CHARACTERIZATION OF IMMUNOREGULATORY T CELLS POST ALLOGENIC BMT

为了T细胞的激活和后续的功能程序 发生时，T细胞不能只看到外源抗原肽在上下文中 但他们还必须接收到一个“第二信号”，这个信号可以由 一些辅助分子如CD28/CTLA-4，CD5，CD2，LFA-1， 它们表达在T细胞的表面。我们最近做了 确定了其他共刺激分子CD26的身份， VLA/CD29和CD27，其中VLA/CD29和CD26都起重要作用 在CD45RO CD29记忆T细胞的共刺激中，而CD27在 CD45RA-CD45RO-初始T细胞共刺激中的重要作用在……里面 对此，我们发现从异基因骨髓移植后获得的T细胞 患者表现为T细胞增殖反应长期受损 由固定化抗CD3+抗CD29/VLAbeta单抗触发或 固定化细胞外基质蛋白与T细胞的比较 来自正常对照组。该提案(项目2)的主要目标是 确定免疫调节性T细胞的细胞和分子缺陷 在异基因骨髓移植后的患者。这项建议的具体目的是：1) VLA介导的T细胞共刺激Will缺陷的分子本质 要下定决心。Ppl 25FAK，ppl 05，其他酪氨酸的重组 VLA-4和FAK-4连接诱导的磷酸化蛋白 参与VLA介导的T细胞共刺激的相关分子将是 学习。此外，VLA介导的T细胞下游事件的缺陷 细胞共刺激作用将被确定。2)共刺激活性 通过CD26的记忆T细胞将被确定。免疫重建 CD26介导的共刺激作用及其缺陷的分子基础 CD26介导的共刺激作用将被研究。此外，免疫增强 重组可溶性CD26对抗原特异性T细胞应答的影响 和巨细胞病毒)和sCD26/DPPIV水平 血清/血浆及其与异基因骨髓移植临床并发症的关系 将会被确定。3)幼稚T细胞的共刺激活性 CD27将被确定。CD27介导的免疫重建 将对异基因骨髓移植过程中的共刺激作用和CD27-配体进行研究。 此外，CD27介导了这类患者的生化信号事件。 将会被确定。此外，血清/血浆中sCD27水平和 将确定与allo-BMT临床并发症的相关性。4) 移植物抗宿主病患者T细胞异常的分子基础 基于上述分子(CD29/VLA、CD26和CD27)的allo-BMT 将会被确定。我们的项目将为 了解免疫功能障碍的确切分子机制 异基因骨髓移植后以及移植后GVHD的病理生理学 北京时间。更重要的是，这些项目将产生新的概念 开发合理的治疗方法来处理发现的缺陷 这样的病人。

In order for T cell activation and subsequent functional programs to occur, T cells must not only see foreign antigen peptide in the context of MHC but they must also receive a "second signal" which can be provided by a number of accessory molecules such as CD28/CTLA-4, CD5, CD2, LFA-1, which are expressed on the surface on the T cell. We have recently established the identity of additional costimlatory molecules, CD26, VLA/CD29 and CD27 in which both VLA/CD29 and CD26 play an important role in the costimulation of CD45RO+CD29+ memory T cells, whereas CD27 plays an important role in the costimulation of CD45RA+ CD45RO- naive T cells. In this regard, we found that the T cells obtained from post allo-BMT patients exhibited prolonged impairment of T cell proliferative response triggered by immobilized anti-CD3 plus anti-CD29/VLAbeta mAb or immobilized extracellular matrix proteins (ECMs) compared with T cells from normal controls. The major goal of this proposal (project 2) is to determine the cellular and molecular defects in immunoregulatory T cells in patients after allo-BMT. The specific aims of this proposal are: 1) The molecular nature of the defect of VLA-mediated T cell costimulation will be determined. The reconstitution of ppl 25FAK, ppl 05, other tyrosine phosphorylated proteins induced by ligation of VLA-4 and that of FAK- associated molecules involved in VLA mediated T cell costimulation will be studied. Moreover, the defect of the downstream events of VLA-mediated T cell costimulation will be determined. 2) The costimulatory activity of memory T cells via the CD26 will be determined. The immune reconstitution of CD26 mediated costimulation and the molecular basis for the defect of CD26 mediated costimulation will be studied. Moreover, the immunoenhancing effect of recombinant soluble CD26 on antigen-specific T cell response (TT and CMV) in allo-BMT patients and the levels of sCD26/DPPIV in serum/plasma and its correlation with clinical complications of allo-BMT will be determined. 3) The costimulatory activity of naive T cells via the CD27 will be determined. The immune reconstitution of CD27 mediated costimulation and CD27-ligand in the course of allo-BMT will be studied. Moreover, the CD27 mediated biochemical signaling events in such patients will be determined. In addition, the levels of sCD27 in serum/plasma and correlation with clinical complication of allo-BMT will be determined. 4) The molecular basis for T cell abnormalities in patients with GVHD following allo-BMT based on the above molecules (CD29/VLA, CD26 and CD27) will be determined. Our projects would provide important insights into understanding the precise molecular mechanisms of immune dysfunction following allo-BMT as well as the pathophysiology of GVHD seen after allo- BMT. More importantly, these projects will yield new concepts for developing rational therapy for the manipulation of the defects found in such patients.