Transient blockade of chemokine receptors (CCR2, CCR5) does not prevent type 1 diabetes in prediabetic NOD-mice

Background Migration of proinflammatory lymphocytes into the islets of Langerhans during pathogenesis of type 1 diabetes depends on expression of certain chemokines and their receptors. It was the aim of this study to determine if the blockade of the chemokine receptors CCR5 or CCR2 can prevent the late invasion of destructive lymphocytes into the islets in prediabetic female NOD-mice and thus prevent diabetes. Material and methods: Monoclonal antibodies against CCR2 or CCR5 or an isotype control (rat IgG2b) were injected i.p. in 11 week old female NOD-mice (15 mice were treated in each of the three groups). Every mouse received 150µg of the specific antibody every 3 days over a period of 13 days. Mice were monitored for development of type 1 diabetes until age of 30 weeks. Mice were sacrificed when diabetic or at 30 weeks of age. Secretion of IFN-γ, Interleukin 4 (IL-4) and Interleukin 10 (IL-10) was determined by ELISPOT in splenocyte cultures and lymphocyte cultures from peripancreatic lymphnodes. Cultures were stimulated with the peptide 9–23 of insulin B-chain. The degree of insulitis was analysed histologically. Results: 7 of 15 mice of both the anti-CCR2 group and the isotype control group were diabetic at the 30th week of age. 12 of 15 mice became diabetic in the group treated with anti-CCR5. Numbers of splenocytes or peripancreatic lymphocytes secreting IFN- γ, IL-4 or IL-10 were similar in all three groups. Scoring of insulitis revealed somewhat more intrainsulitis in the anti-CCR2-group as compared to the other two groups (non-significant). Conclusions: Blockade of the chemokine receptors CCR5 or CCR2 does not prevent development of type 1 diabetes in prediabetic, female NOD-mice. There was rather a trend to acceleration of disease in anti-CCR5 treated mice when compared to isotype control treated animals (p=0,08). Redundancy of chemokines and their receptors may account for this observation.