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

描述（由申请人提供）：同种异体造血细胞移植（HCT）是许多其他致命的恶性和非恶性疾病的常用治疗方法。然而，仅使用药物免疫抑制的常规T细胞填充HCT常常并发移植物抗宿主病（GVHD）。16%的HCT受者死于GVHD， 40%的HCT受者患有中度或重度慢性GVHD，大多数患者的生活质量严重受损。此外，长期GVHD排除了使用T细胞免疫疗法来预防或控制HCT后白血病复发的可能性。T细胞耗损是目前免疫抑制药物的唯一替代方案，尽管对预防GVHD有效，但由于免疫恢复缓慢和机会性感染率高而变得复杂。该项目的目标是开发一种改进的HCT策略，以预防GVHD，提供病原体特异性免疫的快速重建，并促进未来的免疫治疗方法，以减少在缺乏免疫抑制药物的情况下复发。包括我们的合作研究者W. Shlomchik在内的几个研究小组在小鼠模型中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）比单纯（TN）或未分离的T细胞引起的GVHD更少。根据这些研究，我们启动了一项首次人体临床试验，以评估同种异体PBSC移植物选择性去除TN联合他克莫司单药治疗是否可以消除GVHD并保持匹配相关供体（MRD） HCT治疗急性白血病患者的免疫重建。我们的初步数据表明，可重复的干细胞移植，轻度胃肠道急性GVHD，非常低的慢性GVHD发病率，病原体特异性免疫的快速重建，低水平的复发和治疗相关死亡率以及高的总生存率。在这里，我们寻求改进这些令人兴奋的MRD受体TN消耗的初步结果，并将这种方法扩展到匹配的非亲属供体（MUD） HCT。拟议的临床试验将辅以详细的相关和机制实验室研究，包括对免疫能力的深入分析和研究，以评估胃肠道免疫浸润和肠道干细胞损伤的潜在差异

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.