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.
Akita
K
K
Transplantation Unit, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
Ogawa
M
M
Mandel
T E
TE
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000954:Antigens, Surface / Q000032:analysis; D015704:CD4 Antigens / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000601:surgery; D005260:Female; D016332:Fetal Tissue Transplantation / Q000276:immunology*; D006084:Graft Rejection / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects; D016381:Islets of Langerhans Transplantation / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D016688:Mice, Inbred NOD; D016035:Pancreas Transplantation / Q000276:immunology*; D011236:Prediabetic State / Q000601:surgery; D013045:Species Specificity; D013552:Swine; D016176:T-Lymphocyte Subsets / Q000276:immunology; D016559:Tacrolimus / Q000627:therapeutic use*; D013997:Time Factors; D014183:Transplantation, Heterologous / Q000276:immunology*
D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D015704:CD4 Antigens; D016559:Tacrolimus