THE IMMUNOSUPPRESSIVE ANTAGONISM OF LOW-DOSES OF FK506 AND CYCLOSPORINE

Clinical immunosuppression with potentially toxic agents may be optimized by combining drugs that act synergistically at low doses. The studies presented herein attempted to apply this strategy to the macrolide FK506 and the endecapeptide cyclosporine, which similarly inhibit T cell responses but display distinctive arrays of toxic side effects. The interaction between these agents was subjected to rigorous pharmacologic analysis using the median effect and combination index equations to determine synergistic, antagonistic, or additive drug interactions. FK506 and CsA showed pharmacologic antagonism in inhibiting in vitro proliferation upon phytohemagglutinin, anti-CD3 antibody, and mixed lymphocyte reaction (MLR) stimulation, and interleukin 2 generation by activated normal human peripheral blood lymphocytes. The antagonistic relationship was confirmed in vivo using low doses of FK506 in combination with CsA to treat Wistar-Furth recipients of heterotopic Buffalo rat cardiac allografts, a major plus minor histocompatibility barrier. This antagonistic relation suggests that FK506/CsA combination therapy does not permit dose reduction of the individual drugs to mitigate toxic complications.