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/文摘