ACTIVITY OF EXPANDED GAMMA/DELTA T CELLS

描述 （改编自申请人摘要）T的承诺和问题无处不在 基于细胞的治疗，比骨髓移植（BMT）更清楚。 一方面，T细胞可以诱导潜在的致命移植物抗宿主 在移植物抗宿主病（GVHD）中，它们还能够1）介导移植物抗肿瘤（GVT）， 作用，2）促进造血干细胞（HSC）植入和3） 提供防御病原生物体通常遇到的 后骨髓移植时期。 因此，理想化的T细胞群体将是一个 拥有这些积极的属性，缺乏消极的属性。vs T细胞 一种罕见的T细胞群，其功能在很大程度上是未知的。 很少有研究评价vs T细胞在BMT和现有研究中的作用 呈现相互矛盾的结果。 虽然有些人发现vs T细胞并不 GVHD的发生与T细胞的作用有关，而GVHD的发生与T细胞的作用有关。 此外，研究 提示vs T细胞可能介导GVT，促进HSC植入， 提供对多种病原体的防御。 因此，与T细胞相比， 是过继免疫疗法的有吸引力的候选人群。 鉴于 外周血中vs T细胞缺乏，免疫治疗方法是 如果没有扩大这种稀有种群的方法，这是不切实际的。 我们 最近发现，在体外活化条件下， α/β TCR + CD 8 + T细胞抑制vs T细胞的生长。 与此 信息，我们已经开发出体外扩增大的方法， vs T细胞的数量。 本项目的长期目标是确定 体外扩增的T细胞群是否增加了骨髓的益处 移植 本建议的目的是评估以下方面的作用： 在BMT动物模型中离体扩增的细胞与T细胞。 核心假设 这项工作的一个重要原因是，vs T细胞可以离体扩增， 在后骨髓移植时期，人口的健康提供了重要的益处。 这 假设将通过追求三个具体目标进行测试：1）评估 CD 8 + T细胞对vs T细胞的离体扩增的影响; 2）确定 扩增的vs T细胞的体外生物学特性;和3） 评价扩增的相对于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个罕见的， GVHD、GVT和易化的敏感动物模型中的细胞群 移植。 预计这些研究将提供临床前 关于在BMT后环境中使用扩增的vs T细胞的信息。 这项工作的重要性在于它将研究 CD 8 +T细胞和vs T细胞。 此外，我们将评估T细胞 功能和交通在后BMT设置。 拟议的培训计划 是在一个充满活力的研究环境与广泛的知识和技术 支持. 因此，候选人将获得技能，以确保教师 作为一名儿科骨髓移植临床科学家。

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.