Immune Mechanisms of Alloinjury

描述(申请人提供)：慢性肺移植排斥反应，也称为闭塞性细支气管炎综合征(BOS)，是一种炎症过程，最终导致移植肺的纤维闭塞；然而，涉及的确切机制(S)尚不清楚。我们的初步数据表明，CCR4/配体(CCL17和CCL22)的相互作用对同种异体移植排斥反应的传入和传出臂都很重要。具体而言，CCR4/配体 同种异体反应性传入臂中的生物轴通过促进：1)原始的CD4和CD8 T细胞归巢到次级淋巴组织，以及2)CD4辅助T细胞和抗原提呈细胞(APC)之间的结内相互作用，从而允许APC产生同种异体特异性CD8 T细胞，来协调同种异体致敏作用。同种异体反应性传出臂中的CCR4/配体生物轴促进：1)CD4辅助T细胞维持CD8记忆细胞的克隆性群体，并促进同种异体特异性CD8T细胞向移植物的募集，最终导致慢性肺移植物功能障碍。这一提议产生的发现将成为未来药物试验的基础，这些药物可以抑制CCR4/配体的相互作用，目的是预防/治疗肺移植后的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.