Immune Mechanisms of Alloinjury

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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: ) the homing of naive 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. PUBLIC HEALTH RELEVANCE: Chronic lung allograft rejection, also known as bronchiolitis obliterans syndrome (BOS), is an inflammatory process that ends in fibro-obliteration of the allograft airways. In this proposal we will test the overall hypothesis that the CCR4/ligand biological axis during alloreactivity orchestrates rejection by promoting: 1) the homing of naive CD4 and CD8 T cells to secondary lymphoid tissues; 2) the intranodal interactions between CD4 helper T cell and antigen presenting cells (APC) which licenses the APC to generate allospecific CD8 T cells; 3) CD4 helper T cells to maintain clonal populations of CD8 memory cells and 4) enhances the recruitment of allospecific CD8 T cells to the allograft that eventually leads to chronic lung allograft dysfunction. Our human and pre-clinical murine data from this proposal will lead to the use of CCR4/ligand inhibition in the human lung transplantation setting which will reduce human BOS and improve overall survival.