Approaches to Tolerance of Allogeneic Kidney and Islet Transplants

同种异体肾脏和胰岛移植的耐受性方法

基本信息

批准号：
8401720
负责人：
A BENEDICT COSIMI
金额：
$ 155.95万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8401720
关键词：
Achievement Age Allogenic Allograft Tolerance Allografting American B-Lymphocytes Bone Marrow Bone Marrow Transplantation Cells Child Chimerism Chronic Clinic Clinical Clinical Trials Complications of Diabetes Mellitus Data Diabetes Mellitus Diabetic Nephropathy Donor person Elements End stage renal failure Engraftment Equilibrium Failure Freezing Genetic Goals Healthcare Systems Human Hyperglycemia Immune Tolerance Immunologics Immunosuppression Immunosuppressive Agents Individual Inflammation Infusion procedures Insulin-Dependent Diabetes Mellitus Islets of Langerhans Transplantation Kidney Kidney Failure Kidney Transplantation Laboratories Life Living Donors Macaca fascicularis Maintenance Memory Modality Modeling Morbidity - disease rate Natural Immunity Organ Organ Donations Organ Transplantation Outcome Pancreas Transplantation Pancreatectomy Parents Patients Pharmaceutical Preparations Population Procedures Program Research Project Grants Protocols documentation Regimen Regulatory T-Lymphocyte Rehabilitation therapy Renal Glycosuria Renal function Reporting Research Role Seminal Staging Survival Rate T memory cell Therapeutic Time Tissue Donations Tissues Translations Transplant Recipients Transplantation Transplantation Tolerance United States adaptive immunity clinically relevant conditioning diabetic improved islet islet allograft kidney allograft novel strategies offspring peripheral blood programs response statistics success

项目摘要

Despite improvements in early post-transplant survival rates over the last two decades, a relentless annualattrition of 3-5% in recipients of previously functioning organ allografts continues to limit longer term outcomes. Success rates following pancreatic islet transplantation are even less acceptable. The major objectives of this multi-project research Program are to improve the long-term outcome following kidney and kidney/islet transplantation for both living and deceased donor transplants. We intend to investigate, in clinically relevant NHP models 1) the conditions necessary for consistent induction of durable allograft tolerance for both living and deceased donor transplants; 2) the genetic and technical parameters required for successful composite IK transplants from living donors; and 3) the immunological mechanisms involved in tolerance of kidney, islet, and islet-kidney (IK) allografts. Clinical translation of therapeutic protocols for reliably achieving donor-specific immunologic non-responsiveness would eliminate much of the currently observed annual attrition of transplanted organs and tissues as well as the morbidities associated with the administration of lifelong immunosuppressive agents. We have previously shown that allograft tolerance can be induced in NHP via several approaches, one of which (mixed chimerism) we have extended to humans. In those seminal trials, long-term (2-8yrs) immunosuppression-free, stable renal function has been achieved in 7/10 initial recipients of HLA mismatched live-donor renal allografts selected for study. Although this achievement is dramatic, it is currently reliant upon conditioning, the application of which is limited to living donor recipients (beginning 6 days pre-transplant) and to a "tolerogenic" organ (kidney). The main hypotheses to be pursued in this Program are: 1) that reproducible induction of more robust and durable chimerism or cotransplantation of the kidney with islets will extend the application of this means of tolerance induction to a much wider population of allograft recipients, including those of deceased-donor kidneys and of islets, and, 2) that the current protocol can be effectively extended to islets from a living donor if the islet are included as part of a composite IK allograft. The studies planned will clarify the mechanisms involved with tolerance induction via the mixed chimerism approach and define the parameters that will allow rapid translation of these clinically relevant observations to treatment of diabeti patients who are candidates for kidney/pancreas transplantation.

尽管过去二十年移植后早期存活率有所提高，但先前功能正常的同种异体器官移植受者每年 3-5% 的持续流失仍然限制了长期结果。胰岛移植后的成功率更令人难以接受。该多项目研究计划的主要目标是改善活体和死者供体移植肾和肾/胰岛移植后的长期结果。我们打算在临床相关的 NHP 模型中研究：1）对活体和死亡供体移植物持续诱导持久同种异体移植耐受所需的条件； 2) 活体捐献者成功复合 IK 移植所需的遗传和技术参数； 3) 涉及肾、胰岛和胰岛-肾 (IK) 同种异体移植物耐受的免疫机制。可靠地实现供体特异性免疫无反应的治疗方案的临床转化将消除目前观察到的移植器官和组织的每年损耗以及与终身免疫抑制剂给药相关的发病率。我们之前已经证明，可以通过多种方法在 NHP 中诱导同种异体移植耐受，我们已将其中一种（混合嵌合）扩展到人类。在这些开创性试验中，选择用于研究的 HLA 不匹配活体供体肾同种异体移植物的初始接受者中，7/10 已实现长期（2-8 年）无免疫抑制、稳定的肾功能。虽然这一成就是引人注目的，但目前它依赖于条件调节，其应用仅限于活体供体受体（移植前 6 天开始）和“耐受性”器官（肾脏）。该计划要追求的主要假设是：1）可重复诱导更稳健和持久的嵌合或肾脏与胰岛的共移植将把这种耐受诱导方法的应用扩展到更广泛的领域。同种异体移植受者群体，包括已故供体肾脏和胰岛的群体，以及 2) 如果胰岛作为复合 IK 同种异体移植物的一部分，则当前方案可以有效扩展到活体供体的胰岛。计划的研究将通过混合嵌合方法阐明与耐受诱导有关的机制，并定义参数，使这些临床相关观察结果能够快速转化为肾/胰腺移植候选者的糖尿病患者的治疗。