Abstract
Aims/hypothesisThe aim of this study was to determine whether therapy with the cytokine IL-22 could be used to prevent the development of, or treat, autoimmune diabetes in the NOD mouse.MethodsSix-week-old NOD mice were administered bi-weekly either recombinant mouse IL-22 (200 ng/g) or PBS (vehicle control) intraperitoneally until overt diabetes was diagnosed as two consecutive measurements of non-fasting blood glucose ≥ 11 mmol/l. At this time, NOD mice in the control arm were treated with LinBit insulin pellets and randomised to bi-weekly therapeutic injections of either PBS or IL-22 (200 ng/g) and followed until overt diabetes was diagnosed, as defined above.ResultsIL-22 therapy did not delay the onset of diabetes in comparison with the vehicle-treated mice. We did not observe an improvement in islet area, glycaemic control, beta cell residual function, endoplasmic reticulum stress, insulitis or macrophage and neutrophil infiltration as determined by non-fasting blood glucose, C-peptide and histological scoring. Therapeutic administration of IL-22 did not reduce circulating lipopolysaccharide, a marker of impaired gut mucosal integrity.Conclusions/interpretationOur study suggests that, at this dosing regimen introduced either prior to overt diabetes or at diagnosis of diabetes, recombinant mouse IL-22 therapy cannot prevent autoimmune diabetes, or prolong the honeymoon period in the NOD mouse.
Highlights
Electronic supplementary material The online version of this article contains peer-reviewed but unedited supplementary material, which is available to authorised users.In an attempt to prevent or reverse type 1 diabetes, basic and clinical research has focused intensely on immunotherapies, beta cell replacement and preservation of beta cell function and mass [1]
Median diabetes-free survival in mice treated with recombinant mouse IL-22 (rmIL-22) was 175 days compared with 162 days in the vehicle controltreated mice (p = 0.90, Mann–Whitney U test; Fig. 1a). rmIL22 therapy for 32 weeks did not result in an alteration in body weight or non-fasted blood glucose, compared with vehicle-treated mice
After overt diabetes had been confirmed in animals treated in the prophylactic control arm, mice were given suboptimal insulin therapy (LinBit insulin pellets) and reallocated to receive therapeutic doses of either rmIL-22 or vehicle to determine whether therapy could prolong the ‘honeymoon phase’ of diabetes progression
Summary
Electronic supplementary material The online version of this article (doi:10.1007/s00125-017-4392-2) contains peer-reviewed but unedited supplementary material, which is available to authorised users. In an attempt to prevent or reverse type 1 diabetes, basic and clinical research has focused intensely on immunotherapies, beta cell replacement and preservation of beta cell function and mass [1]. The complexity of type 1 diabetes pathogenesis [2] and the human beta cell [3] has shifted the focus to better understanding disease heterogeneity. Posttranslational modifications of beta cell proteins have been identified as ‘neo-antigens’ in the NOD mouse [4] and individuals with type 1 diabetes (reviewed in [5]), further contributing to the complexity of this disorder. The mechanism of why and how neo-antigens are produced remain unknown. It has been hypothesised that the normal physiological role of beta cells as highly secretory
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