title: Immunosuppressive drugs in islet xenotransplantation: a tool for gaining further insights in the mechanisms of the rejection process.
abstract: BACKGROUND
  The aim of the present study was to examine the effect of tacrolimus (TAC) and prednisolone (PRE) in islet xenotransplantation and to use the immunosuppressive effects of these drugs and others to further characterize the mechanisms behind islet xenograft rejection.
  
  
  METHODS
  Fetal porcine islet-like cell clusters (ICCs) were transplanted under the kidney capsule in Lewis rats. The animals were treated with TAC, cyclosporine A (CsA) plus 15-deoxyspergualin (DSG), CsA plus sirolimus (SIR) or CsA plus leflunomide (LEF), with or without the addition of PRE. Rejection was assessed by immunohistological evaluation 12 days after transplantation. In selected groups, the intragraft cytokine mRNA expression was analyzed with real-time quantitative reverse-transcriptase polymerase chain reaction (RT-PCR).
  
  
  RESULTS
  In untreated rats, the ICC xenografts were completely rejected. Treatment with PRE alone had no, or only a marginal, protective effect. TAC alone at a dose of 1 or 0.5 mg/kg of body weight (BW) prevented xenograft rejection. The addition of PRE to TAC treatment had a paradoxical unfavorable effect. In contrast, when PRE was added to CsA-based protocols (CsA+DSG, CsA+SIR, or CsA+LEF), the immunosuppressive effect was slightly enhanced. In comparison with untreated rats, the messengers for interleukin (IL)-1beta, IL-2, IL-4, IL-10, interferon (IFN)-gamma, and tumor necrosis factor (TNF)-alpha were reduced in both CsA and TAC treated rats. Notably, the amount of IL-12p40 transcripts was only inhibited in rats given TAC alone, whereas this messenger was increased to approximately the same levels in untreated, CsA treated, and TAC plus PRE treated rats.
  
  
  CONCLUSIONS
  TAC exerted a pronounced immunosuppressive effect in the pig-to-rat islet xenotransplantation model. So far, no other single drug protocol has shown a comparable efficacy. Notably, the graft protective effect of TAC was markedly abrogated when PRE was added to the treatment protocol, suggesting that TAC exerts its effect by a unique mechanism of action. In contrast with the other studied immunosuppressive regimens, treatment with TAC alone inhibited intragraft mRNA expression of all the Th1 associated cytokines, indicating that Th1 response is one important rejection mechanism that needs to be inhibited to achieve islet xenograft survival.
authors.affiliation: Division of Clinical Immunology, Rudbeck Laboratory, Uppsala University, SE-751 85 Uppsala, Sweden.
authors.forename: Henrik
authors.initials: H
authors.lastname: Krook
authors.forename: Lars
authors.initials: L
authors.lastname: Wennberg
authors.forename: Anette
authors.initials: A
authors.lastname: Hagberg
authors.forename: Zhenshun
authors.initials: Z
authors.lastname: Song
authors.forename: Carl-Gustav
authors.initials: CG
authors.lastname: Groth
authors.forename: Olle
authors.initials: O
authors.lastname: Korsgren
mesh_terms: D000199:Actins / Q000235:genetics; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000910:Antibodies, Heterophile / Q000097:blood; D016572:Cyclosporine / Q000494:pharmacology; D005260:Female; D016332:Fetal Tissue Transplantation; D006084:Graft Rejection / Q000188:drug therapy* / Q000276:immunology; D006146:Guanidines / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007378:Interleukins / Q000235:genetics; D016381:Islets of Langerhans Transplantation; D007555:Isoxazoles / Q000494:pharmacology; D000077339:Leflunomide; D008297:Male; D011239:Prednisolone / Q000494:pharmacology; D011247:Pregnancy; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011917:Rats, Inbred Lew; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013552:Swine; D016559:Tacrolimus / Q000494:pharmacology*; D014183:Transplantation, Heterologous
chemical_list: D000199:Actins; D000893:Anti-Inflammatory Agents; D000910:Antibodies, Heterophile; D006146:Guanidines; D007166:Immunosuppressive Agents; D007378:Interleukins; D007555:Isoxazoles; D012333:RNA, Messenger; D016572:Cyclosporine; D011239:Prednisolone; D000077339:Leflunomide; C037258:gusperimus; D016559:Tacrolimus