Depletion, Repopulation and Tolerance in Sensitized Recipients

致敏受体的消耗、再生和耐受性

• 批准号: 10214496
• 负责人: Stuart Johnston Knechtle
• 金额: $ 109.4万
• 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 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10214496
• 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; 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; Serology; Shapes; Sirolimus; Structure of germinal center of lymph node; T-Lymphocyte; TNFSF5 gene; Therapeutic; Transfusion; Transplant Recipients; Transplantation; Viral; Virus Diseases; alemtuzumab; allotransplant; comparative; desensitization; kidney allograft; nonhuman primate; polyclonal antibody; post-transplant; preservation; prevent; response; tocilizumab

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(克内克特尔，项目负责人) 而围手术期应用多克隆抗体或阿伦图珠单抗去除免疫细胞 在美国的大多数肾脏移植中，我们的实验室都显示了人类和非人类灵长类动物(NHP)的肾移植。 体内平衡耗竭后的再繁殖与B细胞激活、BAFF水平升高有关， 和新的供体特异性同种异体抗体(DSA)。我们还表明，贝拉塔塞特有能力 在耗尽后的NHP中抑制这种DSA。最近，我们在一个预敏化的NHP模型中展示了 阻断CD28和CD154结合蛋白酶体抑制可显著降低同种异体抗体 移植前的水平，扰乱生发中心，降低浆细胞数量。然而，耗尽了 蛋白酶体单独抑制浆细胞也与生发中心和TFH细胞的激活有关。 因此，免疫细胞的耗尽对以下方面既有好处也有坏处 宽容。该项目试图确定致敏宿主中免疫细胞耗尽的因素，这些因素促进了 宽容。我们认为淋巴细胞和浆细胞的耗尽和随后的稳态再繁殖 既提供了塑造同种异体反应免疫系统以支持耐受性的机会，也存在破坏的风险 调节、点燃病毒感染和诱导同种异体反应克隆的激活。我们假设 致敏宿主中免疫细胞耗尽的后果通过免疫产生代偿反应 这一系统是可预测的，需要通过治疗控制来促进耐受性。要探索这一点 假设，我们提出了三个具体目标：1)开发更安全、更有效的手段来降低 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辅助辅助治疗；2) 使用耗竭、供者特异性输血和雷帕霉素来重塑免疫谱系以促进 致敏受者的调节、AICD和前耐受性内稳态再种群；以及3)评估 贝拉泰普与雷帕霉素合用与不合用作为移植后成分的安全性和有效性 免疫抑制方案促进脱敏治疗后移植肾的长期存活 如上文SA1和2中所述。