ACTIVITY OF EXPANDED GAMMA/DELTA T CELLS

扩增的 Gamma/Delta T 细胞的活性

基本信息

批准号：
6258622
负责人：
Michael R. Verneris
金额：
$ 12.72万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-04-06 至 2006-03-31
项目状态：
已结题

项目摘要

DESCRIPTION (Adapted from applicant's abstract) Nowhere are the promises and problems of T cell based therapy, clearer than following bone marrow transplantation (BMT). While on the one hand T cells can induce potentially lethal graft vs. host disease (GVHD), they also are capable of 1) mediating graft vs. tumor (GVT) effects, 2) facilitating hematopoietic stem cell (HSC) engraftment and 3) providing defense against pathogenic organisms commonly encountered in the post-BMT period. Thus, an idealized population of T cells would be one possessing these positive attributes and lacking the negative. vs T cells are a rarely occurring population of T cells whose function is largely unknown. Few studies have evaluated the role of vs T cells in BMT and existing studies present conflicting results. While some have found that vs T cells do not cause GVHD, others implicate vs T in pathogenesis of GHVD. Moreover, studies suggest that vs T cells may mediate GVT, facilitate HSC engraftment and provide defense against a variety of pathogens. Thus, vs T cells potentially are an attractive candidate population for adoptive immunotherapy. Given the paucity of vs T cells in the peripheral blood, immunotheraptic approaches are impractical without methods for the expansion of such a rare population. We recently have discovered that under in vitro activation conditions, the outgrowth of vs T cells is inhibited by alpha/betaTCR+CD8+ T cells. With this information, we have developed methodology for the ex vivo expansion of large numbers of vs T cells. The long-range goal of this project is to determine whether ex vivo expanded T cell populations add benefit to bone marrow transplantation. The objective of this proposal is to evaluate the role of ex vivo expanded vs T cells in animal models of BMT. The central hypothesis to this work is that vs T cells can be ex vivo expanded and that such populations provide important benefits in the post-BMT period. This hypothesis will be tested by pursuing three specific aims: 1) to evaluate the effect of CD8+ T cells on the ex vivo expansion of vs T cells; 2) to determine the in vitro biological characteristics of expanded vs T cells; and 3) to evaluate the in vivo biological activity of expanded vs T cells with respect to GVHD, GVT and facilitation of HSC engraftment. The proposed work is innovative because we will be studying and transferring an otherwise rare population of cells in sensitive animal models of GVHD, GVT and facilitation of engraftment. It is expected that these studies will provide preclinical information regarding the use of expanded vs T cells in the post-BMT setting. This work is significant in that it will examine the interactions between CD8+T cells and vs T cells. Further, we will evaluate how vs T cells function and traffic in the post-BMT setting. The proposed training program is in a dynamic research setting with extensive intellectual and technical support. Thus, the candidate will acquire the skills to secure a faculty position as a pediatric bone marrow transplantation clinical-scientist.

描述（改编自申请人的摘要）T的承诺和问题都消失了基于细胞的治疗，比骨髓移植（BMT）更明确。一方面，T 细胞可以诱导移植物对宿主的潜在致命性疾病 (GVHD)，它们还能够 1) 介导移植物抗肿瘤 (GVT) 效果，2) 促进造血干细胞 (HSC) 植入，3) 提供针对常见病原微生物的防御 BMT 后时期。因此，理想化的 T 细胞群将是拥有这些积极的特质而缺乏消极的特质。 vs T 细胞是一种罕见的 T 细胞群体，其功能很大程度上未知。很少有研究评估 VS T 细胞在 BMT 和现有研究中的作用呈现出相互矛盾的结果。虽然有些人发现 VS T 细胞并不引起 GVHD，其他人则认为 T 与 GHVD 的发病机制有关。此外，研究表明 vs T 细胞可能介导 GVT，促进 HSC 植入并提供针对多种病原体的防御。因此，vs T 细胞可能是过继免疫疗法的有吸引力的候选人群。鉴于由于外周血中缺乏 T 细胞，免疫治疗方法如果没有方法来扩大如此稀有的种群是不切实际的。我们最近发现，在体外激活条件下， α/βTCR+CD8+ T 细胞抑制 vs T 细胞的生长。有了这个信息，我们已经开发了大型体外扩增的方法与 T 细胞的数量。该项目的长期目标是确定离体扩增的 T 细胞群是否有利于骨髓移植。该提案的目的是评估在 BMT 动物模型中与 T 细胞进行体外扩增。中心假设这项工作的重点是 VS T 细胞可以离体扩增，并且这样人群在 BMT 后时期提供了重要的好处。这假设将通过追求三个具体目标来检验：1）评估 CD8+ T 细胞对 vs T 细胞离体扩增的影响； 2）确定扩增的 T 细胞的体外生物学特性； 3) 至评估扩增细胞与 T 细胞的体内生物活性 GVHD、GVT 和促进 HSC 植入。拟议的工作是创新，因为我们将研究和转移一种罕见的 GVHD、GVT 和促进敏感动物模型中的细胞群的植入。预计这些研究将提供临床前有关在 BMT 后环境中使用扩增 T 细胞的信息。这项工作意义重大，因为它将研究之间的相互作用 CD8+T 细胞和 vs T 细胞。此外，我们将评估如何与 T 细胞 BMT 后设置中的功能和流量。拟议的培训计划处于充满活力的研究环境中，拥有广泛的知识和技术支持。因此，候选人将获得获得教师资格的技能作为一名儿科骨髓移植临床科学家。