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

计划说明/摘要： 发展和维持免疫耐受是减少同种异体移植并发症的关键 造血细胞移植(HCT)治疗非恶性血液病，允许供体细胞 植入，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保持免疫耐受性的巨大潜力。然而，这些机制 通过它可以实现异基因HCT后适应性免疫系统的先天免疫调节 人们对此了解甚少。了解这些机制将使我们能够更好地应用它们来生成 移植供者和受者之间的免疫耐受，从而扩大替代供者红细胞移植治疗非 恶性血液病。我们最近描述了新的先天机制，通过这种机制，接受者可以 髓系树突状细胞(MDC)在非骨髓消融性全淋巴照射(TLI)和T细胞- 耗尽型抗胸腺细胞血清可诱导供者体内Foxp3调节性T细胞的增殖 通过主要组织相容性复合体(MHC)屏障进行移植。自那以后，我们确定了一个修改后的预制 促进这些调节性髓系细胞恢复的移植准备方案和关键 调节功能所需的信号机制，并导致持久的供受者免疫 β-地中海贫血小鼠骨髓嗜多染红细胞不合后的耐受性。我们的中心假设是一群 非清髓性条件下的受者髓系前体细胞发育为调节性MDC 通过与另一个接受者的先天免疫细胞群体直接相互作用，这些髓系 因此，前体细胞在调节MHC不相合的HCT后的供者免疫反应中起着核心作用。我们会 通过4个具体问题来检验这些假设：1.这些细胞能否调节移植物抗宿主免疫 血细胞移植后的反应？2.这些髓系细胞是如何在其他特定先天因素的影响下形成的 受体的免疫细胞？3.当其他烷基化物 在人类镰状细胞病(SCD)的高保真小鼠模型中，添加到TLI/ATS条件反射中？4.Do 当这些TLI/ATS/烷化剂疗法应用于SCD时，类似的免疫耐受机制也会发挥作用。我们的 研究应该为MHC错配的特定免疫调节机制提供关键的见解 移植耐受和红细胞移植治疗血红蛋白疾病的新治疗选择 全球流行率和相关性都很高。

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.