Determinants of donor-specific B cell tolerance in kidney transplantation in sensitized recipients

致敏受者肾移植中供体特异性 B 细胞耐受的决定因素

• 批准号: 10622058
• 负责人: Jean Kwun
• 金额: $ 118.11万
• 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 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10622058
• 关键词: Adjuvant Therapy; Alloantigen; Allogenic; Animals; Antibodies; Antigen Presentation; Antigens; Apoptotic; Award; B cell repertoire; B cell therapy; B-Cell Activation; B-Lymphocytes; B-cell receptor repertoire sequencing; Binding; Bone Marrow; Cell Culture Techniques; Cells; Clinical; Clinical Trials; Complement; Cytomegalovirus; Dialysis procedure; Disease; Donor person; Elements; End stage renal failure; Exposure to; Face; Female; Goals; Graft Survival; HLA Antigens; Health Care Costs; Immune; Immune Tolerance; Immune response; Immunity; Immunobiology; Immunosuppression; Infusion procedures; Kidney; Kidney Transplantation; Knowledge; Lymphocyte Depletion; Lymphoproliferative Disorders; Maintenance; Modeling; Molecular; Morbidity - disease rate; Outcome; Pathway interactions; Patients; Phenotype; Plasma Cells; Population; Pregnancy; Proteasome Inhibitor; Publishing; Quality of life; Regulation; Risk; Shapes; Structure of germinal center of lymph node; T memory cell; T-Lymphocyte; Testing; Therapeutic; Time; Transfusion; Transplant Recipients; Transplantation; Transplantation Tolerance; Vaccines; Viral; Virus Diseases; Waiting Lists; antibody-mediated rejection; cost comparison; desensitization; donor-specific antibody; efficacy evaluation; experience; immunoregulation; improved; mortality; nonhuman primate; parous; pathogenic virus; pharmacologic; plasma cell differentiation; post-transplant; preservation; prevent; response; side effect; single cell technology; targeted agent; targeted treatment; vaccine immunogenicity

ABSTRACT – Project 2 Kidney transplantation is the preferred treatment for end-stage renal failure due to improved patient survival, quality of life, and healthcare costs compared to dialysis. However, sensitized patients with preformed human leukocyte antigen (HLA) antibodies due to prior exposure to allogeneic HLA via transfusion, pregnancy, and previous transplantation face lower rates of transplantation that result in higher waitlist mortality. Furthermore, even if these patients are transplanted after desensitization, they frequently have worse short- and long-term graft survival compared to non-sensitized patients due to increased risk of rejection. We have shown that a combination of plasma cell targeting with proteasome inhibitor (carfilzomib) and co-stimulation blockade with belatacept reduces preformed antibody prior to kidney transplantation in sensitized nonhuman primates (NHP). Together with cytolytic induction, this pharmacological desensitization prevented early antibody-mediated rejection (AMR) and significantly prolonged graft survival in sensitized recipients. However, the peri-transplant desensitization was not able to control late AMR. Interestingly, post-transplant belatacept was able to suppress donor-specific antibody (DSA), disrupt germinal centers, and prevent plasma cell increase in NHP following depletion. This approachachievedprolonged graft survival with less AMR but promoted significant complications including viral reactivation and post-transplant lymphoproliferative disorders (PTLD). We hypothesize that the more specific (and even donor-specific) targeting of humoral responses including B cells, plasma cells, and complement may better control post-transplant AMR in sensitized hosts and create a therapeutic window to induce donor-specific tolerance. We will evaluate guided homeostatic repopulation with apoptotic donor cells for re-establishing an immune repertoire that favors transplantation tolerance. To explore this hypothesis, we propose 3 specific aims: 1) To evaluate adjuvant therapies targeting down-stream post-transplant humoral responses following desensitization. 2) To determine efficacy of antigen-specific pro-tolerant approaches in highly sensitized NHPs recipients. 3) To identify the functional phenotype of allo-specific T and B cell repertoires required to establish tolerance in sensitized recipients.

摘要-项目2 肾移植是终末期肾衰竭的首选治疗方法，因为它可以提高患者的生存率， 生活质量和医疗成本。然而，使用预成型人体的致敏患者 白细胞抗原（HLA）抗体，由于先前通过输血、妊娠和 以前的移植面临较低的移植率，导致较高的等待名单死亡率。此外，委员会认为， 即使这些患者在脱敏后进行移植，他们也经常会有更差的短期和长期反应。 与非致敏患者相比，由于排斥风险增加，移植物存活率降低。我们已经证明， 浆细胞靶向与蛋白酶体抑制剂（卡非佐米）的组合和共刺激阻断与 belatacept减少致敏非人灵长类动物（NHP）肾移植前形成的抗体。 与细胞溶解诱导一起，这种药理学脱敏阻止了早期抗体介导的细胞毒性。 排斥反应（AMR），并显着延长移植物的存活在致敏受体。然而，移植前后 脱敏不能控制晚期AMR。有趣的是，移植后贝拉西普能够抑制 供体特异性抗体（DSA）破坏生发中心，并防止NHP中浆细胞增加 耗尽这种方法延长了移植物的存活时间，减少了AMR，但增加了严重的并发症 包括病毒再活化和移植后淋巴增生性疾病（PTLD）。我们假设 更特异性（甚至是供体特异性）靶向体液应答，包括B细胞、浆细胞， 补体可以更好地控制致敏宿主中的移植后AMR，并创造一个治疗窗口， 诱导供体特异性耐受。我们将评估凋亡供体细胞的引导稳态再增殖， 重建有利于移植耐受的免疫库。为了验证这个假设，我们 提出3个具体目标：1）评估针对移植后体液免疫下游的辅助治疗， 脱敏后的反应。2)为了确定抗原特异性促耐受方法在 高度敏感的国家卫生方案受益者。3)鉴定同种异体特异性T和B细胞库的功能表型 需要在致敏受体中建立耐受性。