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

血红蛋白病同种异体 HCT 中免疫耐受诱导的新先天机制

基本信息

批准号：
10067378
负责人：
Asha Bhaskaran Pillai
金额：
$ 44.12万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10067378
关键词：
Adaptive Immune System Alkylating Agents Allogeneic Bone Marrow Transplantation Allogenic Antigen Presentation Antigens Antithymoglobulin B-Lymphocytes Bone Marrow Transplantation Cell Communication Cells Clinical Trials Design Confounding Factors (Epidemiology)Cyclophosphamide Data Dendritic Cells Development Disease Donor person Dose Engraftment FOXP3 gene Generations Germ Lines Goals Health Hematological Disease Hemoglobin Hemoglobinopathies Histocompatibility ITGAM gene Immune Immune Tolerance Immune response In Vitro Innate Immune System Interleukin-4 Knockout Mice Knowledge Laboratories Maintenance Major Histocompatibility Complex Methods Modeling Mus Myelogenous Myeloid Cells Myeloid-derived suppressor cells Non-Malignant Oryctolagus cuniculus Outcome Pathway interactions Play Population Pre-Clinical Model Preparation Prevalence Process Program Description Publishing Recovery Regimen Regulation Regulatory T-Lymphocyte Role Serum Sickle Cell Anemia Signal Transduction System T-Lymphocyte Techniques Testing Thalassemia Thiotepa TimeLine Transplant Recipients Transplantation Transplantation Conditioning Transplantation Tolerance beta Thalassemia conditional knockout conditioning cytokine graft vs host disease hematopoietic cell transplantation human model immunoreaction immunoregulation improved in vivo innate immune mechanisms insight lymphoid irradiation macrophage mouse model neutrophil novel novel therapeutics pre-clinical precursor cell prevent response success thymocyte

项目摘要

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.

程序说明/摘要：免疫耐受性的开发和维持对于最大程度地减少同种异体并发症至关重要造血细胞移植（HCT），用于非恶性血液学疾病，允许供体细胞植入同时最大程度地减少移植物抗宿主病（GVHD）。利用先天免疫机制在组织相容性障碍之间保持免疫耐受性的巨大潜力。但是，机制同种异体HCT之后，可以实现自适应免疫系统的先天免疫调节知之甚少。了解这些机制将使我们能够更好地应用它们来产生移植供体和受体之间的免疫耐受性，从而扩大替代供体HCT以治愈非恶性血液疾病。我们最近描述了接受者调节的新型先天机制髓样树突状细胞（MDC）通过非肉食烧蚀总淋巴样辐射（TLI）和T细胞 - 消耗性抗心理细胞血清（ATS）可以诱导供体中Foxp3+调节T细胞的增殖跨主要组织相容性复合物（MHC）屏障的移植物。从那以后，我们确定了修改的前移植制备的方案增加了这些调节性髓样细胞和钥匙的恢复调节功能所需的信号传导机制，这会导致耐用的供体 - 恢复免疫 MHC匹配的HCT在β-丘脑血症小鼠中的耐受性。我们的核心假设是一群受体髓样前体细胞通过非毛然性调节发展到调节性MDC中所保险的通过与另一个接受者先天免疫物种群的直接互动，这些髓样因此，前体在调节MHC不匹配的HCT后调节供体免疫反应中起着核心作用。我们将通过4个特定问题测试这些假设：1。这些细胞可以调节移植物与宿主免疫 HCT之后的响应？ 2。如何在其他特定先天的影响下形成这些髓样细胞受体的免疫细胞？ 3。当其他烷基剂时，可以实现类似的免疫耐受性诱导在人类镰状疾病（SCD）的高保真鼠模型中添加到TLI/ATS条件中？ 4。做当SCD中应用这些TLI/ATS/烷基疗法时，类似的免疫耐受机制会运行吗？我们的研究应提供对MHC不匹配调节的特定免疫组机制的关键见解 HCT中血红蛋白病的移植耐受性和新的治疗选择，健康状况全球盛行和相关性很高。