title: CD8(+) T cells resistant to costimulatory blockade are controlled by an antagonist interleukin-15/Fc protein.
abstract: BACKGROUND
  Although permanent engraftment is often achieved with new therapeutics, chronic rejection and graft failure still occur. As the importance of CD8(+) T cells in rejection processes has been underlined in various transplant models, and as interleukin (IL)-15 is involved in the activation of CD8(+) T cells, we hypothesize that CD8(+) T cell "escape" from costimulation blockade might be a IL-15/IL-15R dependent process.
  
  
  METHODS
  In a murine islet allograft model employing a fully major histocompatibility complex-mismatched strain combination of Balb/c donors to CD4 C57BL/6 recipients, a monotherapy with the IL-15 antagonist, IL-15 mutant/Fcgamma2a, or the costimulatory blockade molecule, CTLA4/Fc, was used. In addition to monitoring graft survival, infiltration of alloreactive immune cells was analyzed by histology and immunohistochemistry, and alloimmune response of proliferative CD8(+) T cells was measured in vivo.
  
  
  RESULTS
  Sixty percent of the recipients treated with CTLA4/Fc acutely rejected their islet allograft, comparable to untreated control animals (50% survival). In contrast, the IL-15 antagonist proved to be highly effective, with 100% of recipients accepting their allograft. Immunohistology study demonstrated a remarkable decrease of CD8(+) T-cell intragraft infiltration in IL-15 mutant/Fcgamma2a treated animals with well-preserved islet architecture and a reduced frequency of proliferating alloreactive CD8(+) T cells in comparison with that of untreated and CTLA4/Fc treated groups.
  
  
  CONCLUSIONS
  In this study, we determined the efficacy and potential therapeutic benefit of the IL-15 antagonist on CD4-independent CD8(+) T-cell responses to alloantigens. Targeting the IL-15/IL-15R pathway represents a potent strategy to prevent rejection driven by CD8(+) T cells resistant to costimulation blockade.
authors.affiliation: Department of Medicine, Harvard Medical School, Division of Immunology, Beth Israel Deaconess Medical Center, Boston, MA, USA. sylvie.ferrari@hcuge.ch
authors.forename: Sylvie
authors.initials: S
authors.lastname: Ferrari-Lacraz
authors.forename: Xin Xiao
authors.initials: XX
authors.lastname: Zheng
authors.forename: Alberto Sanchez
authors.initials: AS
authors.lastname: Fueyo
authors.forename: Wlodzimierz
authors.initials: W
authors.lastname: Maslinski
authors.forename: Thomas
authors.initials: T
authors.lastname: Moll
authors.forename: Terry B
authors.initials: TB
authors.lastname: Strom
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000494:pharmacology*; D000943:Antigens, Differentiation / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D060908:CTLA-4 Antigen; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D019409:Interleukin-15 / Q000037:antagonists & inhibitors* / Q000235:genetics; D016381:Islets of Langerhans Transplantation / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008817:Mice, Mutant Strains; D053647:Receptors, Interleukin-15 / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; C508025:Il15ra protein, mouse; D019409:Interleukin-15; D053647:Receptors, Interleukin-15