Immune response to combined liver and bone marrow transplant for tolerance in NHP

NHP 患者对肝脏和骨髓联合移植耐受的免疫反应

基本信息

批准号：
9330503
负责人：
Megan Sykes
金额：
$ 32万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-19 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9330503
关键词：
Accounting Achievement Adverse effects Allogenic Allograft Tolerance Animals Antibodies Antigen-Presenting Cells Antigens Bacterial Infections Biological Markers Blood Bone Marrow Bone Marrow Stem Cell Bone Marrow Transplantation CD8-Positive T-Lymphocytes CD8B1 gene Cell Differentiation process Cells Chest Chimerism Chronic Clinical Clinical Trials Data Development Disease Outcome Engraftment Environment Equilibrium Failure Homing Human Immune response Immunologics Immunosuppression Immunosuppressive Agents In Vitro Infection Inflammatory Inflammatory Response Interleukin 6 Receptor Interleukin-6 Intestines Ischemia Kidney Kidney Transplantation Lead Life Liver Liver diseases Lymphocyte Lymphopenia Macaca Macaca fascicularis Malignant Neoplasms Medical Memory Metabolic Methods Modeling Organ Organ Transplantation Outcome Patients Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Portal vein structure Pre-Clinical Model Primates Protocols documentation Regimen Regulatory T-Lymphocyte Reperfusion Injury Reperfusion Therapy Reporting Residual state Risk Rodent Model Role Staging T cell response T memory cell T-Cell Depletion T-Lymphocyte Testing Therapeutic immunosuppression Time Tissues Toxic effect Translations Transplant Recipients Transplantation United States Vena caval structure Virus Diseases Weaning allograft rejection allotransplant base cadmium ion cancer risk cell type conditioning cytokine graft vs host disease inflammatory modulation kidney allograft liver allograft liver function liver transplantation lymph nodes nonhuman primate operation pre-clinical preclinical study prevent programs receptor response success thymocyte translational approach treatment choice

项目摘要

PROJECT SUMMARY The liver is the second-most transplanted organ in the United States, with approximately 6,000 transplants per year. Outcomes are limited due to the need for the vast majority of patients to take immunosuppressive drugs for life to prevent allograft rejection. These patients are at increased risk for bacterial or viral infections, cancer, and toxic side effects of the immunosuppressive medications. While several strategies for tolerance induction are effective in rodent models, very few methods have succeeded in inducing tolerance in primates or humans. Transient mixed chimerism, however, achieved kidney allograft tolerance in primates and humans. We developed a nonhuman primate model of allogeneic liver transplantation in order to study the ability of transient mixed chimerism to induce tolerance to liver allografts. We have established the only existing NHP liver allotransplant model in the US, and, to our knowledge, the only active program in the world. Our preliminary data suggest that memory T cell responses (particularly effector/memory CD8 T cells) and the relatively large ischemia-reperfusion inflammatory response (with enhanced levels of IL-6/Th17 cytokines) that results from the operation may represent significant barriers to the induction of tolerance to the liver, despite the development of transient chimerism. Enhanced T cell depletion by targeting host CD2+ memory cells results in enhanced multilineage donor chimerism (including T cell chimerism) and prevents allograft rejection, but led to graft-versus-host disease in one animal due to large numbers of passenger memory T cells in the donor liver. We hypothesize that suppression of both host and donor effector/memory responses by T cell depletion or cytokine modulation will result in donor-specific liver tolerance without graft-versus-host disease. In Aim 1, we will test these hypotheses by comparing the ability of four different immunosuppressive regimens to promote the induction of tolerance to liver transplants in cynomolgus macaques. The first is based on the regimen that successfully achieves tolerance to kidneys in the cynomolgus model and will define the baseline immune response. We will then examine the ability of enhanced donor and recipient T cell depletion with anti- CD2 mAb (regimen 2) +/- modulation of the inflammatory/Th17 response by administering anti-IL-6 receptor mAb (regimen 4) to promote tolerance. We will also perform liver transplants without co-administration of donor bone marrow to define the role of chimerism in modulating the immune response (regimen 3). In Aim 2, we will characterize the cellular, humoral and cytokine response in each regimen, both in the periphery and locally in the graft. The results of these studies will enhance our understanding of the barriers to tolerance induction and the mechanisms of tolerance or rejection in this model. We anticipate that the development of a protocol for safe, rapid and reliable tolerance induction in this pre-clinical NHP model will lead to prompt clinical translation.

项目摘要肝脏是美国的第二大移植器官，大约有6,000个移植物年。由于绝大多数患者需要服用免疫抑制药物，结果受到限制生命以防止同种异移植排斥。这些患者患细菌或病毒感染的风险增加，癌症和免疫抑制药物的有毒副作用。而宽容的几种策略诱导在啮齿动物模型中有效，很少有方法成功地诱导灵长类动物的耐受性或人类。然而，瞬时混合嵌合体在灵长类动物和人类中实现了肾脏同种异体的耐受性。我们开发了一种非人类灵长类动物模型的同种异体肝移植，以研究的能力瞬时混合嵌合体诱导对同种异体移植的耐受性。我们已经建立了唯一现有的NHP 在美国，肝脏同种异体移植模型，据我们所知，是世界上唯一的活跃计划。我们的初步数据表明，内存T细胞响应（尤其是效应器/存储器CD8 T细胞）和相对较大的缺血再灌注炎症反应（IL-6/Th17细胞因子的水平增强）手术的结果可能代表着诱导肝脏耐受性的重大障碍，尽管瞬态嵌合体的发展。通过靶向主机CD2+记忆单元，增强T细胞耗竭导致增强的多列属供体嵌合体（包括T细胞嵌合体），并防止同种异体移植排斥反应，但由于大量的乘客记忆T细胞，导致了一种动物的移植物抗宿主病供体肝。我们假设T细胞抑制宿主和供体效应子/记忆反应耗竭或细胞因子调节将导致供体特异性的肝耐受性，而没有移植物抗宿主病。在AIM 1中，我们将通过比较四种不同免疫抑制方案的能力来检验这些假设促进膀胱猕猴中对肝移植的耐受性。第一个是基于成功地实现cynomolgus模型中肾脏的耐受性并将定义基线的方案免疫反应。然后，我们将检查增强的供体和受体T细胞用抗耗尽的能力 CD2 mAb（方案2）+/-通过给予抗IL-6受体的炎症/Th17反应调节 mAb（疗法4）以促进耐受性。我们还将进行肝移植，而无需共同管理供体骨髓来定义嵌合在调节免疫反应中的作用（方案3）。在AIM 2中，我们将表征每个方案中的细胞，体液和细胞因子反应，无论是在外围和局部移植。这些研究的结果将增强我们对耐受性诱导障碍的理解和在此模型中的耐受性或拒绝机制。我们预计开发协议的在这种临床前NHP模型中，安全，快速和可靠的耐受性诱导将导致迅速的临床翻译。