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：
9111818
负责人：
A BENEDICT COSIMI
金额：
$ 153.97万
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 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9111818
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 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 long-term rehabilitation 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.

尽管过去二十年来移植后早期存活率有所提高，但先前正常运行的器官同种异体移植物的接受者的每年不懈的年度态度继续限制长期的长期结果。胰岛移植后的成功率甚至更不可接受。该多项目研究计划的主要目标是改善肾脏和肾脏/胰岛移植后的长期结局，用于生活和已故供体移植。我们打算在临床相关的NHP模型中调查1）对生物和已故供体移植持续诱导同种异体耐受性持续耐受性所必需的条件； 2）成功的捐助者成功复合IK移植所需的遗传和技术参数； 3）与肾脏，胰岛和胰岛胰岛（IK）同种异体的耐受性有关的免疫机制。可靠地实现供体特异性免疫学无反应性的治疗方案的临床翻译将消除许多当前观察到的移植器官和组织的磨损以及与终生免疫培养剂的施用相关的疾病。我们先前已经表明，可以通过几种方法在NHP中诱导同种异体移植耐受性，其中一种（混合嵌合）已扩展到人类。在那些开创性试验中，在7/10的HLA不匹配的实时肾脏肾脏同种异体移植物中，已实现了长期（2-8岁）免疫抑制，稳定的肾功能。尽管这一成就是戏剧性的，但目前依赖于调节，其应用仅限于活着的捐助者接受者（开始移植前6天）和“耐受性”器官（肾脏）。在该计划中要提出的主要假设是：1）可再现的诱导更健壮，更耐用的嵌合或肾脏与胰岛的共转移将扩展这种耐受性感应方式的应用到更广泛的范围同种异体移植受体的人口，包括死者肾脏肾脏和胰岛的人口，以及2）如果将胰岛作为复合IK同种异体移植物的一部分，则可以有效地将目前的方案扩展到活体供体的胰岛。计划的研究将通过混合嵌合治疗方法阐明与耐受性诱导有关的机制，并定义参数，这些参数将允许这些临床相关的观察结果快速转化为治疗糖尿病患者，这些糖尿病患者是肾脏/胰腺移植的候选者。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Tolerance induction after organ transplantation, "delayed tolerance," via the mixed chimerism approach: planting flowers in a battle field.

器官移植后的耐受诱导，通过混合嵌合方法“延迟耐受”：在战场上种花。

DOI：
10.4161/chim.20096
发表时间：
2012
期刊：
Chimerism
影响因子：
0
作者：
Yamada,Yohei;Benichou,Gilles;Cosimi,ABenedict;Kawai,Tatsuo
通讯作者：
Kawai,Tatsuo

The rejuvenating effects of leuprolide acetate on the aged baboon's thymus.

醋酸亮丙瑞林对老年狒狒胸腺的恢复活力作用。

DOI：
10.1016/j.trim.2014.09.001
发表时间：
2014
期刊：
Transplant immunology
影响因子：
1.5
作者：
Scalea,JosephR;Torabi,Radbeh;Tena,Aseda;Tasaki,Masayuki;Gillon,BradfordC;Moran,Shannon;Cormack,Taylor;Villani,Vincenzo;Shimizu,Akira;Sachs,DavidH;Yamada,Kazuhiko
通讯作者：
Yamada,Kazuhiko

Diagnostic challenges in chronic antibody-mediated rejection.

DOI：
10.1038/nrneph.2012.61
发表时间：
2012-03-27
期刊：
NATURE REVIEWS NEPHROLOGY
影响因子：
41.5
作者：
Farkash, Evan A.;Colvin, Robert B.
通讯作者：
Colvin, Robert B.

Both rejection and tolerance of allografts can occur in the absence of secondary lymphoid tissues.

DOI：
10.4049/jimmunol.1401157
发表时间：
2015-02-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
Kant CD;Akiyama Y;Tanaka K;Shea S;Yamada Y;Connolly SE;Marino J;Tocco G;Benichou G
通讯作者：
Benichou G

Below the waterline -- the danger of de novo donor-specific HLA antibodies.

水线以下——从头供体特异性 HLA 抗体的危险。