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

产品描述/总结： 免疫耐受的发展和维持对于减少同种异体移植的并发症至关重要。 造血细胞移植（HCT）用于非恶性血液病，允许供体细胞 移植物抗宿主病（GVHD）最小化。利用先天免疫机制 具有跨越组织相容性屏障维持免疫耐受的巨大潜力。然而，机制 通过该方法可以在同种异体HCT后实现适应性免疫系统的先天免疫调节 我们对此知之甚少。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，以治疗非移植性肝细胞癌。 恶性血液病我们最近描述了一种新的先天机制，通过这种机制，受体调节 骨髓树突状细胞（MDC）通过非骨髓消融性全淋巴照射（TLI）和T细胞- 耗竭性抗胸腺细胞血清（ATS）可诱导供体Foxp 3+调节性T细胞增殖 主要组织相容性复合体（MHC）屏障。我们已经确定了一个修改后的预- 移植准备方案，增强这些调节性骨髓细胞的恢复， 调节功能所需的信号传导机制，并导致持久的供体-受体免疫 β-地中海贫血小鼠中MHC不匹配HCT后的耐受性。我们的主要假设是， 非清髓性预处理保留的受体髓样前体细胞发育为调节性MDC 通过与另一个受体先天免疫细胞群的直接相互作用，这些骨髓细胞 因此，前体在调节MHC错配HCT后的供体免疫应答中起核心作用。我们将 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 HCT后的反应？2.这些髓样细胞是如何在其他特定的先天免疫系统的影响下形成的？ 接受者的免疫细胞3.当其他烷化剂 在高保真人类镰状细胞病（SCD）小鼠模型中，将TLI/ATS加入到条件反射中？4.做 当这些TLI/ATS/烷化剂治疗应用于SCD时，类似的免疫耐受机制起作用？我们 这些研究应该为调节MHC错配的特异性免疫机制提供重要的见解。 HCT中用于血红蛋白病的移植耐受性和新的治疗选择， 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.