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转移T细胞介导的有益作用而不引起移植物抗宿主病（GVHD）。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，而不会引起GVHD。本申请的目的是进一步表征和发展我们的中心假设，即记忆T细胞不会引起严重的GVHD。我们还假设记忆T细胞具有提供强大的抗感染和抗恶性肿瘤活性的潜力。在强有力的初步数据的指导下，该假设将通过追求三个具体目标来检验：1）描绘记忆T细胞诱导GVHD的能力降低的机制; 2）确定记忆T细胞诱导GVHD的能力降低的机制。 记忆T细胞的抗肿瘤潜力;和3）使用记忆T细胞进行I期临床试验以促进免疫恢复而不诱导GVHD。根据第一个目标，记忆T细胞诱导GVHD的能力下降的机制将使用一个经典的和一个新的GVHD模型异源特异性转基因T细胞介导的研究。在第二个目标下，我们将 分析记忆T细胞的抗肿瘤活性，并测试是否可以通过接种供体来增强抗肿瘤活性。在最后一个目标下，我们将确定向单倍体相合异基因造血细胞移植受者输注幼稚T细胞耗尽的供体淋巴细胞的安全性。还将研究对移植后免疫恢复的影响。这项研究是使用这种创新方法预防人类GVHD的重要一步。这项研究具有重要意义，因为这种方法具有很大的潜力，以提高安全性和扩大异基因造血细胞移植的范围和有效性。预计这些结果将从根本上推进对记忆T细胞如何响应同种异体抗原的理解。

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.