Modulation of virus-induced innate immunity and type 1 diabetes by IL-1 blockade.
We used the LEW1.WR1 model of Kilham rat virus (KRV)-induced type 1 diabetes (T1D) to test the hypothesis that blocking IL-1 pathways early in the course of the disease can modulate virus-induced innate immunity and prevent disease progression. Administering KRV plus IL-1 receptor antagonist (Anakinra) for 14 d prevented insulitis and T1D. Anakinra reversed the KRV-induced systemic inflammation evidenced by the accumulation of T cells in the spleen and pancreatic lymph nodes on d 5 post-infection. Blocking IL-1 modulated the level of IRF-7 and IL-6 gene expression in the spleen and the p40 subunit of IL-12 and IL-23 in the serum. Anakinra did not interfere with the ability of LEW1.WR1 rats to clear the virus from the spleen, pancreatic lymph nodes or serum. Consistent with these data, normal levels of KRV-specific adaptive immune responses were detected in in the spleen and peripheral blood of the treated animals. Finally, blocking IL-1 pathways reversed the KRV-induced modulation of gut bacterial communities. The data may imply that IL-1 pathways are directly linked with early mechanisms whereby KRV infection leads to islet destruction, raising the hypothesis that blocking IL-1 pathways early in the course of the disease could be a useful therapeutic approach for disease prevention.
Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO, USA.
Naoko
N
Hara
Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO, USA.
Aimon K
AK
Alkanani
Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, CO, USA.
Charles A
CA
Dinarello
Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO, USA danny.zipris@ucdenver.edu.
Danny
D
Zipris
D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology / Q000276:immunology*; D005260:Female; D007113:Immunity, Innate / Q000276:immunology*; D007249:Inflammation / Q000188:drug therapy; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology* / Q000627:therapeutic use; D007375:Interleukin-1; D018664:Interleukin-12 / Q000378:metabolism; D008198:Lymph Nodes / Q000166:cytology / Q000187:drug effects; D008297:Male; D064307:Microbiota / Q000187:drug effects; D010322:Parvoviridae Infections / Q000150:complications* / Q000276:immunology*; D017992:Parvovirus / Q000276:immunology*; D051381:Rats; D011917:Rats, Inbred Lew; D013154:Spleen / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects
D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D018664:Interleukin-12
Gut bacteria; IL-1 receptor antagonist; Kilham rat virus; inflammation; innate immunity; type 1 diabetes