Tertiary Lymphoid Organs in Transplantation

移植中的第三淋巴器官

• 批准号: 10378520
• 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/10378520
• 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 Transplantation; Outcome; Pathogenesis; Pathway interactions; Patients; Peyer' s Patches; Play; Process; Prognosis; Regulatory T-Lymphocyte; Rheumatoid Arthritis; Role; Severity of illness; Solid; Synovial Membrane; T-Lymphocyte; Testing; Therapeutic immunosuppression; Time; Tissues; Transplantation; Wild Type Mouse; allograft rejection; chronic infection; cytokine; experimental study; heart allograft; immune activation; immune function; improved; insight; isoimmunity; kidney allograft; lung allograft; lymph nodes; novel therapeutics; prevent; secondary lymphoid organ; skin allograft; tertiary lymphoid organ; 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 在固体器官移植中，免疫抑制疗法已显着改善了短期器官外观 通过降低急性排斥率来生存。但是，慢性排斥 - 由T细胞，抗体（ABS）或 两者都没有在事件中下降，并且仍然是同种异体生存的重要障碍。可能， 慢性排斥反应的发病机理的重要原因是三级淋巴机构（TLO）的形成 在移植物中。 TLO在拒绝中起因作用的证据，源自小鼠和人类，如Tlo 在大多数长期拒绝的小鼠和人合金中都记录了记录 模型表明它们支持幼稚的T和B细胞激活并影响移植结果。而且， 人类肾脏同种异体活检的分析表明，在TLO内，B细胞超数和AB产生。 总之，这些研究支持以下假设，即TLO是局部（内部）免疫激活 慢性同种异体移植排斥。在本赠款申请的目标1中，我们将建立因果关系 在小鼠中TLO和慢性肾移植排斥之间。在AIM 2中，我们将研究细胞和 负责TLO形成合金的细胞因子机制，特别着重于先天淋巴样 细胞（ILC）子集。在AIM 3中，我们将描述TLO在慢性排斥中的特定免疫功能，并使用 专注于B细胞激活和抗体产生。拟议的研究解决了治疗的未满足挑战 并防止慢性拒绝，还将阐明TLO发挥重要作用的其他条件 例如自身免疫性和癌症。