Tertiary Lymphoid Organs in Transplantation

摘要 在实体器官移植中，免疫抑制治疗显著改善了短期器官移植 降低急性排斥反应率。然而，由T细胞、抗体（Abs）或 两者的发生率都没有下降，仍然是同种异体移植物长期存活的重要障碍。很可能， 慢性排斥反应发病机制的一个重要因素是三级淋巴样器官（TLO）的形成 在移植物内。TLO在排斥反应中起致病作用的证据来自小鼠和人类， 在大多数慢性排斥的小鼠和人同种异体移植物中， 模型显示它们支持幼稚T和B细胞活化并影响移植结果。此外，委员会认为， 对人肾同种异体移植物活组织检查的分析已经证实了TLO内的B细胞超突变和Ab产生。 总之，这些研究支持了TLO是局部（移植物内）免疫激活的病灶的假设。 慢性同种异体移植排斥在本拨款申请的目的1中，我们将建立因果关系 TLO和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，特别强调先天性淋巴 细胞（ILC）子集。在目的3中，我们将描述TLO在慢性排斥反应中的特异性免疫功能， 专注于B细胞活化和抗体产生。拟议的研究解决了治疗的未满足的挑战 和预防慢性排斥反应，也将揭示TLO发挥重要作用的其他疾病， 例如自身免疫和癌症。

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.