TIM-4 blockade of KCs combined with exogenous TGF-β injection helps to reverse acute rejection and prolong the survival rate of mice receiving liver allografts

An acute reaction response (AR) following liver transplantation (LT) is caused by immune responses that are primarily mediated by T lymphocytes. Kupffer cells (KCs) are the largest antigen presenting cell (APC) group in vivo and are the primary modulators of the inflammatory or tolerogenic immune response in liver tissues. T cell immunoglobulin-domain and mucin-domain-4 (TIM-4), the only TIM protein not expressed on T cells, is expressed on APCs; suggesting that it mediates the various immune responses. However, to the best of our knowledge, the role of TIM-4 expressed by KCs in LT injury remains unknown. The present study aimed to explore whether and how TIM-4 expressed by KCs is involved in the AR of liver allografts. Orthotopic liver transplantation (OLT) was performed in mice to establish a model of AR and results demonstrated that LT may lead to the augmented expression of TIM-4 in activated KCs. It was also revealed that TIM-4 blockade markedly attenuated AR injury in vivo via the nuclear factor-κB (NF-κB) and p38 mitogen-activated protein kinase (p38 MAPK) signaling pathways. In addition, levels of transforming growth factor-β (TGF-β) were increased following TIM-4 blockade. Furthermore, in a KC/cluster of differentiation (CD)4(+) T cell co-culture system, blocking TIM-4 inhibited T helper 2 (Th2) differentiation, stimulated the conversion of naive (CD)4(+) T cells into CD4(+)CD25(+)Forkhead box protein p3(+) T regulatory cells and suppressed interleukin-4/signal transducer and activator of transcription 6/transcription factor gata3 signaling. These effects were enhanced following the addition of TGF-β. It was also demonstrated that LT mouse models treated with TIM-4 blockade in combination with exogenous TGF-β injections, increased the survival times of mice and enhanced the amelioration of AR in LT. These results indicate that blocking the expression of TIM-4 by KCs via exogenous TGF-β injection may be an effective therapeutic strategy to inhibit the AR of liver allografts.