NOVEL INNATE MECHANISMS OF IMMUNE TOLERANCE INDUCTION IN ALLOGENEIC HCT FOR HEMOGLOBINOPATHIES

计划描述/摘要： 免疫耐受的发展和维持对于最大限度地减少同种异体并发症至关重要 造血细胞移植（HCT）用于治疗非恶性血液疾病，允许供体细胞 移植同时最大限度地减少移植物抗宿主病（GVHD）。利用先天免疫机制 跨越组织相容性障碍维持免疫耐受的巨大潜力。然而，这些机制 通过异体HCT后可以实现适应性免疫系统的先天免疫调节 人们了解甚少。了解这些机制将使我们能够更好地应用它们来生成 移植供体和受体之间的免疫耐受，从而扩大替代供体 HCT 来治愈非 恶性血液疾病。我们最近描述了新的先天机制，通过该机制受体调节 骨髓树突状细胞 (MDC) 不受非骨髓消融性全淋巴放疗 (TLI) 和 T 细胞的影响 耗尽抗胸腺细胞血清 (ATS) 可诱导供体中 Foxp3 调节性 T 细胞增殖 移植物跨越主要组织相容性复合体 (MHC) 屏障。此后我们确定了修改后的预 移植准备方案可增强这些调节性骨髓细胞的恢复和关键 调节功能所需的信号传导机制，从而产生持久的供体-受体免疫 β地中海贫血小鼠 MHC 不匹配 HCT 后的耐受性。我们的中心假设是一组 受非清髓性调理所幸免的受体骨髓前体细胞发育成调节性MDC 通过与另一个受体先天免疫细胞群的直接相互作用，并且这些骨髓细胞 因此，前体在 MHC 不匹配的 HCT 后调节供体免疫反应中发挥着核心作用。我们会 通过 4 个具体问题检验这些假设： 1. 这些细胞能否调节移植物抗宿主免疫 HCT 后的反应？ 2. 这些骨髓细胞是如何在其他特定先天因素的影响下形成的 接受者的免疫细胞？ 3. 其他烷基化剂能否实现类似的免疫耐受诱导 在人类镰状细胞病 (SCD) 的高保真鼠模型中添加到 TLI/ATS 调节中？ 4. 做 当这些 TLI/ATS/烷化剂疗法应用于 SCD 时，是否会产生类似的免疫耐受机制？我们的 研究应该为 MHC 不匹配调节的特定免疫机制提供重要见解 移植耐受性和 HCT 治疗血红蛋白病、健康状况的新治疗选择 高全球流行率和相关性。

PROGRAM DESCRIPTION/ SUMMARY: Development and maintenance of immune tolerance is critical to minimizing complications of allogeneic hematopoietic cell transplantation (HCT) for non-malignant hematologic disorders, allowing donor cell engraftment while minimizing graft-versus-host disease (GVHD). Harnessing innate immune mechanisms has great potential to maintain immune tolerance across histocompatibility barriers. However, the mechanisms through which innate immune regulation of the adaptive immune system can be achieved after allogeneic HCT are poorly understood. Understanding these mechanisms will allow us to better apply them to generate immune tolerance between transplant donor and recipient, thus expanding alternative donor HCT to cure non- malignant blood disorders. We recently described novel innate mechanisms through which recipient regulatory myeloid dendritic cells (MDC) spared by non-marrow ablative total lymphoid irradiation (TLI) and T cell- depletive anti-thymocyte serum (ATS) can induce the proliferation of Foxp3+ regulatory T cells in the donor graft across major histocompatibility complex (MHC) barriers. We have since determined a modified pre- transplant preparative regimen which augments the recovery of these regulatory myeloid cells and key signaling mechanisms required for regulatory function, and which results in durable donor-recipient immune tolerance after MHC-mismatched HCT in β-thalassemic mice. Our central hypotheses are that a group of recipient myeloid precursor cells spared by non-myeloablative conditioning develop into regulatory MDC through direct interactions with another recipient innate immune cell population, and that these myeloid precursors thus play a central role in regulating donor immune responses after MHC-mismatched HCT. We will test these hypotheses through 4 specific questions: 1. Can these cells regulate graft-versus-host immune responses after HCT? 2. How are these myeloid cells formed under the influence of other specific innate immune cells of the recipient? 3. Can similar immune tolerance induction be achieved when other alkylators are added to TLI/ATS conditioning, in a high-fidelity murine model of human sickle-cell disease (SCD)? 4. Do similar immune tolerance mechanisms operate when these TLI/ATS/alkylator therapy is applied in SCD? Our studies should provide critical insights into specific immune mechanisms of regulation of MHC-mismatched transplantation tolerance and new therapeutic options in HCT for hemoglobinopathies, health conditions with high global prevalence and relevance.