Effect of FK506 and anti-CD4 therapy on fetal pig pancreas xenografts and host lymphoid cells in nod/Lt, CBA, and BALB/c mice.

Varying doses of FK506, and a cell-depleting anti-CD4 monoclonal antibody, GK1.5, were tested as either monotherapy or in combination for their effect on the survival of renal subcapsular xenografts of organ-cultured fetal pig pancreas in three strains of mice. Subcutaneous injections of FK506 at 4.0 mg/kg/day for 28 d prevented graft rejection to day 35 posttransplantation (i.e., 7 days after cessation of treatment in NOD/Lt, and CBA mice) while BALB/c mice had intact grafts at 28 days. Lower doses were less effective and immunosuppression was less effective in NOD mice than in the other strains. Even 2.0 mg/kg/day of FK506 prevented rejection in CBA mice until day 35, but not in NOD/Lt mice. GK1.5 alone did not prevent rejection in NOD/Lt mice but when a low dose of FK506 (2.0 mg/day) was added, the grafts were present, essentially intact, at 35 days. There were no obvious toxic effects of FK506 in NOD/Lt and CBA mice. With FK506 treatment there was no significant difference in absolute numbers of total leucocytes or lymphocytes in peripheral blood and spleen, but there was a decrease in thymus cellularity. Flow cytometric analysis of lymphocyte subsets in blood and spleen also showed no significant differences, but in the thymus the percentage of immature CD4/CD8 "double positive" cells increased while the more mature CD3"high", and CD4 or CD8 "single-positive" cells decreased. Thus, prolonged discordant xenograft survival in mice is possible and the use of two agents that act on different parts of the immune system allows a reduction in the dose of FK506 to safe levels.