title: Cyclosporine combined with nonlytic interleukin 2/Fc fusion protein improves immune response to hepatitis B vaccination in a mouse skin transplantation model.
abstract: BACKGROUND
  Improving immune responses to vaccination in immunosuppressed patients is extremely important. Previously, we observed that cyclosporine (CsA) combined with a nonlytic interleukin (IL)-2/fragment crystallizable (Fc) fusion protein induces immune tolerance to mouse skin transplantations. In the present study, we asked whether this combination improved hepatitis B (HBV) vaccine efficacy in immunosuppressed mice while also prolonging skin graft survival.
  
  
  METHODS
  After C57BL/6 mice received DBA/2 skin grafts, they were administered a 14-day course of CsA (30 mg/kg intraperitoneal) combined with IL-2/Fc (1 μg, intraperitoneal). HBV vaccine (2 μg) was injected intramuscularly on the day of skin transplantation. On day 14, the serum levels of hepatitis B surface antibody (HBsAb), IL-4, IL-10, interferon (IFN-γ), and IL-2 were measured by enzyme-linked immunosorbent assay. We assessed the percentages of CD4(+)CXCR5(+) follicular T helper cells, CD4(+)FoxP3(+) regulatory T cells (Treg) and expressions of IL-17, IL-21, FoxP3, Bcl-6 in the spleen. Animals were divided into four groups: control, vaccine-treated, CsA + vaccine-treated, CsA + IL-2/Fc + vaccine-treated hosts.
  
  
  RESULTS
  Combination therapy significantly increased HBsAb levels and also prolonged skin graft survival. Serum levels of Th1 cytokines IL-2 and IFN-γ were significantly higher in the combination group, while Th2 cytokines, IL-4 and IL-10 were lower. Combined treatment increased the percentage of Treg and the expression of Foxp3 and IL-21, meanwhile inhibiting the expression of Bcl-6. But the percentage of Tfh did not significantly change among the groups.
  
  
  CONCLUSIONS
  These observations suggested that a combination of CsA and IL-2/Fc fusion protein enhanced immune responses after HBV vaccination and prolonged skin graft survival.
authors: Department of Hepatobiliary Surgery, Peking University People's hospital, Peking University Center for Transplantation, Beijing, China.
authors: Z
authors: Z
authors: Li
authors: D
authors: D
authors: Zhang
authors: J
authors: J
authors: Gao
authors: W-X
authors: WX
authors: Li
authors: J-Y
authors: JY
authors: Zhu
mesh_terms: D000818:Animals; D016572:Cyclosporine / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D016207:Cytokines / Q000097:blood; D004167:Diphtheria Toxin / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects; D006510:Hepatitis B Antibodies / Q000097:blood; D017325:Hepatitis B Vaccines / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology*; D007114:Immunization; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D007273:Injections, Intramuscular; D007274:Injections, Intraperitoneal; D007376:Interleukin-2 / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D023421:Models, Animal; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D016038:Skin Transplantation; D013154:Spleen / Q000187:drug effects / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology; D013997:Time Factors
chemical_list: D016207:Cytokines; D004167:Diphtheria Toxin; D006510:Hepatitis B Antibodies; D017325:Hepatitis B Vaccines; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D011993:Recombinant Fusion Proteins; C078456:denileukin diftitox; D016572:Cyclosporine