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 肾脏移植是由于改善患者生存而导致终末期肾衰竭的首选治疗方法， 与透析相比，生活质量和医疗费用。但是，敏感的患者预先形成了人类 白细胞抗原（HLA）抗体因输血，怀孕和 先前的移植面临较低的移植率，导致候补名单较高的死亡率。此外， 即使这些患者在脱敏后移植，他们也经常短期和长期差 与非敏感患者相比，由于排斥风险增加，移植物的存活率与非敏感患者相比。我们已经证明了 等离子体细胞靶向与蛋白酶体抑制剂（Carfilzomib）的结合，并与共同刺激阻塞 Belatacept在敏感的非人类原发性（NHP）中肾移植前还原了预制的抗体。 与细胞溶解诱导一起，这种药物脱敏阻止了早期抗体介导的 排斥（AMR）和敏感受体中的移植物生存率显着延长。但是，移植植物 脱敏无法控制晚期AMR。有趣的是，移植后Belatacept能够抑制 供体特异性抗体（DSA），破坏生发中心并防止NHP的血浆细胞增加 消耗。这种方法以较少的AMR为单位的嫁接存活率，但促进了显着的并发症 包括病毒重新激活和移植后淋巴细胞增生疾病（PTLD）。我们假设 更具体的（甚至是供体特异性的）靶向包括B细胞，浆细胞和 完成可以更好地控制敏感主机中移植后AMR，并创建一个治疗窗口 诱导特定的供体公差。我们将用凋亡供体细胞评估指导的稳态重填充 重新建立有利于移植耐受性的免疫曲目。为了探讨这一假设，我们 提案3特定目的：1）评估针对下游移植后体液的调整疗法 脱敏后的响应。 2）确定在 高度敏感的NHP受体。 3）识别异子特异性T和B细胞库的功能表型 需要在敏感接受者中建立公差。