The role of cytokines during rejection of foetal pig and foetal mouse pancreas grafts in nonobese diabetic mice.

The rejection of discordant foetal pig islet xenografts in nonimmunosuppressed nonobese diabetic (NOD) mice is dominated by polymorphonuclear cell infiltration whereas allografts are almost exclusively infiltrated by mononuclear cells. To determine if this variation is due to different proinflammatory factors generated at the graft site, we analysed graft-site mRNA expression of various cytokines, and the eosinophil attractant chemokine, eotaxin, in a renal subcapsular islet transplant model using organ cultured foetal pig (xenograft) and foetal BALB/c (allograft) pancreas in prediabetic NOD mice. Using semiquantitative RT-PCR on samples recovered at multiple time points during the first 15 post-transplantation days from mice transplanted with either allogeneic or xenogeneic tissue, we found increased expression of IL-2, IL-4. TNF-beta and IL-10 mRNAs at the peak of the cellular infiltrate (on day 5) in both xenografts and allografts but, in contrast to the allografts, no enhanced transcription of IFN-gamma mRNA in the rejecting xenografts. When an allograft and a xenograft were placed at the opposite pole of the same kidney the histological appearance of the rejecting allograft site resembled the xenograft site with significant numbers of eosinophils in both, and enhanced expression of eotaxin and iNOS. Additionally, the xenograft response, unlike the allograft response, was marked by an early increased expression of TNF-alpha and IL-S (day 3) and an almost complete absence of IFN-gamma expression. The results suggest a distinct cell-mediated mechanism for rejection of foetal pancrease xenografts compared to the rejection of foetal pancreas allografts.