Immune Mechanisms of Alloinjury

描述（由申请人提供）：慢性肺同种异体移植物排斥反应，也称为闭塞性细支气管炎综合征（BOS），是一种炎症过程，最终导致同种异体移植物气道纤维闭塞;然而，涉及的确切机制尚不清楚。我们的初步数据表明，CCR 4/配体（CCL 17和CCL 22）的相互作用是重要的同种异体移植排斥反应的传入和传出臂。具体而言，CCR 4/配体 同种异体反应性的传入臂中的生物轴通过促进：1）初始CD 4和CD 8 T细胞归巢至次级淋巴组织和2）CD 4辅助T细胞和抗原呈递细胞（APC）之间的结内相互作用（其允许APC产生同种异体特异性CD 8 T细胞）来协调同种异体致敏。同种异体反应性的传出臂中的CCR 4/配体生物轴促进：1）CD 4辅助T细胞维持CD 8记忆细胞的克隆群体，并增强同种异体特异性CD 8 T细胞向同种异体移植物的募集，最终导致慢性肺同种异体移植物功能障碍。该提案产生的发现将成为未来抑制CCR 4/配体相互作用的药物治疗试验的基础，目的是预防/治疗肺移植后BOS。

DESCRIPTION (provided by applicant): Chronic lung allograft rejection, also known as bronchiolitis obliterans syndrome (BOS), is an inflammatory process that ends in fibro-obliteration of the allograft airways; however the exact mechanism(s) involved are unknown. Our preliminary data demonstrates that CCR4/ligands (CCL17 and CCL22) interaction is important for both the afferent and efferent arms of allograft rejection. Specifically, CCR4/ligand biological axis in the afferent arm of alloreactivity orchestrates allosensitization by promoting: 1) the homing of naïve CD4 and CD8 T cells to secondary lymphoid tissues and 2) the intranodal interactions between CD4 helper T cell and antigen presenting cells (APC) which licenses the APC to generate allospecific CD8 T cells. The CCR4/ligand biological axis in the efferent arm of alloreactivity promotes: 1) CD4 helper T cells to maintain clonal populations of CD8 memory cells and enhances the recruitment of allospecific CD8 T cells to the allograft that eventually leads to chronic lung allograft dysfunction. Discoveries generated by this proposal will be the basis for future therapeutic trials of pharmaceutical agents that inhibit CCR4/ligands interaction with the goal of preventing/treating BOS post-lung transplantation.