Unique gene expression profiles of heart allograft rejection in the interferon regulatory factor-1-deficient mouse.

ABSTRACT

Interferon regulatory factor-1 (IRF1) is a transcription factor for many genes involved in innate and adaptive immune responses. By using DNA array technology, we have previously demonstrated that IRF1 is significantly upregulated during acute rejection in rat heart allografts and is restored to isograft levels when recipients are treated with the immunosuppressants tacrolimus or cyclosporin A (CsA). To understand the precise role of IRF1 in transplant rejection, we investigated the rejection responses of mice completely deficient of IRF1 protein. Heterotopic heart transplantations were performed using C57BL/6J wild-type (WT B6) and IRF1-deficient (IRF1-/-) mice as recipients, and C3H mice as donors. Graft survival was determined by abdominal palpation and rejection was confirmed by histology. On day 6 after transplantation, isografts and allografts were harvested and subjected to gene expression analysis by a commercial nylon array and by real-time RT-PCR. Median survival time of heart allografts was 8 days in the WT B6 mice and 10 days in the IRF1-/- mice. The gene expression profiles of allografts from the WT B6 and IRF1-/- recipients were nearly identical to each other and very different from the profile of the isograft control. Both WT B6 and IRF1-/- profiles showed 13 genes upregulated (IFN-gamma, MCP-2, MIP-1alpha, MIP-1beta, CCR5, MIG, IP-10 and others) and one gene downregulated (SDF2) among the 76 genes detectable on the array. In more detailed analyses, distinct cytokine and chemokine gene expression profiles were identified in the allografts from the WT B6 and IRF1-/- recipients. Whereas IL-4, IL-6, IL-13, MCP-1, MCP-3, and MPIF-2 were upregulated, RANTES, IL-2Rgamma and gp130 were downregulated in allografts from the IRF1-/- recipients when compared to the WT B6 control. Although the inactivation of the IRF1 gene did not sufficiently prevent acute allograft rejection in this model, a unique cytokine and chemokine gene expression profile was found in the absence of IRF1.