Objective: The effectiveness of tolerizing immunotherapeutic strategies, such as anti-CD40L or dendritic cells (DC), is greater when administered to young NOD mice than at peak insulitis. RelBlo DC, generated in the presence of an NF-κB inhibitor, induce T regulatory (Treg) cells and suppress inflammation in a model of rheumatoid arthritis. IL-1β is over-expressed in humans and mice at risk of T1DM, dysregulates Treg cells, and accelerates diabetes in NOD mice. We investigated the relationship between IL-1β production and the response to RelBlo DC in the pre-diabetic period.
Methods: We injected RelBlo DC s.c. into 4 or 14 week-old NOD mice, and tracked the incidence of diabetes and effect on Treg cell function. We measured expression of proinflammatory cytokines by stimulated splenocytes and unstimulated islets from mice of different ages and strains, and proliferative and cytokine responses of T effectors to Treg in vitro.
Results: Tolerising RelBlo DC significantly inhibited diabetes progression when administered to 4 week but not 14 week-old mice. IL-1β production by NOD splenocytes and mRNA expression by islets increased from 6-16 weeks of age, when MHC-restricted islet antigen presentation to autoreactive T cells occurred. IL-1 reduced the capacity of Treg cells to suppress effector cells and promoted their conversion to Th17 cells. RelBlo DC exacerbated the IL-1-dependent decline in Treg function and promoted Th17 conversion.
Conclusion: IL-1β, generated by islet-autoreactive cells in MHC-susceptible mice, accelerates diabetes by differentiating Th17 at the expense of Treg. Tolerizing DC-therapies can regulate islet autoantigen priming and prevent diabetes, but progression past the IL-1β/IL-17 checkpoint signals the need for other strategies.
- Received January 22, 2010.
- Accepted October 13, 2010.
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