MECHANISM OF COSTIMULATORY BLOCKADE RESISTANT REJECTION

共刺激性封锁抵抗排斥机制

• 批准号: 6348914
• 负责人: CHRISTIAN P LARSEN
• 金额: $ 37.5万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6348914
• 关键词: B lymphocyte; CD28 molecule; CD40 molecule; CD95 molecule; T lymphocyte; antigen presenting cell; cellular immunity; cytokine; immune tolerance /unresponsiveness; laboratory mouse; natural killer cells; polymerase chain reaction; skin transplantation; tissue /cell culture; transplant rejection

Simultaneous blockade of the CD28 and CD40 co-stimulatory pathways promotes prolonged survival of skin allografts and xenografts. However, in the long-term the majority of these skin grafts fail over a period of several weeks. This late failure appears to occur via CD4/CD28 independent mechanisms, as prolonged costimulation blockade does not prevent late graft loss. The overall goal of this project is to define the mechanisms involved in costimulation blockade-resistant rejection of skin allografts in mice. We will focus primarily on the most difficult allogeneic combination, BALB/c to B6, in which the co-stimulatory blockade resistant-rejection is most prominent. Our central hypothesis is that CD8+ T cells and possibly NK cells play a pivotal role in co-stimulation blockade-resistant rejection. Furthermore, we hypothesize that 4-1BBL or fasL are important accessory molecules in this process. We believe that by understanding the relevant cells and signaling pathways in these mice we can develop additional strategies to more effectively inhibit allograft rejection. The specific aims of this project are: (1) To determine which lymphocyte subsets contribute to costimulation blockade-resistant rejection; 92) To determine if alternative co-stimulatory mechanisms contribute to CD40 and CD28 blockade-resistant rejection, with particular emphasis on the 4-1BB co- stimulatory pathway; and (3) To determine the role of fas ligand in costimulation blockade-resistant rejection. We will use the knowledge gained from these experiments to direct our efforts to optimize costimulation pathway blockade strategies to induce transplantation tolerance. These studies will first be performed first in mice and then in primates in Project #3 of this Program Project grant.

同时阻碍CD28和CD40联合刺激途径 促进皮肤同种异体移植和异种移植物的长期生存。但是，在 这些皮肤移植物中的大多数在一段时间内失败了 几个星期。这种晚期失败似乎通过CD4/CD28独立发生 机制，因为长时间的共刺激封锁并不能阻止迟到 移植损失。 该项目的总体目标是定义涉及的机制 在小鼠中对皮肤同种异体移植的共刺激封锁抑制作用。我们 将主要关注最困难的同种异体组合，BALB/C 到B6，其中联合刺激性阻滞性拒绝最多 著名的。我们的中心假设是CD8+ T细胞以及可能的NK 细胞在抗封闭阻滞抑制反应中起关键作用。 此外，我们假设4-1BBL或FASL是重要的附件 在此过程中的分子。我们相信，通过了解相关 这些小鼠中的细胞和信号通路，我们可以开发更多 更有效地抑制同种异移植排斥的策略。具体 该项目的目的是：（1）确定哪些淋巴细胞子集 有助于避免封锁的拒绝； 92）确定 如果替代共同刺激机制有助于CD40和CD28 避免封锁的拒绝，特别强调4-1BB的共同 刺激途径； （3）确定FAS配体在 避免封锁的拒绝。我们将使用知识 从这些实验中获得的来指导我们的努力以优化 共刺激途径阻滞策略引起移植 宽容。这些研究将首先在小鼠中首先进行，然后在 该计划项目赠款的项目＃3中的灵长类动物。