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）可治愈多种良性和恶性造血系统疾病 但移植物抗宿主病 (GVHD) 仍然是移植相关发病的主要原因 和死亡率，从而限制了同种异体 HCT 的治疗潜力。供体 T 细胞包含在 干细胞接种物并识别广泛分布的受体同种抗原，导致 GVHD，但这些 T 细胞还可以促进干细胞植入和介导移植物抗白血病 (GVL) 影响。因此，预防GVHD的理想方法是选择性灭活同种反应性T细胞 特异性针对广泛表达的同种抗原，同时保留具有其他特异性的 T 细胞。占主导地位的 调节性 T 细胞 (Treg) 介导的耐受机制具有明显的治疗意义 预防GVHD。为了将Tregs应用于临床HCT，目前的方法主要集中于过继转移 在 HCT 之前或之后将多克隆、离体扩增的 Tregs 移植到移植受者体内。然而，这些 预计多克隆 Tregs 在控制 GVHD 方面的效力较低，并且提供非选择性 免疫抑制从而否定 GVH 和 GVL 反应的分离。我们证明抗原- 临床前 BMT 中，特异性 Tregs 在预防急性 GVHD 方面远优于多克隆 Tregs 模型。这些临床前研究为支持首次检测宿主同种异体抗原的临床试验提供了理论基础 GVHD 中的反应性 Tregs。尽管宿主同种异体抗原反应性 CD4 iTregs 在控制 GVHD，它们也可能损害 GVL 效应。虽然该项目是我们当前研究的连续体，但我们 将把我们的注意力更多地转移到同种异体反应性 CD8 iTregs 上，因为这是最近发现的 Treg 子集 因为它们有可能减轻甚至增强 GVL 效应。我们的长期目标是使用 同种异体抗原反应性 Tregs 可预防 GVHD，同时保留人类 HCT 后的 GVL 效应。这 该提案的目的是测试有效且可转化的策略，以在临床前实现这一目标 同种异体 BMT 的小鼠模型。根据我们的初步数据的有力支持，我们假设 控制 GVHD 同时保留 GVL 活性可以通过与同种异体的联合治疗来实现 反应性 CD4 和 CD8 iTregs，或通过稳定 CD8 iTregs 的单一疗法。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 使用 CD4 和 CD8 iTreg 进行治疗以控制 GVHD 和肿瘤复发； 2）增强稳定性 以及 CD8 iTreg 在预防 GVHD 方面的潜力。如果该项目的目标得以实现， 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，最终将使血液系统恶性肿瘤患者受益。