Separation of GVH and GVL Responses Using Alloreactive CD8 iTregs

使用同种异体反应性 CD8 iTreg 分离 GVH 和 GVL 反应

• 批准号: 9333524
• 负责人: Xue-Zhong Yu
• 金额: $ 38.57万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9333524
• 关键词: Acute Graft Versus Host Disease; Adoptive Transfer; Alloantigen; Allogeneic Bone Marrow Transplantation; Allogenic; Animal Model; Antigens; Benign; Biological Preservation; Bone Marrow Transplantation; C3AR1 gene; CD8B1 gene; Cancer Etiology; Clinical; Clinical Trials; Combined Modality Therapy; Complement Receptor; Complex; Complication; Cytokine Signaling; Data; Disease; Effectiveness; Engraftment; FOXP3 gene; Future; Goals; Hematologic Neoplasms; Hematopoietic; Human; IL2RA gene; Immunosuppression; Impairment; In Vitro; Infection; Inflammatory; Interleukin-2; Knowledge; Lymphoid Tissue; Malignant - descriptor; Mediating; Modeling; Molecular; Morbidity - disease rate; Mus; Patients; Peripheral; Prevention; Reaction; Regulatory T-Lymphocyte; Relapse; Research; Sirolimus; Specificity; Stem cells; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Therapeutic Effect; Transplant Recipients; Transplantation; Xenograft procedure; clinical practice; design; graft vs host disease; hematopoietic cell transplantation; immunoregulation; improved; leukemia; mortality; mouse model; pre-clinical; preclinical study; prevent; response; tumor

Hematopoietic cell transplantation (HCT) can cure a variety of benign and malignant hematopoietic disorders, but graft-versus-host disease (GVHD) remains the primary cause of transplant-related morbidity and mortality, thereby limiting the therapeutic potential of allogeneic HCT. Donor T cells that are included in the stem cell inoculums and recognize widely distributed recipient alloantigens cause GVHD, but these T cells are also beneficial by facilitating stem cell engraftment and mediating graft-versus-leukemia (GVL) effects. Therefore, an ideal approach to prevent GVHD is to selectively inactivate alloreactive T cells specific for broadly expressed alloantigens, while sparing T cells with other specificities. A dominant mechanism of tolerance mediated by regulatory T cells (Tregs) has obvious therapeutic implications in preventing GVHD. To apply Tregs in clinical HCT, current approaches are focused on adoptive transfer of polyclonal, ex vivo-expanded Tregs to transplant recipients, before or after the HCT. However, these polyclonal Tregs are expected to have a low potency in controlling GVHD and provide non-selective immune suppression thereby negating separation of GVH and GVL reactions. We demonstrate that antigen- specific Tregs are far superior to polyclonal Tregs in the prevention of acute GVHD in pre-clinical BMT models. These preclinical studies provide rationale to support the first clinical trial in testing host-alloantigen reactive Tregs in GVHD. Although host-alloantigen reactive CD4 iTregs are highly effective in controlling GVHD, they may impair the GVL effect as well. While the project is a continuum of our current research, we will shift our focus more on alloreactive CD8 iTregs, because this is Treg subset recently discovered and because they have the potential to spare or even enhance the GVL effect. Our long-term goal is to use alloantigen-reactive Tregs to prevent GVHD while preserving the GVL effect after HCT in humans. The objective of this proposal is to test effective and translatable strategies to achieve this goal in pre-clinical murine models of allogeneic BMT. As strongly supported by our preliminary data, we hypothesize that the control of GVHD while preserving the GVL activity can be achieved by a combinational therapy with allo- reactive CD4 and CD8 iTregs, or by a singular therapy with stabilized CD8 iTregs. We plan to test our hypothesis and accomplish the objective by pursuing two Specific Aims: 1) To establish the combinational therapy with CD4 and CD8 iTregs for the control of GVHD and tumor relapse; 2) To enhance the stability and potential of CD8 iTregs in the prevention of GVHD. If the aims of this project are achieved, the acquired knowledge will shift the paradigm in validating and applying alloreactive CD8 iTregs for controlling GVHD and leukemia relapse, which will eventually benefit patients with hematological malignancies.

造血细胞移植(HCT)可治疗多种良恶性血液病 疾病，但移植物抗宿主病(GVHD)仍然是移植相关发病率的主要原因 和死亡率，从而限制了异基因血细胞移植的治疗潜力。包括的供体T细胞 干细胞接种和识别广泛分布的受体同种异体抗原会引起GVHD，但这些T细胞 细胞通过促进干细胞植入和介导移植物抗白血病(GVL)也是有益的。 效果。因此，预防移植物抗宿主病的理想方法是选择性地灭活同种异体反应性T细胞 对广泛表达的同种异体抗原具有特异性，而对具有其他特异性的T细胞则不敏感。占主导地位的 调节性T细胞(Tregs)介导的耐受机制具有明显的治疗意义 预防GVHD。为了将TRGs应用于临床HCT，目前的方法主要集中在通过移植 多克隆体外扩增的Tregs给移植受者，在HCT之前或之后。然而，这些 多克隆Tregs在控制GVHD方面的效力预计较低，并提供非选择性 免疫抑制从而否定了GVH和GVL反应的分离。我们证明了这种抗原- 特异性Tregs在预防临床前骨髓移植急性移植物抗宿主病中远优于多克隆Tregs 模特们。这些临床前研究提供了支持检测宿主同种异体抗原的第一个临床试验的理论基础 GVHD中的反应性Tregs。尽管宿主-同种异体抗原反应性CD4iTregs在控制 GVHD，它们也可能削弱GVL效应。虽然该项目是我们目前研究的一个连续体，但我们 将把我们的重点更多地转移到allactive CD8 iTregs上，因为这是最近发现的Treg子集和 因为它们有可能避免甚至增强GVL效应。我们的长期目标是利用 同种异体抗原反应性Tregs预防人类移植物抗宿主病，同时保留人类HCT后的移植物抗宿主病效应。这个 这项建议的目标是测试有效和可翻译的策略，以在临床前实现这一目标 异基因骨髓移植的小鼠模型。由于我们的初步数据有力地支持，我们假设 在控制移植物抗宿主病的同时保持移植物抗宿主病的活性可以通过联合异体血凝素治疗来实现。 反应性的CD4和CD8 iTregs，或使用稳定的CD8 iTregs的单一治疗。我们计划测试我们的 假设并通过追求两个具体目标来实现目标：1)建立组合 用CD4和CD8 iTregs治疗移植物抗宿主病和肿瘤复发；2)增强稳定性 CD8iTregs在预防移植物抗宿主病中的潜力。如果这个项目的目标实现了， 获得的知识将改变验证和应用同种异体反应性CD8 iTregs进行控制的范式 GVHD和白血病复发，这最终将使血液系统恶性肿瘤患者受益。