Lung transplantation is currently the only therapeutic option available for a variety of end-stage pulmonary disorders. The major limitation to patient survival following transplantation is chronic rejection of the lung, called bronchiolitis obliterans (BO). T cell immunoglobulin and mucin domain 3 (Tim3) is a protein preferentially expressed on the surface of differentiated Th1 cells. Animal data suggests that Tim3 may play a critical role in transplantation tolerance, but it has never been studied in lung transplantation. Our laboratory has several mouse models that will allow us to specifically address the role of Tim3 in lung transplantation. Preliminary data suggests that in the absence of Tim3, immunologic balance leans toward tolerance rather than rejection. Our hypothesis is that Tim3 is an important regulatory protein that helps mediate tolerance in lung transplantation and that manipulation of Tim3 activity could enhance transplant function and survival. We further hypothesize that the effects of Tim3 are up- and down-regulated in order to control the generation and termination of a Th1 response, and that this effect may in part be due to interactions between CD8+ lymphocytes and antigen presenting cells. Specifically, we seek to determine the following: 1) the role of Tim3 in lung allograft rejection in vivo using a murine model of BO, 2) the role of Tim3 in regulating CD8+ effector T lymphocytes both in vitro and in vivo, and (3) the expression profile of Tim3 on leukocytes and antigen presenting cells in human lungs following lung transplantation and the correlation of these findings with the presence of BO. These experiments will comprehensively delineate the role of Tim3 in the development of BO and in CD8+ T cell-mediated rejection. Correlation of our findings with human disease may identify new diagnostic markers for BO and offer insights about Tim3 as a potential therapeutic target to improve outcomes in lung transplantation. Lung transplantation is currently the only therapeutic option available for a variety of end-stage pulmonary disorders. Despite advances in surgical techniques and immunosuppression, patients with lung transplantation suffer from worse outcomes compared with other solid organ transplants. Investigation of pathways that regulate the immune system, such as Tim3, may help to discover novel therapies that could improve outcomes for patients following lung transplantation.
| Cho, Josalyn L; Roche, Marly I; Sandall, Barry et al. (2012) Enhanced Tim3 activity improves survival after influenza infection. J Immunol 189:2879-89 |
