Depletion, Repopulation and Tolerance in Sensitized Recipients

摘要-项目2（Knechtle，项目负责人） 虽然在围手术期使用多克隆抗体或阿仑单抗进行免疫细胞耗竭， 美国大部分的肾移植手术，我们的实验室在人类和非人类灵长类动物（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）。我们还证明了贝拉西普能够 在消耗后抑制NHP中的这种DSA。最近，我们在一个presensitized NHP模型中证明了 阻断CD 28和CD 154与蛋白酶体抑制组合显著降低同种抗体 移植前的水平，破坏生发中心和降低浆细胞数量。然而， 浆细胞通过单独的蛋白酶体抑制也与生发中心和Tfh细胞活化有关。 因此，免疫细胞的消耗导致关于免疫缺陷的有益和有害后果。 宽容该项目旨在确定致敏宿主中免疫细胞耗竭的要素， 宽容我们认为淋巴细胞和浆细胞的耗竭以及随后的稳态再增殖 这既提供了塑造同种异体反应性免疫库以促进耐受的机会，也存在破坏免疫耐受的风险。 调节，点燃病毒感染并诱导同种异体反应性克隆的激活。我们假设 致敏宿主中免疫细胞耗竭的结果产生免疫细胞的代偿反应， 这些系统是可预测的，需要在治疗上加以控制，以促进耐受性。探索这个 假设，我们提出了3个具体目标：1）开发更安全，更有效的手段，以降低量 以及同种异体特异性抗体、浆细胞和记忆B细胞的数量，这些细胞阻止同种异体移植， 肾移植前蛋白酶体抑制与补充辅助治疗; 2） 使用耗竭、供体特异性输血和雷帕霉素重塑免疫库， 调节、AICD和致敏受体中的促耐受稳态再增殖;以及3）评估 贝拉西普与雷帕霉素联合或不联合作为移植后药物成分的安全性和有效性 免疫抑制剂对脱敏治疗后移植肾长期存活的影响 如上文SA 1和SA 2中所述。

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.