title: In Vivo Expansion of Regulatory T Cells by Low-Dose Interleukin-2 Treatment Increases Allograft Survival in Corneal Transplantation.
abstract: BACKGROUND
  Corneal allograft survival dramatically decreases in hosts with inflamed or vascularized recipient beds. We have previously shown that in rejected corneal allografts regulatory T cells (Treg) demonstrate diminished Foxp3 expression and immunoregulatory function. Treatment with low doses of IL-2 selectively expands Treg and has been proposed for the treatment of autoimmune diseases. In this study, we investigated the effect of low-dose IL-2 administration on Treg function and corneal allograft survival.
  
  
  METHODS
  Allogeneic corneal transplantation was performed on inflamed host beds. Low-dose systemic IL-2 was administered starting 3 days before grafting until 6 weeks after transplantation. Frequencies of Treg and their immunosuppressive function and antigen specificity were assessed using flow cytometry, in vitro proliferation assays, and adoptive transfer experiments. Frequencies of effector T cells (Teff) and graft infiltrating immune cells were measured at 2 weeks posttransplantation. Long-term allograft survival was evaluated for up to 9 weeks using Kaplan-Meier survival analysis.
  
  
  RESULTS
  Treatment with low-dose IL-2 significantly increased frequencies of CD4CD25Foxp3 Treg and their immunosuppressive function. It also suppressed alloimmune response as shown by the decreased CD4 IFNγ T cell frequencies and graft infiltration of CD45 and CD4 cells. Clinical evaluation of the grafts showed significant improvement in long-term corneal allograft survival in the IL-2 treated group compared with controls.
  
  
  CONCLUSIONS
  Our study is the first to report that treatment with low-dose IL-2 increases survival of corneal allografts. We propose that IL-2-mediated Treg expansion can be an effective tool to prevent alloimmunity and to improve long-term allograft survival in transplantation.
authors.affiliation: 1 Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA. 2 Kresge Eye Institute, Detroit, MI.
authors.forename: Maryam
authors.initials: M
authors.lastname: Tahvildari
authors.forename: Masahiro
authors.initials: M
authors.lastname: Omoto
authors.forename: Yihe
authors.initials: Y
authors.lastname: Chen
authors.forename: Parisa
authors.initials: P
authors.lastname: Emami-Naeini
authors.forename: Takenori
authors.initials: T
authors.lastname: Inomata
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Dohlman
authors.forename: Abigail E
authors.initials: AE
authors.lastname: Kaye
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Chauhan
authors.forename: Reza
authors.initials: R
authors.lastname: Dana
mesh_terms: D019264:Adoptive Transfer; D064591:Allografts; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D003315:Cornea / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000601:surgery*; D016039:Corneal Transplantation / Q000009:adverse effects / Q000379:methods*; D004334:Drug Administration Schedule; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D006085:Graft Survival / Q000187:drug effects*; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D007376:Interleukin-2 / Q000008:administration & dosage*; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects*; D008297:Male; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D013997:Time Factors
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C508018:Il2ra protein, mouse; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D007371:Interferon-gamma