title: Neutralization of interleukin-16 protects nonobese diabetic mice from autoimmune type 1 diabetes by a CCL4-dependent mechanism.
abstract: OBJECTIVE
  The progressive infiltration of pancreatic islets by lymphocytes is mandatory for development of autoimmune type 1 diabetes. This inflammatory process is mediated by several mediators that are potential therapeutic targets to arrest development of type 1 diabetes. In this study, we investigate the role of one of these mediators, interleukin-16 (IL-16), in the pathogenesis of type 1 diabetes in NOD mice.
  
  
  METHODS
  At different stages of progression of type 1 diabetes, we characterized IL-16 in islets using GEArray technology and immunoblot analysis and also quantitated IL-16 activity in cell migration assays. IL-16 expression was localized in islets by immunofluorescence and confocal imaging. In vivo neutralization studies were performed to assess the role of IL-16 in the pathogenesis of type 1 diabetes.
  
  
  RESULTS
  The increased expression of IL-16 in islets correlated with the development of invasive insulitis. IL-16 immunoreactivity was found in islet infiltrating T-cells, B-cells, NK-cells, and dendritic cells, and within an insulitic lesion, IL-16 was derived from infiltrating cells. CD4(+) and CD8(+) T-cells as well as B220(+) B-cells were identified as sources of secreted IL-16. Blockade of IL-16 in vivo protected against type 1 diabetes by interfering with recruitment of CD4(+) T-cells to the pancreas, and this protection required the activity of the chemokine CCL4.
  
  
  CONCLUSIONS
  IL-16 production by leukocytes in islets augments the severity of insulitis during the onset of type 1 diabetes. IL-16 and CCL4 appear to function as counterregulatory proteins during disease development. Neutralization of IL-16 may represent a novel therapy for the prevention of type 1 diabetes.
authors.affiliation: Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada.
authors.forename: Craig
authors.initials: C
authors.lastname: Meagher
authors.forename: Josh
authors.initials: J
authors.lastname: Beilke
authors.forename: Guillermo
authors.initials: G
authors.lastname: Arreaza
authors.forename: Qing-Sheng
authors.initials: QS
authors.lastname: Mi
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Konstantin
authors.initials: K
authors.lastname: Salojin
authors.forename: Noah
authors.initials: N
authors.lastname: Horst
authors.forename: William W
authors.initials: WW
authors.lastname: Cruikshank
authors.forename: Terry L
authors.initials: TL
authors.lastname: Delovitch
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002251:Carbon Tetrachloride / Q000494:pharmacology*; D002465:Cell Movement; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000503:physiopathology / Q000517:prevention & control*; D006946:Hyperinsulinism / Q000503:physiopathology; D015151:Immunoblotting; D019410:Interleukin-16 / Q000235:genetics / Q000502:physiology*; D007515:Islets of Langerhans / Q000276:immunology / Q000502:physiology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010179:Pancreas / Q000502:physiology / Q000503:physiopathology; D012333:RNA, Messenger / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D019410:Interleukin-16; D012333:RNA, Messenger; D002251:Carbon Tetrachloride