Naive T cell depletion to prevent graft-versus-host disease

描述(申请人提供)：异基因造血细胞移植(HCT)经常治愈许多其他致命的恶性和非恶性疾病。然而，单纯使用药物免疫抑制的传统T细胞充盈型HCT常常会并发移植物抗宿主病(GVHD)。16%的HCT受者可归因于GVHD的死亡，而在大多数中重度慢性GVHD患者中，40%的HCT受者的生活质量受到极大影响。此外，长期的移植物抗宿主病排除了使用T细胞免疫疗法来预防或控制血细胞移植后白血病复发的可能性。T细胞耗竭是目前免疫抑制药物的唯一替代药物，虽然对预防GVHD有效，但免疫恢复缓慢和机会性感染的发生率较高。该项目的目标是开发一种改进的HCT策略来预防GVHD，提供病原体特异性免疫的快速重建，并促进未来在没有免疫抑制药物的情况下减少复发的免疫治疗方法。包括我们的合作者W.Shlomchik在内的几个小组在小鼠模型上进行的临床前研究表明，移植纯化的同种异体记忆T细胞(TM)比移植NA�ve(TN)或未分离的T细胞引起的移植物抗宿主病更少。在这些研究的启发下，我们启动了一项人类首例临床试验，以评估选择性去除异基因PBSC移植物中的TN联合他克莫司单一治疗是否可以消除GVHD并保护急性白血病匹配亲属供者(MRD)HCT受者的免疫重建。我们的初步数据显示，干细胞可重复植入，轻度胃肠道急性移植物抗宿主病，慢性移植物抗宿主病的发生率非常低，病原体特异性免疫迅速重建，低水平的复发和与治疗相关的死亡率和高总存活率。在这里，我们试图改进这些令人兴奋的MRD受者TN耗竭的初步结果，并将这一方法扩展到匹配的无关供者(MUT)的HCT。拟议的临床试验将得到详细的相关和机械性实验室研究的补充，包括对免疫能力的深入分析，以及评估受者胃肠道免疫渗透和肠道干细胞损伤的潜在差异的研究。 TN耗尽和T细胞充盈的红细胞压积。拟议的研究结果有可能减少GVHD和免疫抑制的持续时间，这将从根本上改变我们对同种异体MRD和MUD HCT的方法，并为深入了解急性GVHD的发病机制提供依据。研究的具体目的是：1.确定去除外周血单核细胞移植中的TN后加用他克莫司和短程甲氨蝶呤是否能减少MRD和MUD HCT受者的移植物抗宿主病。2.评估TN耗竭和T细胞充盈的HCT受者的病原体特异性和调节性T细胞的重建、T细胞受体的多样性和对新抗原的免疫应答。3.对浸润性T细胞和肠道干细胞的评价 移植物抗宿主病患者TN耗尽和T细胞充填的受者的细胞损伤。

DESCRIPTION (provided by applicant): Allogeneic hematopoietic cell transplantation (HCT) is frequently curative for many otherwise fatal malignant and nonmalignant diseases. However, conventional T cell-replete HCT using pharmacological immunosuppression alone is often complicated by graft versus host disease (GVHD). Mortality attributed to GVHD occurs in 16% of HCT recipients and quality of life is greatly compromised in most patients with moderate or severe chronic GVHD that occurs in 40% of HCT recipients. Moreover, prolonged GVHD precludes the use of T cell immunotherapy to prevent or manage recurrence of leukemia following HCT. T cell depletion is the only current alternative to immunosuppressive drugs and, although effective for preventing GVHD, is complicated by slow immune recovery and high rates of opportunistic infection. The objective of the project is to develop an improved HCT strategy to prevent GVHD, provide for rapid reconstitution of pathogen-specific immunity, and facilitate future immunotherapeutic approaches to reduce relapse in the absence of immunosuppressive drugs. Preclinical studies in murine models by several groups, including by our co-investigator W. Shlomchik, have demonstrated that transplant of purified allogeneic memory T cells (TM) caused less GVHD than did na�ve (TN) or unfractionated T cells. Informed by these studies, we initiated a first-in-human clinical trial to evaluate whether selective depletion of TN from allogeneic PBSC grafts combined with tacrolimus monotherapy could abrogate GVHD and preserve immune reconstitution in recipients of matched related donor (MRD) HCT for acute leukemia. Our preliminary data demonstrates reproducible stem cell engraftment, mild gastrointestinal acute GVHD, a very low incidence of chronic GVHD, rapid reconstitution of pathogen-specific immunity, low levels of relapse and treatment-related mortality and high overall survival. Here, we seek to improve upon these exciting initial results of TN depletion in MRD recipients, and extend this approach to matched unrelated donor (MUD) HCT. The proposed clinical trial will be complemented by detailed correlative and mechanistic laboratory studies, including an in-depth analysis of immune competence and studies to evaluate potential differences in gastrointestinal immune infiltrates and intestinal stem cell damage in recipients of TN-depleted and T cell-replete HCT. The results of the proposed studies have the potential to reduce GVHD and the duration of immunosuppression, which would fundamentally change our approach to allogeneic MRD and MUD HCT, and to provide insight into the pathogenesis of acute GVHD. The specific aims are: 1. To determine whether depletion of TN from PBSC grafts followed by tacrolimus and a short course of methotrexate can reduce GVHD in MRD and MUD HCT recipients. 2. To evaluate reconstitution of pathogen-specific and regulatory T cells, T cell receptor diversity, and immune responses to new antigens delivered by vaccination in TN-depleted and T cell-replete HCT recipients. 3. To evaluate infiltrating T cells and intestinal stem cell damage in recipients of TN-depleted and T cell-replete HCT with GVHD.