data also show that delivery of additional donor antigen, in the form of splenocytes, at the time of transplantation, is required to synergize with costimulatory blockade to induce tolerance. In the absence of donor antigen, animals are transiently immunosuppressed but undergo chronic rejection. Specific aim #2 will identify the cell and MHC type which is required in the donor- transfusion to induce tolerance. We will then test the hypothesis that immunogenic allopeptides can substitute for intact cells to induce tolerance. Lastly, using the allopeptides, we will test the postulate that chronic rejection is linked to failure to tolerize to indirect allorecognition. Finally, based on data that costimulation through CD28 induces the cell survival gene bcl-x which is required for lymphocyte survival, in specific aim #3 we will use bcl-x transgenic mice to test the hypothesis that immunosuppression through CD28- blockade operates by induction of cell death and that bcl-x transgenic mice will be resistant to tolerance induction through this maneuver. These studies will have important implications for the development of implementation of therapies for transplantation and autoimmunity.