CHARACTERIZATION OF IMMUNOREGULATORY T CELLS POST ALLOGENIC BMT

同种异体 BMT 后免疫调节 T 细胞的表征

• 批准号: 6099462
• 负责人: Chikao Morimoto
• 金额: $ 18.9万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-01 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6099462
• 关键词: CD antigens; T lymphocyte; biological signal transduction; bone marrow transplantation; cellular immunity; graft versus host disease; homologous transplantation; human tissue; leukemia; phosphorylation; surface antigens; tissue /cell culture; transplantation immunology; tyrosine

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.

为了使T细胞活化和随后的功能程序， 发生时，T细胞不仅必须看到外来抗原肽的背景下， 但是它们还必须接收一个“第二信号”， 许多辅助分子，例如CD 28/CTLA-4、CD 5、CD 2、LFA-1， 在T细胞表面表达。我们最近 确定了另外的共刺激分子，CD 26， 其中VLA/CD 29和CD 26均起重要作用 在CD 45 RO + CD 29+记忆T细胞的共刺激中，而CD 27则发挥作用 在CD 45 RA + CD 45 RO-初始T细胞的共刺激中起重要作用。在 在这方面，我们发现从allo-BMT后获得的T细胞 患者表现出T细胞增殖反应的长期损害 由固定的抗CD 3+抗CD 29/VLA β mAb触发，或 与T细胞相比，固定化细胞外基质蛋白（ECM） 从正常的控制。本提案（项目2）的主要目标是 确定免疫调节性T细胞中的细胞和分子缺陷 allo-BMT后的患者。这项建议的具体目标是：1） VLA介导的T细胞共刺激缺陷的分子本质将 被确定。ppl 25 FAK、ppl 05、其他酪氨酸激酶的重建 VLA-4和FAK-1连接诱导的磷酸化蛋白 涉及VLA介导的T细胞共刺激的相关分子将被 研究了此外，VLA介导的T细胞下游事件的缺陷， 将测定细胞共刺激。2)共刺激活性 通过CD 26的记忆T细胞将被确定。免疫重建 CD 26介导的共刺激和CD 26缺陷的分子基础 将研究CD 26介导的共刺激。此外，免疫增强 重组可溶性CD 26对抗原特异性T细胞应答影响 和CMV）和sCD 26/DPPIV水平。 异基因骨髓移植患者血清/血浆水平及其与临床并发症的关系 将被确定。3)初始T细胞的共刺激活性通过 将测定CD 27。CD 27介导的免疫重建 共刺激和CD 27配体在异基因骨髓移植过程中的作用。 此外，在这些患者中，CD 27介导的生化信号传导事件 将被确定。此外，血清/血浆中sCD 27水平和 将确定与allo-BMT临床并发症的相关性。四、 GVHD患者T细胞异常的分子基础 基于上述分子（CD 29/VLA、CD 26和CD 27）的allo-BMT后 将被确定。我们的项目将提供重要的见解， 了解免疫功能障碍的精确分子机制 在allo-BMT之后，以及在allo-BMT之后观察到的GVHD的病理生理学， BMT。更重要的是，这些项目将产生新概念， 发展合理的治疗方法， 这样的病人。