Depletion, Repopulation and Tolerance in Sensitized Recipients

致敏受体的消耗、再生和耐受性

基本信息

批准号：
9980792
负责人：
Stuart Johnston Knechtle
金额：
$ 125.19万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-15 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9980792
关键词：
Adjuvant Adjuvant Therapy Antibodies Antigens B cell repertoire B-Cell Activation B-Lymphocytes CD28 gene Cell Count Cell Death Cells Cellular Assay Cytomegalovirus Data Disease Elements Fostering Human Immune Immune response Immune system Immunity Immunization Immunotherapy Isoantibodies Kidney Transplantation Lead Lymphocyte Macaca mulatta Memory B-Lymphocyte Metabolic Modeling Monitor Monoclonal Antibodies Morphology Pathway interactions Perioperative Pharmaceutical Preparations Plasma Cells Prior Therapy Proteasome Inhibition Regimen Regulation Risk Safety Serological Shapes Sirolimus Structure of germinal center of lymph node T-Lymphocyte TNFSF5 gene Therapeutic Transfusion Transplant Recipients Transplantation Viral Virus Diseases alemtuzumab comparative desensitization kidney allograft nonhuman primate polyclonal antibody post-transplant preservation prevent response

项目摘要

ABSTRACT – Project 2 (Knechtle, Project Lead) While perioperative immune cell depletion with either polyclonal antibody or alemtuzumab is used in the majority of renal transplants in the U.S., our lab has shown in both humans and non-human primates (NHP) that homeostatic repopulation following depletion is associated with B cell activation, elevated BAFF levels, and de novo donor-specific alloantibody (DSA). We have also shown that Belatacept is capable of suppressing such DSA in NHP following depletion. Recently, we have shown in a presensitized NHP model that blockade of CD28 and CD154 in combination with proteasome inhibition substantially lowers alloantibody levels pre-transplant, disrupting germinal centers and lowering plasma cell numbers. However, depletion of plasma cells by proteasome inhibition alone is also associated with germinal center and Tfh cell activation. Thus, depletion of immune cells leads to both beneficial and deleterious consequences with respect to tolerance. This project seeks to define the elements of immune cell depletion in sensitized hosts that foster tolerance. We believe that lymphocyte and plasma cell depletion and subsequent homeostatic repopulation present both an opportunity to shape the alloreactive immune repertoire to favor tolerance, and a risk to disrupt regulation, ignite viral infection and induce activation of alloreactive clones. We hypothesize that the consequences of immune cell depletion in sensitized hosts create compensatory responses by the immune system that are predictable and need to be therapeutically controlled to promote tolerance. To explore this hypothesis, we propose 3 specific aims: 1) To develop safer and more effective means to lower the amount and number of allospecific antibodies, plasma cells, and memory B cells that prevent allotransplantation using proteasome inhibition together with complementary adjuvant therapies prior to renal transplantation; 2) To reshape the immune repertoire using depletion, donor-specific transfusion, and rapamycin to promote regulation, AICD, and pro-tolerant homeostatic repopulation in the sensitized recipient; and 3) To evaluate the safety and efficacy of Belatacept with and without Rapamycin as components of post-transplant immunosuppressive regimens promoting long-term survival of renal allografts following desensitization therapy as described in SA1 and 2 above.

摘要 – 项目 2（Knechtle，项目负责人）虽然使用多克隆抗体或阿仑单抗进行围手术期免疫细胞清除我们的实验室已在人类和非人类灵长类动物 (NHP) 中证实了美国的大多数肾移植耗竭后的稳态再增殖与 B 细胞激活、BAFF 水平升高相关，和从头供体特异性同种抗体 (DSA) 我们还表明 Belatacept 能够。最近，我们在预敏 NHP 模型中展示了抑制 NHP 中此类 DSA 的作用。阻断 CD28 和 CD154 与蛋白酶体抑制相结合可显着降低同种抗体移植前水平，破坏生发中心并降低浆细胞数量。浆细胞单独受到蛋白酶体抑制也与生发中心和 Tfh 细胞活化有关。因此，免疫细胞的耗竭会导致有益和有害的后果该项目旨在确定致敏宿主体内免疫细胞耗竭的因素，从而促进耐受性。我们相信淋巴细胞和浆细胞的消耗以及随后的稳态重新增殖。既提供了塑造同种异体反应性免疫库以促进耐受性的机会，也提供了破坏的风险调节，引发病毒感染并诱导同种反应性克隆的激活。致敏宿主中免疫细胞耗竭的后果会产生免疫系统的补偿反应系统是可预测的，需要进行治疗控制以促进耐受性。假设，我们提出3个具体目标：1）开发更安全、更有效的手段来降低用量以及阻止同种异体移植的同种异体特异性抗体、浆细胞和记忆 B 细胞的数量肾移植前蛋白酶体抑制和补充辅助治疗 2) 使用耗竭、供者特异性输血和雷帕霉素重塑免疫库以促进调节、AICD 和致敏受体的促耐受稳态再增殖；以及 3) 评估贝拉西普（含或不含雷帕霉素）作为移植后成分的安全性和有效性脱敏治疗后免疫抑制方案促进同种异体肾移植物的长期存活如上面 SA1 和 2 中所述。