The Effect of a Desensitization Protocol in Highly Sensitized Renal Transplant Recipients on T Follicular Helper Cells

脱敏方案对高度敏感的肾移植受者中滤泡辅助 T 细胞的影响

• 批准号: 10748009
• 负责人: Joseph M Ladowski
• 金额: $ 7.75万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-15 至 2024-07-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10748009
• 关键词: Address; Adrenal Cortex Hormones; Allografting; Antibodies; Antibody Formation; Antigens; B-Lymphocytes; Binding; Biological Assay; Calcineurin; Cell Communication; Cell Compartmentation; Cell Proliferation; Cells; Client satisfaction; Coculture Techniques; Complement; Cryopreservation; Development; End stage renal failure; Failure; Flow Cytometry; Frequencies; Future; Graft Rejection; Helper-Inducer T-Lymphocyte; Hemodialysis; Immunoglobulin G; Immunoglobulin M; Immunosuppressive Agents; Individual; Kidney; Kidney Transplantation; Kinetics; Major Histocompatibility Complex; Mediator; Modeling; Organ; Organ failure; Outcome; Patients; Peripheral Blood Mononuclear Cell; Phenotype; Play; Population; Pregnancy; Process; Production; Proliferating; Protocols documentation; Publishing; Regimen; Reporting; Risk; Role; Sampling; Sampling Studies; Severities; Solid; T cell receptor repertoire sequencing; Testing; Therapeutic; Transfusion; Transplant Recipients; Transplantation; Waiting Lists; allotransplant; antibody-mediated rejection; blood product; cost; cytokine; desensitization; donor-specific antibody; experience; experimental study; functional status; graft dysfunction; graft failure; immunological status; improved outcome; insight; kidney allograft; lymph nodes; mortality; mycophenolate mofetil; nonhuman primate; post-transplant; prevent; protein complex; reconstitution; response; success; transplant model

PROJECT SUMMARY/ABSTRACT Title: The Effect of a Desensitization Protocol in Highly Sensitized Renal Transplant Recipients on T Follicular Helper Cells Abstract: Kidney transplantation is the definitive and preferred treatment for end-stage renal disease given it is superior in cost, outcomes, complications, and patient satisfaction compared to hemodialysis. Long-term transplant success is limited by antibody formation and associated antibody-mediated rejection (AMR). Individuals with antibodies against a broad group of donors are considered “highly-sensitized” individuals. Highly-sensitized individuals have a smaller pool of potential donors and experience worse outcomes. Strategies to transplant these individuals, such as desensitization, have so far been unsuccessful. We need to better understand how antibodies are formed and develop strategies to prevent antibody formation and rejection. T follicular helper (Tfh) cells are known to be essential to antibody formation. A particular subset of Tfh cells, Tfh2 & Tfh17, are thought to be responsible for production of the complement-fixing IgG and IgM antibodies that are required for AMR. It is unknown what role Tfh2 & Tfh17 play in the process of sensitization and their response to desensitization. I hypothesize that Tfh2 & Tfh17 are a) predictive of DSA development and graft rejection in the sensitized individual, and b) reconstitution of these cells represents immunosuppressant failure. To test my hypothesis, I plan to use cryopreserved samples from a sensitized non-human primate model of transplantation. I will study samples A) during the process of sensitization and B) during a desensitization protocol. I will use flow cytometry and T cell receptor sequencing to characterize how Tfh2 & Tfh17 cells proliferate during sensitization. I will determine if differences exist between the circulating and lymph node compartment of these cells. Cytokine release and Ig production assays will be used to observe how Tfh cells functionally respond to desensitization protocols; TCR sequencing will confirm Tfh2 & Tfh17 depletion following desensitization with reconstitution proceeding graft rejection. In summary, I believe Tfh2 & Tfh17 cells play a critical role in antibody formation and the resultant AMR. If my hypothesis is correct, reconstitution of these population could represent immunosuppressant failure and these cells could serve as a potential target for future immunosuppressive protocols.

项目摘要/摘要 标题： 脱敏方案在高度敏化的肾移植受者中的影响 卵泡辅助细胞 抽象的： 肾脏移植是终末期肾脏疾病的确定性和优选治疗方法 与血液透析相比，成本，结局，并发症和患者满意度优越。长期 移植成功受抗体形成和相关抗体介导的排斥（AMR）的限制。 针对广泛捐助者的抗体的个体被认为是“高度敏感”的个体。 高度敏感的人的潜在捐助者群较少，并且会经历更糟糕的结果。 到目前为止，移植这些人（例如脱敏）的策略未成功。我们 需要更好地了解抗体的形成方式并制定防止抗体形成的策略 和拒绝。 T卵泡辅助器（TFH）细胞已知对于抗体形成至关重要。一个特定子集 TFH细胞TFH2和TFH17被认为是造成固定IgG和IgM的原因 AMR所需的抗体。尚不清楚TFH2和TFH17在过程中扮演什么角色 敏化及其对脱敏的反应。我假设TFH2和TFH17是A） 敏感个体中的DSA发育和移植排斥，b）重构这些细胞 代表免疫抑制剂衰竭。 为了检验我的假设，我计划使用来自敏感非人类灵长类动物的冷冻保存样品 移植模型。我将研究样本a）在灵敏度和b）期间 脱敏协议。我将使用流式细胞术和T细胞受体测序来表征TFH2 ＆TFH17细胞在灵敏度期间增殖。我将确定循环之间是否存在差异 这些细胞的淋巴结区室。细胞因子释放和IG生产测定将用于 观察TFH细胞对脱敏方案的响应方式； TCR测序将确认TFH2 ＆TFH17脱敏后耗尽，并进行了重组的拒绝。 总而言之，我认为TFH2和TFH17细胞在抗体形成中起着至关重要的作用 AMR。如果我的假设是正确的，那么这些人群的重建可能代表免疫抑制剂 失败和这些细胞可以作为未来免疫抑制方案的潜在目标。