实体器官移植仍然是终末期器官衰竭的挽救生命的治疗方法，但慢性排斥仍然是长期同种异体移植结果的主要障碍，并且尚未得到实质性改善。第三淋巴器官（TLO）是在慢性炎症条件下形成的异位淋巴结构，来自人体移植的证据表明，TLO 在经历慢性排斥的同种异体移植物中定期形成。在这项研究中，我们利用小鼠肾移植模型和对 TLO 形成所必需的淋巴毒素 α (LTα) - 淋巴毒素 β 受体 (LTβR) 途径的操作来定义 TLO 在移植中的作用。我们表明，在同种异体移植物中唯一的淋巴器官是 TLO 的模型中，移植物内 TLO 足以激活同种免疫反应并介导移植排斥。当移植到具有正常次级淋巴器官的受体时，移植物 TLO 或 LTα 过度表达的存在会加速排斥反应。如果供体移植物中的 LTβR 通路被破坏，TLO 的形成就会被消除，移植物的存活时间也会延长。肾 TLO 的活体显微镜检查表明，TLO 中的局部 T 和 B 细胞激活与在次级淋巴器官中观察到的相似。总之，我们证明 TLO 中的免疫激活有助于局部免疫反应，导致早期同种异体移植失败。因此，TLO 和 LTαβ-LTβR 通路是限制局部免疫反应和防止同种异体移植排斥的主要目标。这些发现适用于其他疾病，例如自身免疫或肿瘤，在这些疾病中，限制或增强局部免疫反应是有益的，可以改善疾病结果。

Solid organ transplantation remains the life-saving treatment for end-stage organ failure, but chronic rejection remains a major obstacle to long-term allograft outcomes and has not improved substantially. Tertiary lymphoid organs (TLO) are ectopic lymphoid structures that form under conditions of chronic inflammation, and evidence from human transplantation suggests that TLO regularly form in allografts undergoing chronic rejection. In this study, we utilized a mouse renal transplantation model and manipulation of the lymphotoxin alpha (LTα) - lymphotoxin beta receptor (LTβR) pathway, which is essential for TLO formation, to define the role of TLO in transplantation. We showed that intragraft TLO are sufficient to activate the alloimmune response and mediate graft rejection in a model where the only lymphoid organs are TLO in the allograft. When transplanted to recipients with a normal set of secondary lymphoid organs, the presence of graft TLO or LTα overexpression accelerated rejection. If the LTβR pathway was disrupted in the donor graft, TLO formation was abrogated, and graft survival prolonged. Intravital microscopy of renal TLO demonstrated that local T and B cell activation in TLOs is similar to that observed in secondary lymphoid organs. In summary, we demonstrated that immune activation in TLO contributes to local immune responses, leading to earlier allograft failure. TLO and the LTαβ-LTβR pathway are therefore prime targets to limit local immune responses and prevent allograft rejection. These findings are applicable to other diseases such as autoimmunity or tumors, where either limiting or boosting local immune responses is beneficial and improves disease outcomes.