ACTIVITY OF EXPANDED GAMMA/DELTA T CELLS

描述 (改编自申请者的摘要)T的承诺和问题无处可寻 基于细胞的治疗，比骨髓移植(BMT)后更清楚。 一方面，T细胞可以诱导潜在的致命性移植物对宿主 疾病(GVHD)，它们还能够1)调节移植物对肿瘤(GVT) 效果，2)促进造血干细胞(HSC)植入和3) 提供防御常见的致病微生物 BMT后时期。因此，理想化的T细胞群体将是一个 具有这些积极的属性，但缺乏消极的。VS T细胞是 T细胞是一组罕见的T细胞，其功能在很大程度上尚不清楚。 很少有研究和现有研究评估VS T细胞在骨髓移植中的作用 呈现出相互矛盾的结果。虽然有些人发现VS T细胞不是 引起GVHD，也有人认为VS T参与了GHVD的发病机制。此外，研究 提示VS T细胞可能介导GVT，促进HSC植入 对各种病原体提供防御。因此，VS T细胞有可能 是过继免疫治疗的有吸引力的候选人群。给定 外周血中VS T细胞的缺乏，免疫治疗方法是 如果没有方法来扩大如此稀有的人口是不切实际的。我们 最近发现，在体外激活条件下， VS T细胞的生长受α/βTCR+CD8+T细胞的抑制。有了这个 信息，我们已经开发了大鼠体外扩增的方法学 VS T细胞数。这个项目的长期目标是确定 体外扩增的T细胞是否有益于骨髓 移植。这项提案的目标是评估 骨髓移植动物模型中体外扩增的VS T细胞。中心假说 这项工作是VS T细胞可以体外扩增，这样就可以 人口在后BMT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细胞体外扩增的影响 扩增的VS T细胞的体外生物学特性； 从以下方面评价扩增的VS T细胞的体内生物学活性 对移植物抗宿主病、移植物抗宿主病和促进造血干细胞移植的作用。建议的工作是 创新是因为我们将研究和转移一种原本很少见的 移植物抗宿主病、移植物抗宿主病和易化动物模型中的细胞群 关于嫁接的。预计这些研究将为临床前提供 有关在骨髓移植后设置中使用扩增的VS T细胞的信息。 这项工作具有重要意义，因为它将研究 CD8+T细胞和VS T细胞。此外，我们将评估VS T细胞如何 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，拥有广泛的智力和技术 支持。因此，应聘者将获得获得教员的技能 儿科骨髓移植临床科学家的职位。

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.