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

描述（由申请人提供）：异基因造血细胞移植（HCT）通常可治愈许多其他致命的恶性和非恶性疾病。然而，传统的T细胞充满HCT使用单独的药物免疫抑制剂往往是复杂的移植物抗宿主病（GVHD）。归因于GVHD的死亡率发生在16%的HCT接受者中，并且生活质量在大多数患有中度或重度慢性GVHD的患者中大大受损，所述中度或重度慢性GVHD发生在40%的HCT接受者中。此外，延长的GVHD排除了使用T细胞免疫疗法来预防或管理HCT后白血病复发。T细胞耗竭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，以减少在没有免疫抑制药物的情况下的复发。几个小组在小鼠模型中进行的临床前研究，包括我们的共同研究者W。Shlomchik等人已经证明，移植纯化的同种异体记忆T细胞（TM）比未处理（TN）或未分级的T细胞引起更少的GVHD。根据这些研究，我们启动了一项首次人体临床试验，以评估从异基因PBSC移植物中选择性消耗TN联合他克莫司单药治疗是否可以消除GVHD并保护急性白血病匹配相关供体（MRD）HCT受体的免疫重建。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，慢性GVHD的发生率非常低，病原体特异性免疫的快速重建，低水平的复发和治疗相关的死亡率和高的总生存率。在这里，我们试图改善这些令人兴奋的MRD受体中TN耗竭的初步结果，并将这种方法扩展到匹配的非相关供体（MUD）HCT。拟议的临床试验将通过详细的相关和机制实验室研究进行补充，包括深入分析免疫能力和研究，以评估接受者胃肠道免疫浸润和肠道干细胞损伤的潜在差异。 TN耗尽和T细胞充满的HCT。所提出的研究的结果有可能减少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，并提供对急性GVHD发病机制的见解。具体目标是：1.确定在MRD和MUD HCT受者中，从PBSC移植物中去除TN，然后使用他克莫司和短期甲氨蝶呤是否可以减少GVHD。2.评价病原体特异性和调节性T细胞的重建、T细胞受体多样性以及对TN耗尽和T细胞充满的HCT受者中通过疫苗接种递送的新抗原的免疫应答。3.评估浸润的T细胞和肠干细胞 TN耗尽和T细胞充满的HCT伴GVHD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.