title: Pancreatic islets induce CD4(+) [corrected] CD25(-)Foxp3(+) [corrected] T-cell regulated tolerance to HY-mismatched skin grafts.
abstract: BACKGROUND
  The ability to induce and maintain antigen-specific immunologic tolerance is the ultimate goal in allo-transplantation. Here, we report that the transplantation of unmanipulated murine pancreatic islets across the HY disparity induced transplantation tolerance that prevented HY-mismatched skin grafts being rejected.
  
  
  METHODS
  Three hundred islet equivalent of freshly isolated islets from male C57BL/6 donor mice was transplanted underneath the kidney capsule of syngeneic female recipients rendered diabetic by streptozotocin. Nephrectomy was carried out to remove the islet graft and retransplantation was performed using the contralateral kidney. For skin transplantation, donor tail skin was transplanted onto the lateral thorax.
  
  
  RESULTS
  Islets from male C57BL/6 donors transplanted to syngeneic female recipients cured diabetes and the mice survived indefinitely. The acceptance of second grafts and rejection of third party islet grafts indicated antigen-specific transplantation tolerance. However, flow cytometry and ELISPOT analysis demonstrated that the HY-specific T cells were not deleted or anergized. A 2-fold increase of CD4+Foxp3+ regulatory T cells (Tregs) was observed in spleen and lymph nodes. Notably, CD25- Tregs increased threefold over levels in naïve mice. Adoptive transfer of CD4+ T cells to neonatal mice could transfer tolerance. At the graft site in long-term tolerant mice, CD4+ T cells, 40% of which were CD4+Foxp3+ Tregs (43% CD25-, 57% CD25+) infiltrated the peri-islet spaces.
  
  
  CONCLUSIONS
  Unmanipulated pancreatic islets can induce immunologic tolerance associated with peripherally induced CD4+Foxp3+ Tregs, a significant proportion of which notably are CD25-.
authors.affiliation: Department of Microbiology and Immunology, Seoul National University Hospital, Seoul, South Korea.
authors.forename: Il-Hee
authors.initials: IH
authors.lastname: Yoon
authors.forename: Seung-Eun
authors.initials: SE
authors.lastname: Choi
authors.forename: Yong-Hee
authors.initials: YH
authors.lastname: Kim
authors.forename: Seung-Ha
authors.initials: SH
authors.lastname: Yang
authors.forename: Ji-Hyun
authors.initials: JH
authors.lastname: Park
authors.forename: Chan-Sik
authors.initials: CS
authors.lastname: Park
authors.forename: Youngji
authors.initials: Y
authors.lastname: Kim
authors.forename: Jung-Sik
authors.initials: JS
authors.lastname: Kim
authors.forename: Sang-Joon
authors.initials: SJ
authors.lastname: Kim
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Simpson
authors.forename: Chung-Gyu
authors.initials: CG
authors.lastname: Park
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003921:Diabetes Mellitus, Experimental / Q000601:surgery; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology*; D006085:Graft Survival / Q000276:immunology; D006182:H-Y Antigen / Q000276:immunology*; D006650:Histocompatibility Testing / Q000379:methods; D007108:Immune Tolerance / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology*; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016038:Skin Transplantation / Q000276:immunology*; D013370:Subrenal Capsule Assay; D016176:T-Lymphocyte Subsets / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D023001:Transplantation Tolerance / Q000276:immunology; D014185:Transplantation, Isogeneic
chemical_list: D015703:Antigens, CD; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D006182:H-Y Antigen; D053645:Interleukin-2 Receptor alpha Subunit