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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL112990-01
Application #
8272475
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Eu, Jerry Pc
Project Start
2012-05-15
Project End
2017-02-28
Budget Start
2012-05-15
Budget End
2013-02-28
Support Year
1
Fiscal Year
2012
Total Cost
$447,952
Indirect Cost
$157,074
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Shino, Michael Y; Weigt, S Samuel; Li, Ning et al. (2013) CXCR3 ligands are associated with the continuum of diffuse alveolar damage to chronic lung allograft dysfunction. Am J Respir Crit Care Med 188:1117-25
Gregson, Aric L; Wang, Xiaoyan; Weigt, S Sam et al. (2013) Interaction between Pseudomonas and CXC chemokines increases risk of bronchiolitis obliterans syndrome and death in lung transplantation. Am J Respir Crit Care Med 187:518-26