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： 高敏肾移植受者脱敏方案对T细胞的影响 滤泡辅助细胞 摘要： 肾移植是终末期肾病的最终和首选治疗方法，因为它是 与血液透析相比，在成本、结果、并发症和患者满意度方面都更优越。长期的 移植的成功受到抗体形成和相关抗体介导的排斥反应(AMR)的限制。 对一大群捐赠者产生抗体的个人被认为是“高度敏感”的个人。 高度敏感的人潜在捐赠者较少，结果更差。 移植这些个体的策略，如脱敏，到目前为止还没有成功。我们 需要更好地了解抗体是如何形成的，并制定预防抗体形成的策略 和拒绝。 已知T滤泡辅助细胞(TFH)是抗体形成所必需的。的特定子集 Tfh细胞，Tfh2和Tfh17，被认为负责产生补体固定的Ig G和Ig M AMR所需的抗体。目前尚不清楚Tfh2和Tfh17在这一过程中起什么作用。 敏化及其对脱敏的反应。我假设Tfh2和Tfh17是)预测 致敏个体的DSA发育和移植排斥反应，以及b)这些细胞的重建 代表免疫抑制药物失效。 为了验证我的假设，我计划使用冷冻保存的非人类灵长类动物的样本。 移植模式。我将研究样品A)在敏化过程中和B)在 脱敏方案。我将使用流式细胞术和T细胞受体测序来表征Tfh2如何 &Tfh17细胞在致敏过程中增殖。我会确定在循环中是否存在差异 以及这些细胞的淋巴结室。细胞因子释放和免疫球蛋白产生分析将用于 观察Tfh细胞对脱敏方案的功能反应；TCR测序将确认Tfh2 &Tfh17在脱敏后耗尽，重建后发生移植排斥反应。 总之，我认为Tfh2和Tfh17细胞在抗体的形成和由此产生的 AMR.如果我的假设是正确的，这些群体的重组可能代表着免疫抑制 失败，这些细胞可能成为未来免疫抑制方案的潜在靶点。