title: Role of T-cell-specific nuclear factor κB in islet allograft rejection.
abstract: BACKGROUND
  Pancreatic islet transplantation has the potential to cure type 1 diabetes, a chronic lifelong disease, but its clinical applicability is limited by allograft rejection. Nuclear factor κB (NF-κB) is a transcription factor important for survival and differentiation of T cells. In this study, we tested whether NF-κB in T cells is required for the rejection of islet allografts.
  
  
  METHODS
  Mice expressing a superrepressor form of NF-κB selectively in T cells (IκBαΔN-Tg mice) with or without the antiapoptotic factor Bcl-xL, or mice with impaired T-cell receptor (TCR)- and B cell receptor-driven NF-κB activity (CARMA1-KO mice) were rendered diabetic and transplanted with islet allografts. Secondary skin transplantation in long-term acceptors of islet allografts was used to test for the development of donor-specific tolerance. Immune infiltration of the transplanted islets was examined by immunofluorescence. TCR-transgenic CD4 T cells were used to follow T-cell priming and differentiation.
  
  
  RESULTS
  Islet allograft survival was prolonged in IκBαΔN-Tg mice, although the animals did not develop donor-specific tolerance. Reduced NF-κB activity did not prevent T-cell priming or differentiation but reduced survival of activated T cells, as transgenic expression of Bcl-xL restored islet allograft rejection in IκBαΔN-Tg mice. Abolishing TCR- and B cell receptor-driven activation of NF-κB selectively by CARMA1 deficiency prevented T-cell priming and islet allograft rejection.
  
  
  CONCLUSIONS
  Our data suggest that T cell-NF-κB plays an important role in the rejection of islet allografts. Targeting NF-κB selectively in lymphocytes seems a promising approach to facilitate acceptance of transplanted islets.
authors.affiliation: Department of Medicine, Committee on Immunology, University of Chicago, Gwen Knapp Center for Lupus and Immunology Research, Chicago, IL 60637, USA.
authors.forename: Delia Lozano
authors.initials: DL
authors.lastname: Porras
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Ping
authors.initials: P
authors.lastname: Zhou
authors.forename: Luciana L
authors.initials: LL
authors.lastname: Molinero
authors.forename: Maria-Luisa
authors.initials: ML
authors.lastname: Alegre
mesh_terms: D000818:Animals; D053468:CARD Signaling Adaptor Proteins / Q000502:physiology; D006084:Graft Rejection / Q000209:etiology*; D006085:Graft Survival; D007108:Immune Tolerance; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D007519:Isoantigens / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology*; D014184:Transplantation, Homologous
chemical_list: D053468:CARD Signaling Adaptor Proteins; C496467:Card11 protein, mouse; D007519:Isoantigens; D016328:NF-kappa B