Poster Presentation The 13th International Congress of the Immunology of Diabetes Society 2013

Deficiency in type I interferon signaling prevents the early interferon-gene signature in pancreatic islets but not type 1 diabetes in non-obese diabetic mice. (#179)

Hong Sheng Quah 1 2 , Socorro Miranda-Hernandez 3 , Aimee Khoo 1 2 , Ashley Harding 1 2 , Stacey Fynch 1 , Lorraine Elkerbout 1 , Tom Brodnicki 1 2 , Alan Baxter 3 , Tom Kay 1 2 , Helen Thomas 1 2 , Kate Graham 1 2
  1. St Vincent's Institute, Fitzroy, VIC, Australia
  2. The University of Melbourne Department of Medicine, St. Vincent’s Hospital, Fitzroy, Victoria, Australia
  3. Comparative Genomics Centre, James Cook University, Townsville, Queensland, Australia
Type I interferons (IFN) have been implicated in initiation of islet autoimmunity and development of type 1 diabetes (T1D). To directly test their involvement, we generated non-obese diabetic (NOD) mice deficient in type I IFN receptors (NOD.IFNAR1-/-). Expression of the type I IFN-induced genes Mx1, Isg15, Ifit1 and Oas1a was detectable in NOD islets as early as 2 weeks of age. Of these four genes, expression of Isg15, Ifit1 and Oas1a peaked at 3-4 weeks of age, corresponding with an increase in Ifnα mRNA, and declined at 5-6 weeks of age. Increased IFN-induced gene expression was ablated in NOD.IFNAR1-/- islets. Type I IFN production in islets may be a result of Toll Like Receptor (TLR) 2 or TLR9 signalling activated by cell debris released from dying  cells. We show that loss of TLR2 resulted in reduced islet expression of Mx1 at 2 weeks of age, but TLR2 or TLR9-deficiency did not change expression of other IFN-induced genes in islets compared with wild-type NOD islets. We also observed increased β cell MHC class I expression with age in both NOD and NOD.IFNAR1-/- mice. NOD.IFNAR1-/- mice developed insulitis and diabetes at a similar rate to NOD controls. These effects on diabetes differ markedly from previous studies where diabetes was reduced in mice treated with an IFNAR1 neutralizing antibody. The reason(s) for this difference is unclear, but it is possible that the short duration of antibody administration at a critical time may reveal benefits not observed in IFNAR1-/- NOD mice. While our results do not exclude a role for type I IFNs in human diabetes, this result in NOD mice must be considered when clinical trials of type I IFN neutralization or blockade are planned. Our results make it less likely that a benefit will be observed.