Intestinal allograft tolerance in large animals

大型动物同种异体肠道移植耐受性

• 批准号: 10338101
• 负责人: Megan Sykes
• 金额: $ 69.21万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-08 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10338101
• 关键词: Address; Age; Allogenic; Allograft Tolerance; Allografting; Animal Model; Animals; Automobile Driving; B-Lymphocytes; Blood; Bone Marrow; Case Study; Cell Lineage; Child; Chimerism; Clinical; Clinical Protocols; Engraftment; Genetic; Goals; Haplotypes; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Human; Immune response; Immune system; Immunosuppression; Immunosuppressive Agents; Inbreeding; Infiltration; Institution; Intestines; Kidney; Kinetics; Liver; Living Donors; Long-Term Survivors; Lymphocyte Subset; MHC Class I Genes; Matched Group; Miniature Swine; Modality; Modeling; Morbidity - disease rate; Myelogenous; Myeloid Cells; Organ; Outcome; Pancreas; Parents; Patients; Peripheral; Pre-Clinical Model; Protocols documentation; Reporting; Reproducibility; Rodent Model; Role; Small Intestines; Stomach; T-Lymphocyte; Time; Tissues; Transplant Recipients; Transplantation; Transplantation Tolerance; Visceral; Weaning; clinical application; clinically relevant; comorbidity; conditioning; data registry; donor stem cell; experience; gastrointestinal transplantation; graft vs host disease; hematopoietic engraftment; improved outcome; liver transplantation; patient tolerability; peripheral blood; porcine model; prevent; response; stem cells; success; therapy outcome; transplant model

Project Abstract: Despite recent improvements in immunosuppression, graft/patient survival of small intestinal transplantation (ITx) remains suboptimal, limiting the broader application of this therapy. Induction of donor- specific tolerance to any organ is desirable to eliminate co-morbidities associated with immunosuppressive treatment. The induction of tolerance is particularly desirable for ITx due to: (1) the requirement for high levels of immunosuppression to prevent rejection of small bowel grafts; (2) complications associated with heavy immunosuppression; and (3) the young average age of the recipients. However, to our knowledge, tolerance of intestinal allografts has not been extensively studied in preclinical models. Even in rodent models, there are few reports demonstrating tolerance to small intestine, but one successful strategy has been through the induction of durable mixed allogeneic chimerism. The overall goal of this proposal is to develop a large animal preclinical model for tolerance induction following ITx and to develop a protocol appropriate for tolerance induction in parent to child (living donor LD) ITx. We recently reported that rejection rates appear to be higher in clinical recipients of isolated intestinal transplants (iITx) compared to multivisceral transplants (MVTx), which include donor liver, stomach and pancreas. Notably we have found, for the first time, that T cell mixed chimerism which develops without GVHD following iITx and even more commonly following MVTx, is associated with reduced rejection rates. We hypothesize that the presence of graft-vs-host-reactive (GVHR) clones in these MVTx recipients facilitates engraftment of donor progenitor cells contained within the grafts, and further hypothesize that transplantation of additional hematopoietic stem cells (HSCs) during this period of the GVHR will augment chimerism and tolerance induction even in iITx recipients. The early GVHR that migrates from the graft to the recipient’s peripheral immune system (lymphohematopoietic GVH response, or LGVHR) makes hematopoietic “space” for engraftment of these hematopoietic progenitors. In this proposal, we will utilize MHC inbred miniature swine, the only large animal model that allows reproducible transplantation with defined GVH and host-vs-graft (HvG) genetic barriers, to address the above hypotheses and develop a clinically relevant LD ITx tolerance induction model. We will first establish a porcine model of orthotopic iITx and MvTx that parallels our institution’s clinical protocol and determine the role of GVH and HvG alloreactivity in driving chimerism and clinical outcomes (Aim 1). We will then utilize the LGVHR and donor HSCs to achieve tolerance in long-term allograft acceptors in the models in Aim 1 (Aim 2). The studies in this proposal may have eventual clinical applicability that could solve the most problematic issues in ITx and vastly improve the outcomes of this therapeutic modality.

项目摘要：尽管最近改善了免疫抑制，移植物/患者生存 移植（ITX）仍然是最佳选择，限制了这种疗法的更广泛应用。捐助者的归纳 希望对任何器官的特定容忍度消除与免疫抑制有关的合并症 治疗。由于：（1）高水平的需求，对ITX的耐受性尤其值得 免疫抑制以防止排斥小肠移植物； （2）与沉重有关的并发症 免疫抑制； （3）接受者的年轻平均年龄。但是，据我们所知，宽容 肠道同种异体移植物在临床前模型中尚未广泛研究。即使在啮齿动物模型中，也很少 报告表明对小肠的耐受性，但通过归纳是一种成功的策略 耐用的混合同种异体嵌合体。该提议的总体目标是开发大型动物临床前 在ITX之后耐受性诱导的模型，并制定适合父母耐受性诱导的协议 给孩子（活捐赠者LD）ITX。我们最近报告说，临床接受者的排斥率似乎更高 与多维分子移植（MVTX）相比，分离的肠道移植（IITX）的肠道移植（IITX），其中包括供体肝脏， 胃和胰腺。值得注意的是，我们第一次发现T细胞混合了嵌合体的发展 没有GVHD遵循IITX，甚至更常见的MVTX都与拒绝减少有关 费率。我们假设在这些MVTX受体中存在移植物-VS-host反应（GVHR）克隆 促进移植物中包含的供体祖细胞的植入，并进一步假设 在此期间，GVHR期间的其他造血干细胞（HSC）的移植将增加 即使在IITX接受者中，嵌合和耐受性也是如此。从移植到移植到的早期GVHR 接受者的外周免疫系统（淋巴瘤的GVH反应或LGVHR）使造血 这些造血祖细胞植入的“空间”。在此提案中，我们将利用MHC Inbrored 微型猪，这是唯一允许使用定义的GVH和可重复移植的大型动物模型 宿主-VS-GRAFT（HVG）遗传障碍，以解决上述假设并发展临床相关的LD ITX 公差诱导模型。我们将首先建立一个与我们的原位IITX和MVTX的猪模型 机构的临床方案并确定GVH和HVG同种异体反应性在推动嵌合和 临床结果（AIM 1）。然后，我们将利用LGVHR和供体HSC长期实现公差 AIM 1（AIM 2）中的模型中的同种异移植受体。该提案中的研究可能最终具有临床 可以解决ITX中最有问题的问题并大大改善结果的适用性 治疗方式。