XENOGRAFT REJECTION OF PORCINE ISLET-LIKE CELL CLUSTERS IN NORMAL, INTERFERON-??, AND INTERFERON-?? RECEPTOR DEFICIENT MICE1

The aim of the present study was to evaluate the role of the T-cell cytokine interferon (IFN)-gamma in mediating macrophage activation in xenograft rejection.For this purpose, fetal porcine islet-like cell cluster (ICC) transplants were placed under the renal capsule of normal mice and mice with a homozygous targeted disruption of the IFN-gamma or the IFN-gamma receptor gene. Some of the mice were continuously infused with cyclosporine (CsA, 12.4 mg/kg body weight/day) or CsA vehicle by subcutaneously implanted osmotic pumps. Histological evaluation of the xenografts was performed 6 or 12 days after transplantation.All animals, irrespective of recipient group, readily rejected the ICC xenograft, although the rejection process was slightly delayed in mice deficient in IFN-gamma. Analysis of the infiltrating cells within the xenograft in knockout mice revealed a pattern similar to that found in control animals. Six days after transplantation, there was an abundant infiltration of macrophages (Mac-1, F4/80, and major histocompatibility complex II markers) in the ICC grafts. Quite in contrast, there was only a low to moderate number of T cells (CD3 marker) present in the ICC grafts. Treatment with CsA had no effect on the rejection process. In grafts removed from mice with a disruption of the IFN-gamma gene, occasional surviving endocrine cells, and in some cases also a few intact ICC, were found within the otherwise obliterated xenograft. Few or no surviving endocrine cells were found in the grafts obtained from the other groups of mice.Thus, the present study demonstrates that macrophage activation, and subsequent destruction of an ICC xenograft, can operate in the absence of IFN-gamma in the pig-to-mouse model.