Short-term treatment with mycophenolic acid and tacrolimus is tolerogenic for INS-1 cell clone transplantation and the deleterious effects of the drugs are limited: in vivo and in vitro studies.
One of the major requirements for a successful and life-lasting organ transplant is the access to safe, least toxic and permanent tolerance-inducing drugs. In this study we wished to evaluate the effects of tolerogenic doses of the immunosuppressive drugs mycophenolic acid (MPA) and tacrolimus (Tac) on clonal beta-cell lines, both in vivo and in vitro. Here we demonstrate that combined administration of low-dose MPA and Tac for 23 days induced permanent tolerance in an allogeneic beta-cell line transplant in Wistar rat liver through the portal vein. This short-term treatment of tolerogenic doses of the two drugs was deleterious to the survival of the transplanted cells but a small percentage of the cells could resist the effect and become fully active when the drugs were removed. The surviving cells, retrieved from growth in vivo, did not exhibit increased resistance in comparison to the original cells when tested in vitro at two glucose concentrations, 10 and 20 mM. The presence of a small percentage of resistant cells at the two glucose concentrations was also detected in the in vitro study after a continuous 8-day treatment demonstrating that the in vivo resistance was not related to micro-environmental protection but possibly to a phenotypic cell state that is yet to be determined.
Merck-Santé, Centre de Recherche, 4 Avenue du Président François Mitterand, 91385 Chilly-Mazarin, Cedex, Paris, France.
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Asfari
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Kergoat
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Charon
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D000818:Animals; D002460:Cell Line; D004361:Drug Tolerance; D007108:Immune Tolerance; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000276:immunology* / Q000378:metabolism; D016381:Islets of Langerhans Transplantation; D008297:Male; D009173:Mycophenolic Acid / Q000009:adverse effects / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D016559:Tacrolimus / Q000009:adverse effects / Q000627:therapeutic use*; D013997:Time Factors; D014181:Transplantation Immunology
D007166:Immunosuppressive Agents; D007328:Insulin; D009173:Mycophenolic Acid; D016559:Tacrolimus