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同种异体器官移植 通过降低急性排斥率存活。然而，由T细胞、抗体(Abs)或 两者的发病率都没有下降，仍然是同种异体移植物长期存活的重要障碍。一种可能的， 第三淋巴器官(TLO)的形成是慢性排斥反应发生的重要因素 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 已在大多数长期排斥的小鼠和人类同种异体移植中被记录在案，并进行了实验 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。此外， 对人移植肾活检组织的分析表明，TLO内存在B细胞过度突变和抗体产生。 总之，这些研究支持这样的假设，即TLO是局部(移植物内)免疫激活的NIDUS。 慢性同种异体排斥反应。在这项赠款申请的目标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 同种异体移植物中TLO形成的细胞因子机制，特别强调先天淋巴系 单元(ILC)子集。在目标3中，我们将描述TLO在慢性排斥反应中的特定免疫功能， 重点关注B细胞的激活和抗体的产生。拟议的研究解决了治疗方面尚未满足的挑战 并防止慢性排斥反应，也将有助于阐明TLO在其中发挥突出作用的其他情况。 比如自身免疫和癌症。

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.