Prevention of GVHD by Depletion of Naive T Cells

异基因造血细胞移植的一个主要挑战是如何在不引起移植物抗宿主病(GVHD)的情况下转移T细胞介导的有益效应。我们的长期目标是开发一种临床相关的策略，允许转移针对恶性肿瘤和感染性病原体的同种异体T细胞免疫，而不会导致GVHD。这项申请的目的是为了进一步表征和发展我们的核心假设，即记忆T细胞不会导致严重的GVHD。我们还假设记忆T细胞具有提供强大的抗感染和抗肿瘤活性的潜力。在强大的初步数据的指导下，这一假说将通过追求三个具体目标来检验：1)描绘记忆T细胞诱发移植物抗宿主病的能力降低的机制；2)确定 记忆T细胞的抗肿瘤潜力；以及3)在没有GVHD诱导的情况下，使用记忆T细胞促进免疫恢复的I期临床试验。在第一个目标下，我们将使用一种经典的和一种新的由同种异体特异性转基因T细胞介导的GVHD模型来研究记忆T细胞诱发GVHD的能力降低的机制。在第二个目标下，我们将 分析记忆T细胞的抗肿瘤活性，并测试供者接种疫苗是否能增强其抗肿瘤活性。在最后一个目标下，我们将确定单纯T细胞耗尽供者淋巴细胞输注给半相合异基因造血细胞移植受者的安全性。对移植后免疫恢复的影响也将被研究。这项拟议的研究是朝着使用这种创新方法预防人类移植物抗宿主病迈出的重要一步。这项研究具有重要意义，因为这种方法在提高异基因造血细胞移植的安全性、拓宽范围和有效性方面具有巨大的潜力。预计这一结果将从根本上促进记忆T细胞如何对同种异体抗原做出反应的理解。

A major challenge in allogeneic hematopoietic cell transplantation is how to transfer the beneficial effects mediated by T cells without causing graft-versus-host disease (GVHD). Our long-term goal is to develop a clinically relevant strategy that allows transfer of allogeneic T-cell immunity against malignancies and infectious pathogens without causing GVHD. The objective of this application, which is the next step toward achieving this goal, is to further characterize and develop our central hypothesis that memory T cells do not cause severe GVHD. We also hypothesize that memory T cells have the potential to provide robust anti-infective and anti-malignancy activity. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1)To delineate the mechanism by which memory T cells have decreased ability to induce GVHD; 2)To determine the anti-tumor potential of memory T cells; and 3)To conduct a Phase I clinical trial using memory T cells to promote immune recovery without GVHD induction. Under the first aim, the mechanism by which memory T cells have decreased ability to induce GVHD will be studied using both a classic and a novel GVHD model mediated by allospecific transgenic T cells. Under the second aim, we will analyze the anti-tumor activity of memory T cells and test whether the anti-tumor activity can be enhanced by vaccination of the donor. Under the last aim, we will determine the safety of a naive T-cell depleted donor lymphocyte infusion given to recipients of haploidentical allogeneic hematopoietic cell transplantation. The impact on post-transplant immune recovery will also be studied. The proposed research is an important step toward use of this innovative approach for prevention of GVHD in humans. The proposed research is significant, because this approach has great potential to improve the safety and to broaden the scope and effectiveness of allogeneic hematopoietic cell transplantation. It is also expected that the results will fundamentally advance the understanding of how memory T cells respond to alloantigens.