Effects of rapamycin in experimental organ allografting

The immunosuppressive effect of rapamycin (RAPA), a macrolide antibiotic produced by Streptomyces hygroscopicus, was tested using allografts in the rat and dog. It was immunosuppressive at a dose of 3.0 mg/kg/day for 8 days in skin allografts and 0.1 mg/kg/day for 11 days using cardiac allografts in the rat. It prevented rejection of renal allografts in beagle dogs at a dose of 0.3 mg/kg; however, emaciation and gastrointestinal toxicity resulted in some deaths in dogs. Mucosal necrosis and vasculitis in the submucosal layer were the predominant findings at autopsy in dogs receiving RAPA. Serum amylase values rose soon after commencement of RAPA treatment. Combined drug treatment with CsA at a nonimmunosuppressive dose of 3.2 mg/kg in the rat or 2.5 mg/kg in the dog was synergistic, with a low dose of 0.1 mg/kg/week RAPA. Combined therapy of CsA and RAPA also inhibited the frequency of vasculitis and emaciation in dogs. The present data suggest that RAPA is immunosuppressive in organ allografting and that the combination of CsA and RAPA would be effective clinically.