Deletion Of Smad3 Improves Cardiac Allograft Rejection In Mice

ObjectivesAllograft rejection is the major problem in clinical organ transplantation. TGF-β1/Smad3 pathway directly and indirectly regulates CD4+T helper (Th) cell differentiation that plays critical roles in acute allograft rejection. We used Smad3 knockout (KO) mice as recipients to develop an allogeneic heart transplantation model and investigated the role of Smad3 in Th cell immune response in allograft rejection.MethodsDonor hearts from BALB/c mice were heterotopically transplanted into either C57BL/6 Smad3 KO or wildtype (WT) mice. Allograft survival time was calculated by surveillance of daily abdominal palpation. Heart transplantation from BALB/c mice to BALB/c mice was built as control group. Transplanted hearts, blood, spleens were harvested when the mice were sacrificed to test the inflammation and immune indexes.ResultsWe report here that Smad3 is a key transcriptional factor of TGF-β signaling that differentially regulates T cell immune responses in a mouse model of cardiac allograft rejection in which donor hearts from BALB/c mice were transplanted into Smad3 knockout (KO) and wild type (WT) mice. Results showed that the cardiac allograft survival was prolonged in Smad3 KO recipients. This allograft protection was associated with a significant inhibition of proinflammatory cytokines (IL-1β, TNF-α, and MCP-1) and infiltration of neutrophils, CD3+T cells, and F4/80+macrophages. Importantly, deletion of Smad3 markedly suppressed T-bet and IFN-y while enhancing GATA3 and IL-4 expression, resulting in a shift from the Thl to Th2 immune responses. Furthermore, mice lacking Smad3 were also protected from the Th17-mediated cardiac injury, although the regulatory T cell (Treg) response was also suppressed.ConclusionsIn conclusion, Smad3 is an important participant in mediating cardiac allograft rejection. Loss of Smad3 results in a shift from Thl to Th2 but suppressing Th17 immune responses. Thus, modulation of TGF-β/Smad3 signaling may be a novel therapy for acute allograft rejection.