title: Mizoribine--an inosine monophosphate dehydrogenase inhibitor--acts synergistically with cyclosporine A in prolonging survival of murine islet cell and heart transplants across major histocompatibility barrier.
abstract: BACKGROUND
  Mizoribine (MZR) is an inosine monophosphate dehydrogenase inhibitor. It has been widely used in Japan in the treatment of autoimmune diseases and is known to inhibit T and B cell proliferation. The aim of this study was to evaluate the efficacy of MZR as an immunosuppressive agent and determine its ability to synergize with a commonly used calcineurin inhibitor Cyclosporine A (CsA) in prolonging survival of murine islet cells and heart transplanted across major histocompatibility barrier.
  
  
  METHODS
  Murine allogeneic islet cell transplantation between Balb/c donor mice and C57BL/6 recipient mice and heterotopic heart transplantation was done between C3H/He donor mice and Balb/c recipient mice. Recipients were divided into groups based on immunosuppression: Group 1-No immunosuppression, Group 2-MZR alone (20 mg/kg/day), Group 3-CsA alone (20 mg/kg/day), Group 4-MZR+CsA (20 mg/kg/day). Donor specific IFN-γ, IL-10, IL-2, IL-4 secreting cells were enumerated by ELISpot. Serum cytokine and chemokine concentration was measured by Luminex.
  
  
  RESULTS
  Islet cell allograft recipients treated with CsA and MZR had prolonged islet function compared to other groups [normoglycemia (blood glucose <200 mg/dL) up to 32±4 days, p<0.05]. Similarly, heart allograft survival was significantly improved in mice treated with CsA and MZR compared to other groups (50% 30-day survival, p=0.04). Donor specific IFN-γ, IL-4, IL-2 secreting cells were significantly decreased in recipients treated with CsA and MZR with marked increase in IL-10 secreting cells (p<0.05). There was also an increase in serum IL-10 with decrease in IFN-γ, IL-4, IL-2, MCP-1, and IL-6 in mice treated with CsA and MZR CONCLUSION: MZR and CsA when used in combination are potent immunosuppressive agents in murine islet cell and heart transplantation models. These agents lead to a decrease in donor specific IFN-γ with increase in IL-10 secreting cells leading to improved allograft survival and function.
authors.affiliation: Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Naohiko
authors.initials: N
authors.lastname: Fukami
authors.forename: Vijay
authors.initials: V
authors.lastname: Subramanian
authors.forename: Nataraju
authors.initials: N
authors.lastname: Angaswamy
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: T
authors.initials: T
authors.lastname: Mohanakumar
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Hoshinaga
mesh_terms: D000818:Animals; D016572:Cyclosporine / Q000819:agonists / Q000494:pharmacology*; D016207:Cytokines / Q000276:immunology; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000819:agonists / Q000494:pharmacology*; D006085:Graft Survival / Q000187:drug effects; D016027:Heart Transplantation; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors* / Q000276:immunology; D007515:Islets of Langerhans / Q000201:enzymology / Q000276:immunology*; D016381:Islets of Langerhans Transplantation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009206:Myocardium / Q000201:enzymology / Q000276:immunology*; D012263:Ribonucleosides / Q000819:agonists / Q000494:pharmacology*; D014184:Transplantation, Homologous; D019737:Transplants
chemical_list: D016207:Cytokines; D004791:Enzyme Inhibitors; D012263:Ribonucleosides; C010052:mizoribine; D016572:Cyclosporine; D007168:IMP Dehydrogenase