A comparison of the sensitivity of pig and human peripheral blood mononuclear cells to the antiproliferative effects of traditional and newer immunosuppressive agents

Difficulty in preventing rejection of fetal pig islet-like cell clusters (I CCs) transplanted into pigs using traditional forms of immunotherapy has be en reported. An in vitro study of the efficacy of seven different immunosup pressive agents to inhibit proliferation of pig peripheral blood mononuclea r cells (PBMC) was performed, and a comparison was made between the human a nd pig to determine if the efficacy of these agents differed between specie s. The efficacy of cyclosporine (CsA), azathioprine (Aza), methylprednisolo ne (MP), FK506, rapamycin (RAP), mycophenolate mofetil (MMF) and deoxymethy lspergualin (MeDSG) to inhibit pig and human PBMC proliferation in mitogeni c experiments using phytohaemagglutinin (PHA) as a stimulus was performed. Further, allogeneic pig mixed lymphocyte reactions (MLR) were used to deter mine the activity of these agents in a model more comparable to the allogra ft rejection process. It was found that pig PBMC stimulated with PHA or in a MLR were inhibited by the agents tested, with the exception of MeDSG that was ineffective in mitogenic experiments. The inhibitory effects of these agents differed between PHA and MLR, the respective (50% inhibitory concent ration) IC50 values for pig PBMC being 1.7 and 0.08 mu g/ml for CsA, 1.4 an d 4.4 mu g/ml for Aza, 0.11 and 0.002 mu g/ml for MP, 3.0 and 2.8 ng/ml for FK506, 2.1 and 0.3 ng/ml for RAP and 10.8 and 454 ng/ml for MMF Pig PBMC w ere less sensitive than human PBMC to the antiproliferative effects of CsA, Aza, FK506, RAP and MME but not MP on PHA stimulation, the ratio of the pi g to human IC50 Values being 19, ii, 13, 2.3, 1.4, and 0.4, respectively. T hese data suggest that the doses of most immunosuppressive agents administe red to prevent rejection in pigs need to be higher than those used to achie ve therapeutic benefit in humans.