Reconstitution of Regulatory T Cells After Stem Cell Transplantation

干细胞移植后调节性 T 细胞的重建

• 批准号: 8656486
• 负责人: JEROME RITZ
• 金额: $ 50万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 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/8656486
• 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

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.

异基因造血干细胞移植后正常CD4Treg.的重建提供了一个独特的机会来检查和 确定调节人类Treg在体内的增殖、功能和存活的关键要素。这一代人 而Treg功能在体内的维持是一个动态的过程，受到复杂的 动态平衡信号。在同种异体造血干细胞移植的背景下，Treg的缺陷可导致 移植物抗白血病(GVL)以及自身免疫和同种异体免疫。相反，过度的Treg 功能可以抑制GVL，增加复发和增加感染的易感性。我们之前已经 显示慢性移植物抗宿主病患者的Treg频率显著降低，Treg受损 这些患者的重建与术后第一年的Treg稳态的特殊异常有关 移植，包括减少胸腺生成的幼稚Treg，增加增殖和增加 对细胞凋亡易感性。我们还证明了在体内扩增CD4 Treg可以通过以下方式实现 应用IL-2治疗难治性慢性移植物抗宿主病(CGVHD)，并完成每日小剂量IL-2的临床试验。 我们的结果表明，小剂量的IL-2对活动期cGVHD患者是安全的，并导致选择性 CD4Treg在体内的扩增。扩增的Treg表达FoxP3并保留功能抑制活性。 大多数接受IL-2治疗的患者注意到cGVHD的改善或稳定。在未来5年内。 项目3将继续侧重于异基因造血干细胞移植后Treg的重建，主要目标是 确定调节体内Treg动态平衡的关键机制。结合临床试验 旨在调节HSCT后Treg数量和功能(项目1)，详细分析了 这些操作的效果将使我们更好地理解控制Treg的机制 动态平衡。这些研究将为在体内调节Treg功能的进一步临床试验的设计提供信息。 同种异体造血干细胞移植的背景和目标是开发选择性增强肿瘤的新策略 免疫，抑制同种免疫，改善患者预后。这些实验将会进行 在4个具体目标中：1)定义导致耐受性丧失和 同种异体热后慢性移植物抗宿主病的发生。2)确定细胞机制和V信号 在体内调节Treg生成、增殖和存活的途径。3)定义LL-2的影响 治疗和供者Treg输注对同种异体热后Treg动态平衡的影响。4)检查肿瘤的影响 体内Treg的细胞疫苗接种和其他移植后免疫干预。 相关性(请参阅说明)： 本项目主要研究同种异体移植后供者CD4+调节性T细胞(Treg)的重建。 造血干细胞移植。这些细胞对于建立和维持 因此，免疫耐受在同种免疫和肿瘤免疫中起着重要作用。临床试验 用于在体内调节这些细胞的设计已经到位，该项目中的研究将确定这些影响 对造血干细胞移植后患者的Treg的治疗。