Tertiary Lymphoid Organs in Transplantation

移植中的第三淋巴器官

• 批准号: 9796264
• 负责人: Martin H Oberbarnscheidt
• 金额: $ 38.56万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-17 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9796264
• 关键词: Acute; Address; Allografting; Antibodies; Antibody Formation; Applications Grants; Atherosclerosis; Autoimmunity; B-Cell Activation; B-Lymphocytes; Biopsy; Cell physiology; Chronic; Chronic rejection of renal transplant; Complement; Data; Experimental Models; Functional disorder; Goals; Graft Rejection; Helper-Inducer T-Lymphocyte; High Endothelial Venule; Human; Image; Immune response; Immunologic Techniques; Immunologics; Incidence; Interruption; Kidney Transplantation; Knowledge; Laboratory Animals; Light; Lymphoid; Lymphoid Cell; Lymphoid Tissue; Malignant Neoplasms; Mediating; Molecular; Mus; Organ; Organ Transplantation; Outcome; Pathogenesis; Pathway interactions; Patients; Play; Process; Regulatory T-Lymphocyte; Rheumatoid Arthritis; Role; Severity of illness; Solid; Structure; Structure of aggregated lymphoid follicle of small intestine; Synovial Membrane; T-Lymphocyte; Testing; Therapeutic immunosuppression; Time; Tissues; Transplantation; allograft rejection; chronic infection; cytokine; experimental study; heart allograft; immune activation; immune function; improved; insight; isoimmunity; kidney allograft; lung allograft; lymph nodes; novel therapeutics; outcome forecast; prevent; skin allograft; transplant model; two-photon

Abstract In solid organ transplantation, immunosuppressive therapy has significantly improved short-term organ allograft survival by reducing acute rejection rates. However, chronic rejection - mediated by T cells, antibodies (Abs), or both - has not declined in incidence and remains an important obstacle to long-term allograft survival. A likely, important contributor to the pathogenesis of chronic rejection is the formation of tertiary lymphoid organs (TLO) within the graft. Evidence that TLO play a causative role in rejection derives from both mice and humans, as TLO have been documented in a majority of chronically rejected mouse and human allografts, and experimental models have shown that they support naïve T and B cell activation and influence graft outcome. Moreover, analysis of human renal allograft biopsies has demonstrated B cell hypermutation and Ab production within TLO. Together, these studies support the hypothesis that TLO are niduses of local (intragraft) immune activation in chronic allograft rejection. In Aim 1 of this grant application, we will establish the cause-effect relationship between TLO and chronic renal transplant rejection in the mouse. In Aim 2, we will investigate the cellular and cytokine mechanisms responsible for TLO formation in allografts, with particular emphasis on innate lymphoid cell (ILC) subsets. In Aim 3, we will delineate the specific immunologic functions of TLO in chronic rejection, with focus on B cell activation and antibody production. The proposed studies address the unmet challenge of treating and preventing chronic rejection and will also shed light on other conditions in which TLO play a prominent role, such as autoimmunity and cancer.

抽象的 在实体器官移植中，免疫抑制治疗显着改善短期同种异体器官移植 通过降低急性排斥率来生存。然而，慢性排斥反应 - 由 T 细胞、抗体 (Abs) 或 两者 - 发病率并未下降，仍然是同种异体移植物长期存活的重要障碍。一个可能的， 慢性排斥反应发病机制的重要贡献者是三级淋巴器官（TLO）的形成 移植物内。 TLO 在排斥反应中发挥因果作用的证据来自小鼠和人类，因为 TLO 已在大多数长期排斥的小鼠和人类同种异体移植物中得到记录，并且实验 模型表明它们支持幼稚 T 细胞和 B 细胞激活并影响移植结果。而且， 对人肾同种异体移植物活检的分析表明，TLO 内存在 B 细胞超突变和抗体产生。 总之，这些研究支持这样的假设：TLO 是局部（移植物内）免疫激活的巢穴。 慢性同种异体移植排斥。在本次拨款申请的目标 1 中，我们将建立因果关系 TLO 与小鼠慢性肾移植排斥反应之间的关系。在目标 2 中，我们将研究细胞和 负责同种异体移植物中 TLO 形成的细胞因子机制，特别强调先天淋巴 细胞 (ILC) 子集。在目标 3 中，我们将描述 TLO 在慢性排斥反应中的特异性免疫功能，其中 专注于 B 细胞激活和抗体产生。拟议的研究解决了治疗中尚未解决的挑战 并预防慢性排斥反应，还将阐明 TLO 发挥重要作用的其他情况， 例如自身免疫和癌症。