Tolerance Induction to Islet Transplants

胰岛移植耐受诱导

• 批准号: 6970186
• 负责人: SUZANNE T ILDSTAD
• 金额: $ 32.34万
• 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/6970186
• 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“调节”方法，该方法将取代骨髓毒性药物以在 NOD 小鼠中建立嵌合状态。我们将诱导免疫偏差以促进宿主抗移植物反应低下，从而为造血干细胞（HSC）提供移植机会并建立随后对胰岛同种异体移植物的自我延续的缺失耐受性。我们最近在小鼠模型中的研究表明，HSC 移植调节的主要作用是抑制宿主抗移植物同种异体反应性，而不是在受体的骨髓室中准备空位。这一观察结果表明，可以用抗原特异性方法替代骨髓毒性药物，以在 HSC 移植时诱导宿主抗移植物低反应性或无反应性。随着 T 细胞激活机制的确定，抑制这种同种异体反应性的高度特异性方法已经出现。在 AIM I 中，我们将通过受体的免疫偏差建立嵌合现象。我们将免疫调节受体：（a）针对宿主微环境中的同种反应细胞； (b)诱导同种异体反应性宿主细胞的无反应性和/或抗原特异性细胞凋亡； (c) 通过生成调节性 T 细胞 (Treg)，并开发一种新型非清髓性预处理方案，以诱导 HSC 和胰岛同种异体移植物的抗原特异性低反应性。基于细胞的疗法在诱导移植耐受方面具有巨大潜力。最令人感兴趣的是骨髓来源的树突状细胞（DC）的新亚群，最近已证明它们在某些情况下在体外具有强耐受性。我们是第一个证明前体浆细胞样 DC (p-preDC) 体内植入增强作用的人。这一发现的体内利用及其减少骨髓毒性调节需求的潜力尚未经过测试。造血生长因子还被用来通过产生 p-preDC 或其他耐受性促进细胞（促​​移植细胞 {FC}）来驱动对耐受性 T 辅助细胞 2 (Th2) 表型的免疫反应，进而产生 Treg。在 AIM II 中，我们将利用造血生长因子对供体进行移植前免疫调节，以在 HSC 同种异体移植物中产生耐受性细胞。我们将利用这些因子及其产生的细胞来调节体内供体骨髓接种物的耐受原性，使免疫环境有利于移植物接受，从而在没有骨髓毒性条件的情况下增强骨髓嵌合状态。我们将检查这种情况发生的机制，并确定移植物中哪些细胞类型对于耐受诱导至关重要。暴露于凋亡供体抗原的 P-preDC 通过生成 Treg 在体外具有强效耐受性。该方法的治疗应用尚未在体内进行测试。在 AIM III 中，我们将使用骨髓的体外免疫调节来扩增 p-preDC 和 FC，并诱导用于 HSC 移植的耐受性接种物。