Monoclonal antibody treatment (anti-CD4 and anti-interleukin-2 receptor) combined with cyclosporin A has a positive but not simple dose-dependent effect on rat renal allograft survival.
The use of monoclonal antibodies (MoAbs) in experimental and clinical organ transplantation is of increasing interest since this treatment seems to offer an opportunity for specific immunomodulation. In a rat kidney allograft model, Cyclosporin A (CyA) treatment (12.5 mg/kg/d, day 0-14) was combined with murine anti-rat CD4 (MRC OX-38) and murine anti-rat IL-2R (MRC OX-39) MoAbs at doses of 100 or 300 micrograms/kg/d (day 0-7) and plasma concentrations of the murine MoAb were determined. In both groups receiving combined treatment with CyA and MoAb, graft survival was prolonged to an average of 65 days, compared to a graft survival of 9-10 days in non-treated recipients. Further, the data showed a beneficial effect of CyA + MoAb treatment versus CyA alone (graft survival 32 days). The threefold increased MoAb dose did not seem to improve graft survival or function. Treatment with OX-38 + OX-39 at a dose of 100 micrograms/kg/d each resulted in plasma levels of 280 ng/ml 14 days after transplantation. Corresponding values after the administration of 300 micrograms/kg/d were 1800 ng/ml in graft recipients as well as controls. These findings indicate that the effect of MoAbs in complex organ transplantation models is not simply dose dependent and that in vitro assays are of limited value in predicting the effect of a given MoAb when used in vivo. The determination of MoAb plasma levels, however, may be a useful tool in defining optimal MoAb administration and to monitor therapeutically effective plasma levels.
Steinbrüchel
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DA
Laboratory of Nephropathology, Odense University Hospital, Denmark.
Koch
C
C
Kristensen
T
T
Kemp
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E
D000818:Animals; D000911:Antibodies, Monoclonal / Q000032:analysis / Q000627:therapeutic use*; D015704:CD4 Antigens / Q000276:immunology*; D016572:Cyclosporine / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D006085:Graft Survival / Q000187:drug effects; D016030:Kidney Transplantation; D051381:Rats; D011917:Rats, Inbred Lew; D015375:Receptors, Interleukin-2 / Q000276:immunology*; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D015375:Receptors, Interleukin-2; D016572:Cyclosporine