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.

项目总结/摘要 职务名称： 高致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决定性和首选治疗方法， 与血液透析相比，在成本、结局、并发症和患者满意度方面具有上级优势。长期 移植成功受到抗体形成和相关抗体介导的排斥（AMR）的限制。 具有针对广泛供体群体的抗体的个体被认为是“高度致敏”个体。 高度敏感的人有一个较小的潜在捐助者池和经验更差的结果。 移植这些个体的策略，如脱敏，迄今为止还没有成功。我们 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（Tfh）细胞对于抗体形成是必需的。的特定子集 Tfh细胞Tfh 2和Tfh 17被认为负责产生补体固定IgG和IgM， AMR所需的抗体。目前尚不清楚Tfh 2和Tfh 17在这一过程中起什么作用。 致敏及其对脱敏的反应。我假设Tfh 2和Tfh 17是a）预测 致敏个体的DSA发展和移植排斥，和B）这些细胞的重建 代表免疫抑制剂失效 为了验证我的假设，我计划用一只致敏的非人类灵长类动物的冷冻样本 移植模型。本人将在致敏过程中研究样品A），在致敏过程中研究样品B）， 脱敏方案。我将使用流式细胞术和T细胞受体测序来表征Tfh 2 & Tfh 17细胞在致敏期间增殖。我将确定是否存在差异之间的循环 和淋巴结区室。将使用细胞因子释放和IG产生试验， 观察Tfh细胞如何在功能上对脱敏方案作出反应; TCR测序将确认Tfh 2 和Tfh 17在脱敏后耗尽，重建进行移植物排斥。 总之，我相信Tfh 2和Tfh 17细胞在抗体形成和由此产生的免疫应答中起着关键作用。 AMR。如果我的假设是正确的，这些人群的重组可能代表免疫抑制剂 这些细胞可以作为未来免疫抑制方案的潜在靶点。