Reconstitution of Regulatory T Cells After Stem Cell Transplantation

干细胞移植后调节性 T 细胞的重建

基本信息

批准号：
8710123
负责人：
JEROME RITZ
金额：
$ 48.5万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8710123
关键词：
Allogenic Apoptosis Autologous Cell Vaccine B-Lymphocytes Cancer Vaccines Cells Chronic Clinical Clinical Trials Clinical Trials Design Complex Dendritic Cells Development Dose Elements Failure Frequencies Future Generations Goals Graft Enhancements Hematologic Neoplasms Hematopoietic Stem Cell Transplantation Homeostasis Human Immune Tolerance Immunity Immunologics Infection Infusion procedures Instruction Interleukin-2 Intervention Laboratories Laboratory Study Lead Link Maintenance Methods Natural Killer Cells Outcome Pathway interactions Patients Peripheral Play Predisposition Principal Investigator Process Refractory Regulatory T-Lymphocyte Relapse Risk Role Safety Signal Pathway Signal Transduction Stem cell transplant Steroid Resistance T-Lymphocyte Transplant Recipients Transplantation Tumor Immunity Vaccination chronic graft versus host disease design graft vs host disease immune function improved in vivo leukemia neoplastic cell novel strategies reconstitution research study treatment effect tumor

项目摘要

Reconstitution of normal CD4 Treg.after allogeneic HSCT provides a unique opportunity to examine and define critical elements that modulate human Treg proliferation, function and survival in vivo. The generation and maintenance of Treg function in vivo is known to be a dynamic process that is subject to complex homeostatic signals. In the context of allogeneic HSCT, deficiencies of Treg can lead to enhancement of graft versus leukemia (GVL) as well as auto-immunity and allo-immunity. Conversely, excessive Treg function can suppress GVL, increase relapse and increase susceptibility to infections. We have previously demonstrated that patients with chronic GVHD had significantly reduced frequency of Treg, Impaired Treg reconstitution in these patients was linked to specific abnormalities of Treg homeostasis in the first year post transplant, including decreased thymic generation of naive Treg, increased proliferation and increased susceptibility to apoptosis. We also demonstrated that expansion of CD4 Treg in vivo could be achieved by administration of IL-2 and completed a clinical trial of daily low-dose IL-2 in patients with refractory cGVHD. Our results suggest that low-dose lL-2 is safe in patients with active cGVHD and results in the selective expansion of CD4 Treg in vivo. Expanded Treg express FoxP3 and retain functional suppressive activity. The majority of patients treated with IL-2 noted improvement or stabilization of cGVHD. In the next 5 years. Project 3 will continue to focus on the reconstitution of Treg after allogeneic HSCT with the major goal of defining critical mechanisms that modulate Treg homeostasis in vivo. In conjunction with clinical trials designed to modulate Treg number and function after HSCT (Project 1), detailed analysis of the immunologic effects of these manipulations will lead to a better understanding of the mechanisms that control Treg homeostasis. These studies will inform the design of further clinical trials to modulate Treg function in vivo in the context of allogeneic HSCT with the goal of developing novel strategies for selectively enhancing tumor immunity, suppressing allo-immunity and improving patient outcomes. These experiments will be carried out in 4 Specific Aims: 1) To define abnormalities of Treg homeostasis that contribute to loss of tolerance and development of chronic GVHD after allogeneic HOT. 2) To identify cellular mechanisms andVsignaling pathways that modulate Treg generation, proliferation and survival in vivo. 3) To define the effects of lL-2 therapy and donor Treg infusion on Treg homeostasis after allogeneic HOT. 4) To examine effects of tumor cell vaccination and other post-transplant immunologic interventions on Treg in vivo. RELEVANCE (See instructions): This project focuses on the reconstitution of donor CD4+ regulatory T cells (Treg) after allogeneic hematopoietic stem cell transplantation (HSCT). These cells are essential for establishing and maintaining immune tolerance and therefore play an important role in allo-immunity and tumor immunity. Clinical trials designed to modulate these cells in vivo are already in place and studies in this project will define the effects of these treatments on Treg in patients after HSCT.

同种异体 HSCT 后正常 CD4 Treg 的重建提供了一个独特的机会来检查和定义调节人 Treg 体内增殖、功能和存活的关键元件。一代人众所周知，体内 Treg 功能的维持是一个动态过程，受到复杂的影响稳态信号。在同种异体 HSCT 的背景下，Treg 的缺陷可能导致移植物抗白血病（GVL）以及自身免疫和同种免疫。相反，过多的Treg 功能可抑制GVL，增加复发并增加感染的易感性。我们之前有过证明慢性 GVHD 患者的 Treg 频率显着降低，Treg 受损这些患者的重建与术后第一年 Treg 稳态的特定异常有关移植，包括减少胸腺中幼稚 Treg 的生成、增加增殖和增加细胞凋亡的易感性。我们还证明了 CD4 Treg 在体内的扩增可以通过以下方式实现给予IL-2并完成了每日低剂量IL-2治疗难治性cGVHD患者的临床试验。我们的结果表明，低剂量 lL-2 对于活动性 cGVHD 患者是安全的，并导致选择性 CD4 Treg 在体内的扩增。扩增的 Treg 表达 FoxP3 并保留功能性抑制活性。大多数接受 IL-2 治疗的患者注意到 cGVHD 得到改善或稳定。未来5年。项目3将继续关注同种异体HSCT后Treg的重建，主要目标是定义体内调节 Treg 稳态的关键机制。结合临床试验旨在调节 HSCT 后 Treg 数量和功能（项目 1），详细分析免疫学这些操作的效果将有助于更好地理解控制 Treg 的机制体内平衡。这些研究将为进一步的临床试验设计提供信息，以在体内调节 Treg 功能。同种异体 HSCT 的背景下，目标是开发选择性增强肿瘤的新策略免疫力，抑制同种免疫并改善患者的预后。这些实验将进行 4 个具体目标： 1) 定义导致耐受性丧失和 Treg 稳态异常的因素同种异体 HOT 后慢性 GVHD 的发展。 2) 识别细胞机制和V信号传导体内调节 Treg 生成、增殖和存活的途径。 3) 定义lL-2的效果同种异体 HOT 后治疗和供体 Treg 输注对 Treg 稳态的影响。 4) 检查肿瘤的影响体内 Treg 细胞疫苗接种和其他移植后免疫干预。相关性（参见说明）：该项目重点关注同种异体后供体 CD4+ 调节性 T 细胞 (Treg) 的重建造血干细胞移植（HSCT）。这些细胞对于建立和维持免疫耐受因此在同种免疫和肿瘤免疫中发挥重要作用。临床试验用于在体内调节这些细胞的设计已经到位，该项目的研究将确定其效果 HSCT 后患者对 Treg 的这些治疗。