Cellular rejection of fetal pancreas grafts: Differences between allo- and xenograft rejection

Hyperacute rejection (HAR) is the major immunologic problem with vascularized xenografts between discordant donor/recipient combinations but does not occur in neovascularized grafts of organ-cultured fetal pig pancreas in either mice or cynomolgus monkeys. However, a form of cell-mediated acute rejection with quite different histopathologic features does occur with kinetics that are similar to acute cellular rejection of fetal pancreas allografts in non-immunosuppressed MHC-mismatched mice. Xenograft rejection is dominated by nonlymphoid cells, mostly eosinophils, that appear some days after transplantation. In contrast, in mouse allografts, mononuclear cells are the dominant population throughout the rejection process. The rejected allograft site rapidly resolves to form a mature non-infiltrated scar whereas the infiltrate in the xenograft site remains for weeks and forms a large granuloma before its eventual resolution. There are also differences in the intra-graft cytokine profile in the graft site between allo- and xenografts during acute rejection with an early predominance of IL-5 and TNF-alpha and an absence of INF-gamma in the xenografts. Immunosuppression with a depleting anti-CD4 mAb shows that xenograft rejection is more dependent on CD4+ve T cells but xenografts are more difficult to maintain with conventional immunosuppression that is often effective for allografts. Limited studies in primates have shown that the histopathology of fetal pig pancreas rejection is similar to that seen in mice but occurs at a faster tempo. Thus, although HAR may not be a problem in rejection of neovascularised xenografts, a vigorous form of cellular rejection is present that may require different immunosuppression than is usually used for the control of allograft rejection.