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 (ICCs) transplanted into pigs using traditional forms of immunotherapy has been reported. An in vitro study of the efficacy of seven different immunosuppressive agents to inhibit proliferation of pig peripheral blood mononuclear cells (PBMC) was performed, and a comparison was made between the human and pig to determine if the efficacy of these agents differed between species. The efficacy of cyclosporine (CsA), azathioprine (Aza), methylprednisolone (MP), FK506, rapamycin (RAP), mycophenolate mofetil (MMF) and deoxymethylspergualin (MeDSG) to inhibit pig and human PBMC proliferation in mitogenic experiments using phytohaemagglutinin (PHA) as a stimulus was performed. Further, allogeneic pig mixed lymphocyte reactions (MLR) were used to determine the activity of these agents in a model more comparable to the allograft 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 concentration) IC50 values for pig PBMC being 1.7 and 0.08 microg/ml for CsA, 1.4 and 4.4 microg/ml for Aza, 0.11 and 0.002 microg/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 MME Pig PBMC were less sensitive than human PBMC to the antiproliferative effects of CsA, Aza, FK506, RAP and MMF, but not MP on PHA stimulation, the ratio of the pig to human IC50 values being 19, 11, 13, 2.3, 1.4, and 0.4, respectively. These data suggest that the doses of most immunosuppressive agents administered to prevent rejection in pigs need to be higher than those used to achieve therapeutic benefit in humans.
Wright
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Pancreas Transplant Unit, Prince of Wales Hospital, Sydney, New South Wales, Australia.
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Tuch
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D000818:Animals; D001379:Azathioprine / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D003922:Diabetes Mellitus, Type 1 / Q000601:surgery; D006084:Graft Rejection / Q000517:prevention & control; D006146:Guanidines / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D016381:Islets of Langerhans Transplantation / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects* / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects; D007959:Lymphocyte Culture Test, Mixed; D008775:Methylprednisolone / Q000494:pharmacology; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D010835:Phytohemagglutinins / Q000494:pharmacology; D020123:Sirolimus / Q000494:pharmacology; D013045:Species Specificity; D013552:Swine; D016559:Tacrolimus / Q000494:pharmacology; D014184:Transplantation, Homologous
D006146:Guanidines; D007166:Immunosuppressive Agents; D010835:Phytohemagglutinins; C076911:methyldeoxyspergualin; D016572:Cyclosporine; D009173:Mycophenolic Acid; D001379:Azathioprine; D020123:Sirolimus; D016559:Tacrolimus; D008775:Methylprednisolone