Depletion, Repopulation and Tolerance in Sensitized Recipients

致敏受体的消耗、再生和耐受性

• 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
• 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

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，用多克隆抗体或阿仑单抗进行围手术期免疫细胞耗竭用于大多数肾移植，我们的实验室已经在人和非人灵长类动物（NHP）中显示，耗竭后的稳态再增殖与B细胞活化、BAFF水平升高和从头供体特异性同种抗体（DSA）有关。我们还表明贝拉西普能够在消耗后抑制NHP中的这种DSA。最近，我们在预致敏的NHP模型中显示，阻断CD 28和CD 154与蛋白酶体抑制相结合，可显著降低移植前同种抗体水平，破坏生发中心并降低浆细胞数量。然而，单独通过蛋白酶体抑制对浆细胞的消耗也与生发中心和Tfh细胞活化相关。因此，免疫细胞的耗竭导致耐受性方面的有益和有害后果。该项目旨在确定在致敏宿主中促进耐受性的免疫细胞耗竭的要素。我们认为，淋巴细胞和浆细胞耗竭和随后的稳态再增殖既提供了一个机会，以塑造同种异体反应性免疫库，有利于耐受，和风险，破坏调节，点燃病毒感染和诱导同种异体反应性克隆的激活。我们假设，致敏宿主免疫细胞耗竭的后果产生了免疫系统的代偿反应，这些反应是可预测的，需要在治疗上加以控制以促进耐受。为了探讨这一假说，我们提出了3个具体的目标：1）开发更安全和更有效的方法，以减少同种异体抗体，浆细胞和记忆B细胞的数量和数量，防止肾移植前使用蛋白酶体抑制剂和补充辅助治疗; 2）使用耗竭、供体特异性输血和雷帕霉素来重塑免疫库，以促进致敏受体中的调节、AICD和促耐受稳态再增殖;和3）评估贝拉西普与和不与雷帕霉素一起作为移植后免疫抑制方案的组分的安全性和有效性，所述免疫抑制方案促进如上文SA 1和2中所述的脱敏治疗后肾同种异体移植物的长期存活。