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

• 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
• 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

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 肝脏是美国第二大移植器官，每年约有6,000例移植。 年由于绝大多数患者需要服用免疫抑制药物，结果有限 以防止同种异体移植排斥。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毒副作用。虽然有几种宽容的策略 虽然诱导在啮齿动物模型中是有效的，但是很少有方法成功地在灵长类动物中诱导耐受性 或者人类然而，短暂的混合嵌合体在灵长类动物和人类中实现了肾移植耐受。 我们建立了一个非人灵长类动物同种异体肝移植模型，以研究移植物的免疫调节能力。 短暂的混合嵌合体以诱导对肝同种异体移植物的耐受。我们已经建立了唯一的现有的NHP 肝脏同种异体移植模型在美国，而且，据我们所知，在世界上唯一的积极计划。我们 初步数据表明，记忆性T细胞应答（特别是效应/记忆性CD 8 T细胞）和免疫应答（如免疫应答）可能与免疫应答有关。 相对较大的缺血-再灌注炎症反应（IL-6/Th 17细胞因子水平升高）， 手术的结果可能是诱导肝脏耐受的重要障碍，尽管 短暂嵌合体的发展。通过靶向宿主CD 2+记忆细胞增强T细胞耗竭 导致增强的多谱系供体嵌合（包括T细胞嵌合）并防止同种异体移植排斥， 但由于在一只动物中有大量的乘客记忆T细胞， 捐献的肝脏。我们假设T细胞对宿主和供体效应/记忆反应的抑制， 消耗或细胞因子调节将导致供体特异性肝耐受而没有移植物抗宿主病。 在目标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 促进对食蟹猴肝移植耐受性的诱导。第一种是基于 在食蟹猴模型中成功实现肾脏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细胞消耗的能力， CD 2 mAb（方案2）+/-通过给予抗IL-6受体调节炎症/Th 17应答 mAb（方案4）以促进耐受性。我们还将进行肝脏移植，而无需与供体共同给药 骨髓以确定嵌合体在调节免疫应答中的作用（方案3）。在目标2中，我们将 表征每种方案中外周和局部的细胞、体液和细胞因子反应， 移植物这些研究的结果将增强我们对耐受诱导障碍的理解， 这个模型中的容忍或拒绝机制。我们预计， 在该临床前NHP模型中安全、快速和可靠的耐受诱导将导致迅速的临床转化。