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01.11.2012 | Article

Interleukin-15 plays an essential role in the pathogenesis of autoimmune diabetes in the NOD mouse

verfasst von: D. Bobbala, X.-L. Chen, C. Leblanc, M. Mayhue, J. Stankova, T. Tanaka, Y.-G. Chen, S. Ilangumaran, S. Ramanathan

Erschienen in: Diabetologia | Ausgabe 11/2012

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Abstract

Aims/hypothesis

IL-15, induced by innate immune stimuli, promotes rheumatoid arthritis and inflammatory bowel disease. However, its role in autoimmune type 1 diabetes is unclear. Our aim is to define the role of IL-15 in the pathogenesis of diabetes in the NOD mouse model.

Methods

We generated NOD.Il15 ^−/− mice expressing a polyclonal repertoire of T cell antigen receptor (TCR) or a transgenic TCR and monitored diabetes onset and insulitis. NOD Scid.Il15 ^−/− (full name NOD.CB17-Prkdc ^scid/NCrCrl) and NOD Scid.gamma (full name NOD.Cg-Prkdc ^scid Il2rg ^tm1Wjl/SzJ) mice were used to distinguish the requirement for IL-15 signalling in CD8⁺ T cells and antigen-presenting cells (APCs) to induce disease. We examined the effect of blocking IL-15 signalling on diabetes onset in NOD mice.

Results

At 7 months of age, more than 75% of the NOD Il15 ^−/− female mice remained diabetes free compared with only 30% in the control group. Diabetes incidence was also decreased in 8.3-NOD (full name NOD Cg-Tg[TcraTcrbNY8.3]-1Pesa/DvsJ).Il15 ^−/− mice expressing a highly pathogenic transgenic TCR on CD8⁺ T cells. Adoptive transfer of splenocytes from diabetic NOD and 8.3-NOD donors induced disease in NOD Scid recipients but not in NOD Scid.Il15 ^−/− or NOD Scid.gamma mice. Transient blockade of IL-15 signalling at the onset of insulitis prevented diabetes in NOD mice.

Conclusions/interpretation

Our results show that IL-15 is needed for the initial activation of diabetogenic CD8⁺ T cells as well as for sustaining the diabetogenic potential of antigen-stimulated cells, acting on both CD8⁺ T cells and on APCs. Our findings demonstrate a critical role for IL-15 in the pathogenesis of autoimmune diabetes and suggest that IL-15 is a promising therapeutic target.

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Titel: Interleukin-15 plays an essential role in the pathogenesis of autoimmune diabetes in the NOD mouse
verfasst von: D. Bobbala
X.-L. Chen
C. Leblanc
M. Mayhue
J. Stankova
T. Tanaka
Y.-G. Chen
S. Ilangumaran
S. Ramanathan
Publikationsdatum: 01.11.2012
Verlag: Springer-Verlag
Erschienen in: Diabetologia / Ausgabe 11/2012
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-012-2675-1

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