Fetal porcine islet-like cell clusters transplanted to cynomolgus monkeys - An immunohistochemical study

Background. The mechanism(s) involved in acute cellular xenograft rejection have hitherto been generated in vitro or in different experimental models, with pig tissue being transplanted to rodents. There is an urgent need to validate these results in a clinically more relevant combination of species . Methods. Fetal porcine islet-like cell clusters (ICC) were transplanted und er the kidney capsule in cynomolgus monkeys, either untreated or given immu nosuppression with cyclosporine (CsA; 10 mg/kg body weight, intramuscularly ) and 15-deoxyspergualin (DSG; 5 mg/kg body weight, intramuscularly), ICC x enografts were examined at 1, 3, 6, or 10-12 days after transplantation, us ing immunohistochemical techniques. Serum levels of xenoreactive antibodies were measured with ELISA. Results. No deposits of IgM, IgG, Clq, or C3 were detected within the ICC x enograft in any of the monkeys. Likewise, no significant increase in the le vels of xenoreactive antibodies were found after transplantation. In untrea ted animals, a few N-Elastase-positive cells (neutrophil granulocytes) were seen in the xenograft at day 1, A few mononuclear cells were present in th e adjacent renal parenchyma, but they did not infiltrate the xenograft, At this time (day 1), early signs of necrosis were observed in the central par ts of the graft, On day 3, the graft had a large, central necrotic area tha t contained polymorphonuclear cells; the remaining parts of the xenograft s howed severe infiltration with CD8(+) T cells. Occasional CD68(+) cells (ma crophages) were seen on days 1 and 3. On day 6, large numbers of macrophage s were found infiltrating the entire graft. A few CD20(+) B cells, accumula ted as small clusters, were also found. Only a few natural killer cells (CD 56(+)) were detected. The CsA/DSG-treated monkeys showed markedly fewer CD2 (+)/CD8(+) T cells on day 6 than the untreated monkeys, and the ICC graft w as clearly better preserved. However, the number of CD8(+) and CD68(+) cell s had increased considerably at 12 days after transplantation and diffusely infiltrated the whole ICC xenograft. Conclusion. Porcine ICC transplanted under the kidney capsule in cynomolgus monkeys were rejected by an acute cell-mediated rejection progressing duri ng the first 6 days after transplantation. The process was not dependent on host Ig or C3 binding to the graft. Although the rejection of porcine ICC was significantly delayed in CsA/DSG-treated monkeys, the ICC xenografts we re almost completely destroyed 12 days after transplantation.