EFFECT OF FK506 AND ANTI-CD4 THERAPY ON FETAL PIG PANCREAS XENOGRAFTSAND HOST LYMPHOID-CELLS IN NOD LT, CBA, AND BALB/C MICE/

Varying doses of FK506, and a cell-depleting anti-CD4 monoclonal antib ody, GK1.5, were tested as either monotherapy or in combination for th eir effect on the survival of renal subcapsular xenografts of organ-cu ltured fetal pig pancreas in three strains of mice. Subcutaneous injec tions 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 day s. Lower doses were less effective and immunosuppression was less effe ctive in NOD mice than in the other strains. Even 2.0 mg/kg/day of FK5 06 prevented rejection in CBA mice until day 35, but not in NOD/Lt mic e. 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, essent ially 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 cellul arity. Flow cytometric analysis of lymphocyte subsets in blood and spl een also showed no significant differences, but in the thymus the perc entage of immature CD4/CD8 ''double positive'' cells increased while t he more mature CD3 ''high'', and CD4 or CD8 ''single-positive'' cells decreased. Thus, prolonged discordant xenograft survival in mice is po ssible and the use of two agents that act on different parts of the im mune system allows a reduction in the dose of FK506 to safe levels.