Introduction: We have shown previously that Interferon Regulatory factor-1 (IRF-1) contributes to liver I/R injury by activating proinflammatory genes, but its role in host responses to liver allografts has not been examined.

Methods: Mouse allogeneic orthotopic liver transplantation (LTx) was performed using IRF-1 wild-type (WT) or knockout (KO) B6 donor mice and C3H recipients. Host immune reactivity was examined by flow cytometry and PCR.

Results: In WT B6 to C3H mouse allograft LTx, intrahepatic IRF-1 mRNA was upregulated by PCR on day 3-7 during acute cellular rejection (ACR) with peak at day 4. IRF-1 KO donor allografts demonstrated significantly less injury compared to WT grafts with less ALT, less portal infiltration, and reduced CD3+T cell infiltration at day 4. Graft mRNA levels of IFNg, TNFa, perforin, granzymeB, and PDL-1 were significantly lower in IRF-1 KO compared to WT grafts. In contrast, IRF-1 KO allografts showed significantly greater CD4+ FoxP3+ regulatory T cell by flow and higher FoxP3 and TGFb mRNA levels. To address the mechanism, we sacrificed allograft LTx mice on day 1. Spleens of IRF-1 KO to C3H LTx mice had less donor cell migration compared to WT B6 to C3H LTx mice, and migrating donor DCs from IRF-1KO grafts were less activated (reduced MHC class II, CD86, CD40, CD80 and PDL-1) compared to those from WT grafts. We also found that IFNg mRNA levels in spleens from IRF-1 KO to C3H LTx mice were significantly reduced but more FoxP3 and TGFb mRNA was expressed compared to WT B6 to C3H on day1. These results suggest that IRF-1 plays a key role in promoting donor DC migration to lymphoid organs and host Th1 type T cell, but not regulatory T cell responses during acute cellular rejection (ACR). Next to investigate the relative importance of hepatocyte (HC) vs. NPC IRF-1, we created IRF-1 KO donor bone marrow chimeric (BMC) mice where IRF-1 was deficient in either donor HC or NPC. NPC IRF-1 KO B6 to WT C3H allografts showed significantly less injury compared to HC IRF-1 KO B6 to WT C3H allografts with less ALT and less CD3+T cell infiltration by flow at day 4. These findings indicate that NPC IRF-1 expression was more important than HC expression for allograft rejection.

Conclusions: The findings highlight the importance of IRF-1 expression during allograft LTx ACR, and suggest a novel therapeutic approach to ameliorating ACR during allogeneic LTx by blocking the action of IRF-1.

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