title: Interleukin-21 is critically required in autoimmune and allogeneic responses to islet tissue in murine models.
abstract: OBJECTIVE
  Type 1 diabetes is an incurable chronic autoimmune disease. Although transplantation of pancreatic islets may serve as a surrogate source of insulin, recipients are subjected to a life of immunosuppression. Interleukin (IL)-21 is necessary for type 1 diabetes in NOD mice. We examined the efficacy of an IL-21-targeted therapy on prevention of diabetes in NOD mice, in combination with syngeneic islet transplantation. In addition, we assessed the role of IL-21 responsiveness in islet allograft rejection in mouse animal models.
  
  
  METHODS
  NOD mice were treated with IL-21R/Fc, an IL-21-neutralizing chimeric protein. This procedure was combined with syngeneic islet transplantation to treat diabetic NOD mice. Survival of allogeneic islet grafts in IL-21R-deficient mice was also assessed.
  
  
  RESULTS
  Evidence is provided that IL-21 is continually required by the autoimmune infiltrate, such that insulitis was reduced and reversed and diabetes inhibited by neutralization of IL-21 at a late preclinical stage. Recovery from autoimmune diabetes was achieved by combining neutralization of IL-21 with islet transplantation. Furthermore, IL-21-responsiveness by CD8+ T-cells was sufficient to mediate islet allograft rejection.
  
  
  CONCLUSIONS
  Neutralization of IL-21 in NOD mice can inhibit diabetes, and when paired with islet transplantation, this therapeutic approach restored normoglycemia. The influence of IL-21 on a graft-mounted immune response was robust, since the absence of IL-21 signaling prevented islet allograft rejection. These findings suggest that therapeutic manipulation of IL-21 may serve as a suitable treatment for patients with type 1 diabetes.
authors.affiliation: Department of Immunology, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
authors.forename: Helen M
authors.initials: HM
authors.lastname: McGuire
authors.forename: Stacey
authors.initials: S
authors.lastname: Walters
authors.forename: Alexis
authors.initials: A
authors.lastname: Vogelzang
authors.forename: Carol M Y
authors.initials: CM
authors.lastname: Lee
authors.forename: Kylie E
authors.initials: KE
authors.lastname: Webster
authors.forename: Jonathan
authors.initials: J
authors.lastname: Sprent
authors.forename: Daniel
authors.initials: D
authors.lastname: Christ
authors.forename: Shane
authors.initials: S
authors.lastname: Grey
authors.forename: Cecile
authors.initials: C
authors.lastname: King
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing; D015551:Autoimmunity / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005434:Flow Cytometry; D006085:Graft Survival / Q000276:immunology*; D007150:Immunohistochemistry; D007165:Immunosuppression Therapy; D007249:Inflammation / Q000276:immunology; D007378:Interleukins / Q000276:immunology*; D007515:Islets of Langerhans / Q000276:immunology; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000098546:Interleukin-21
chemical_list: D057134:Antibodies, Neutralizing; D007378:Interleukins; D000098546:Interleukin-21