Tolerance Induction to Islet Transplants

胰岛移植耐受诱导

• 批准号: 7113228
• 负责人: SUZANNE T ILDSTAD
• 金额: $ 31.58万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7113228
• 关键词: NOD mouse; apoptosis; cell population study; dendritic cells; hematopoietic growth factor; hematopoietic stem cells; hematopoietic tissue transplantation; homologous transplantation; immune tolerance /unresponsiveness; immunopathology; pancreatic islet transplantation; pathologic process; tissue mosaicism; transplantation immunology

DESCRIPTION (provided by applicant): The focus of this proposal is to develop a novel "conditioning" approach that will replace myelotoxic agents to establish chimerism in NOD mice. We will induce immune deviation to promote host-versus-graft hyporesponsiveness, thereby giving the hematopoietic stem cell (HSC) an opportunity to engraft and establish subsequent self-perpetuating deletional tolerance to islet allografts. Our recent studies in a mouse model suggest that the primary role for conditioning for HSC transplantation is to suppress host-versus-graft alloreactivity, rather than to prepare vacant niches in the recipient's bone marrow compartment. This observation suggests that one could replace myelotoxic agents with antigen-specific approaches to induce host-versus-graft hyporeactivity or anergy at the time of HSC transplantation. As the mechanisms underlying T cell activation are defined, highly specific approaches to suppress this alloreactivity have emerged. In AIM I. we will ESTABLISH CHIMERISM THROUGH IMMUNE DEVIATION OF THE RECIPIENT. We will immunomodulate the recipient: (a) targeting alloreactive cells in the host microenvironment; (b) inducing anergy and/or antigen-specific apoptosis of alloreactive host cells; and (c) through generation of regulatory T cells (Treg), and develop a novel nonmyeloablative conditioning regimen to induce antigen-specific hyporesponsiveness to the HSC and islet allografts. Cell-based therapies have great potential for inducing transplantation tolerance. Of greatest interest are the new subpopulations of bone marrow-derived dendritic cells (DC) that have recently been shown to be potently tolerogenic in vitro under certain circumstances. We are the first to demonstrate an in vivo engraftment-enhancing effect for precursor plasmacytoid DC (p-preDC). The exploitation of this discovery in vivo and its potential to reduce the need for myelotoxic conditioning has not yet been tested. Hematopoietic growth factors have also been used to drive the immune response to a tolerogenic T helper 2 (Th2) phenotype through production of p-preDC or other tolerance-promoting cells (graft facilitating cells {FC}) that in turn generate Treg. In AIM II, we will USE PRE-TRANSPLANT IMMUNOMODULATION OF THE DONOR WITH HEMATOPOIETIC GROWTH FACTORS TO GENERATE TOLEROGENIC CELLS IN THE HSC ALLOGRAFT. We will use these factors and the cells they generate to modulate the tolerogenicity of the donor marrow inoculum in vivo to tip the immune milieu in favor of graft acceptance, enhancing bone marrow chimerism without myelotoxic conditioning. We will examine the mechanism by which this occurs and identify which cell types in the graft are critical to tolerance induction. P-preDC exposed to apoptotic donor antigens are potently tolerizing in vitro through generation of Treg. The therapeutic application of this approach has not been tested in vivo. In AIM III, we will USE EX VIVO IMMUNOMODULATION OF THE MARROW to expand p-preDC and FC and induce a tolerogenic inoculum for HSC transplantation.

描述（由申请人提供）：该提案的重点是开发一种新颖的“调理”方法，该方法将取代骨髓毒性剂，以在NOD小鼠中建立嵌合。我们将诱导免疫偏差以促进宿主 - 移植性的低温性，从而使造血干细胞（HSC）有机会植入和建立对胰岛同种异体移植物的随后自我渗透的缺失耐受性。我们在小鼠模型中的最新研究表明，调节HSC移植的主要作用是抑制宿主 - 移植物的同种异体反应性，而不是在接受者的骨髓室中准备空的壁nik。该观察结果表明，在HSC移植时，可以使用抗原特异性方法来代替骨髓毒性剂，以诱导宿主 - 移植物的低血压或反应性。由于定义了T细胞激活的基础机制，因此出现了高度特定的抑制这种同种异体反应性的方法。在目标I中，我们将通过免疫偏差来建立嵌合。我们将免疫调节受体：（a）靶向宿主微环境中的同种反应性细胞； （b）诱导同种异体宿主细胞的反感和/或抗原特异性凋亡； （c）通过生成调节性T细胞（TREG），并开发出一种新型的非乳清状调节方案，以诱导HSC和Islet同种异体移植物诱导抗原特异性的低温性。基于细胞的疗法具有诱导移植耐受性的巨大潜力。最引人注目的是骨髓来源的树突状细胞（DC）的新亚种群，这些细胞（DC）在某些情况下被证明在体外表现出有效的耐受性。我们是第一个证明前体纤溶酶DC（P-PREDC）的体内植入增强作用的人。尚未对这种发现的剥削及其减少对骨髓毒性调节需求的潜力进行测试。造血生长因子也已被用于通过生产P-PredC或其他促耐受性细胞（移植物促进促进细胞{Fc}）的耐受性T助手2（Th2）表型的免疫反应。在AIM II中，我们将使用具有造血生长因子的供体的移植前免疫调节来产生HSC同种异体移植物中的耐受性细胞。我们将使用这些因素及其产生的细胞来调节体内供体骨髓接种物的耐受性，以使免疫环境倾向于接受移植物，从而增强了骨髓嵌合体，而无需骨髓毒性调节。我们将检查发生这种情况的机制，并确定移植物中的哪些细胞类型对于耐受性诱导至关重要。暴露于凋亡供体抗原的P-PREDC通过产生Treg在体外有效耐受。该方法的治疗应用尚未在体内进行测试。在AIM III中，我们将使用骨髓的离体免疫调节扩展P-PREDC和FC，并诱导耐受性接种物进行HSC移植。