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：
10649946
负责人：
Stuart Johnston Knechtle
金额：
$ 73.37万
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 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10649946
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 Goals Graft Rejection Health Human Immune Immune response Immunity Immunization Immunosuppression Immunotherapy Isoantibodies Kidney Transplantation Lymphocyte Macaca mulatta Memory B-Lymphocyte Metabolic Modeling Monitor Monoclonal Antibodies Morphology Organ Pathway interactions Patients Perioperative Pharmaceutical Preparations Plasma Cells Pre-Clinical Model Prior Therapy Proteasome Inhibition Regimen Regulation Risk Safety Serology Shapes Sirolimus Structure of germinal center of lymph node T-Lymphocyte TNFSF5 gene Testing Therapeutic Transfusion Transplant Recipients Transplantation Viral Virus Diseases alemtuzumab allotransplant comparative desensitization improved kidney allograft nonhuman primate novel therapeutic intervention polyclonal antibody post-transplant preservation prevent programs response side effect tocilizumab

项目摘要

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.

虽然在美国的大多数肾移植中使用了多克隆抗体或Alemtuzumab的围手术性免疫细胞耗竭，但我们的实验室在人类和非人类灵长类动物（NHP）中都表明，降低后的体内稳态寄生虫在消耗后与B细胞激活相关联，BAFF级别均与De Notor de Notor Specific Allanib相关。我们还表明，Belatacept能够抑制耗竭后NHP中的DSA。最近，我们在一个持续化的NHP模型中显示，与蛋白酶体抑制相结合，阻断CD28和CD154的封锁基本上降低了同抗体水平前移植，破坏了生发中心并降低了血浆细胞的数量。然而，仅蛋白酶体抑制作用对等离子体细胞的耗竭也与生发中心和TFH细胞活化有关。因此，免疫细胞的耗竭会导致对耐受性的有益和有害后果。该项目旨在定义促进公差的敏化宿主中免疫细胞耗竭的元素。我们认为，淋巴细胞和浆细胞的耗竭以及随后的稳态再生既是塑造同种反应性免疫术的机会，以促进耐受性，以及破坏调节，点燃病毒感染和诱导同种反应性克隆的激活的风险。我们假设，敏化宿主中免疫细胞耗竭的后果通过免疫系统创造了可预测的补偿性反应，这是可预测的，并且需要受到治疗控制以促进耐受性。为了探讨这一假设，我们提出了3个具体目的：1）开发更安全，更有效的手段，以降低同种异体抗体，浆细胞和记忆B细胞的数量和数量，以防止使用蛋白酶体抑制以及肾脏移植前的辅助辅助治疗，以防止同种异体抑制作用； 2）使用耗竭，特异性输血和雷帕霉素重塑免疫曲目，以促进敏化受体中的调节，AICD和耐耐受性稳态再植入； 3）评估有或没有雷帕霉素的Belatacept的安全性和功效，作为移植后免疫抑制方案的组成部分，如SA1和上述2所述，促进肾脏同种异体治疗后肾脏同种异体移植后的长期存活。