ACTIVITY OF EXPANDED GAMMA/DELTA T CELLS

扩增的 Gamma/Delta T 细胞的活性

• 批准号: 6536671
• 负责人: Michael R. Verneris
• 金额: $ 9.25万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-06 至 2002-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6536671
• 关键词: CD8 molecule; T cell receptor; T lymphocyte; antineoplastics; biological models; bone marrow transplantation; cell cell interaction; cell growth regulation; cell mediated cytotoxicity; cell population study; cell proliferation; computer data analysis; cytokine; flow cytometry; gene expression; graft versus host disease; hematopoietic stem cells; human tissue; immunocytochemistry; laboratory mouse; leukemia; model design /development; neoplasm /cancer immunotherapy; nonhuman therapy evaluation; pore forming protein; surface antigens

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 （根据申请人的摘要改编） 基于细胞的疗法，比跟随骨髓移植（BMT）更清晰。 一方面，T细胞可以诱导潜在的致命移植物与宿主 疾病（GVHD），它们也能够1）介导移植物与肿瘤（GVT） 效果，2）促进造血干细胞（HSC）植入和3） 提供针对常见的致病生物的防御 BMT后期。 因此，理想的T细胞群体将是一个 拥有这些积极的属性，缺乏负面属性。与T细胞是 很少发生的T细胞群体的功能在很大程度上未知。 很少有研究评估了与T细胞在BMT和现有研究中的作用 目前的结果矛盾。 虽然有些人发现与T细胞没有 原因GVHD，其他人则与GHVD的发病机理有关。 而且，研究 表明VS T细胞可能介导GVT，促进HSC植入和 为各种病原体提供防御。 因此，与T细胞有可能 是一种有吸引力的候选人群，用于采纳免疫疗法。 鉴于 在外周血中的缺乏与T细胞，免疫治疗方法是 不切实际，没有方法可以扩大如此罕见的人群。 我们 最近发现，在体外激活条件下 α/betatcr+ CD8+ T细胞抑制与T细胞的生长。 与此 信息，我们已经开发了用于体内扩展大型的方法论 与T细胞的数量。 该项目的远程目标是确定 离体扩展的T细胞种群是否为骨髓增加了好处 移植。 该提议的目的是评估 在BMT动物模型中，体内扩展了与T细胞。 中心假设 这项工作是可以在体内扩展与T细胞，因此 人口在BMT后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细胞对与T细胞的离体扩展的影响； 2）确定 扩展的T细胞的体外生物学特征；和3）到 评估扩展的与T细胞的体内生物学活性 进行GVHD，GVT和HSC植入的促进。 拟议的工作是 创新的，因为我们将研究和转移原本罕见的 GVHD，GVT和促进的敏感动物模型中的细胞种群 植入。 预计这些研究将提供临床前 有关在BMT后设置中使用扩展的与T细胞使用的信息。 这项工作很重要，因为它将检查 CD8+T细胞和与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 在动态的研究环境中，具有广泛的智力和技术 支持。 因此，候选人将获得确保教师的技能 作为小儿骨髓移植临床科学家的位置。