Transient Chemokine Receptor Blockade does not Prevent, but may Accelerate Type 1 Diabetes in Prediabetic NOD Mice

Abstract

The influx of autoreactive lymphocytes into the site of an autoimmune inflammation is mediated by certain chemokines. Autoimmune insulitis in type 1 diabetes is viewed as the result of destructive Th-1-cells and their corresponding antigen-presenting cells infiltrating the pancreatic islets. Blocking the chemokine receptors that mediate a Th-1-reaction has been shown to reduce autoimmunity in other experimental autoimmune disorders. We used the NOD mouse model to investigate the potency of anti-CCR2 and anti-CCR5 antibodies to inhibit the influx of Th-1-cells into the pancreatic islets, thus preventing diabetes onset. Eleven-week-old female NOD mice were treated with 500 µg of a monoclonal anti-CCR5 or anti-CCR2 or an isotype control antibody every third day over two weeks. We did not observe any preventive effect in either treatment group, but accelerated diabetes onset in the anti-CCR5 treated group. The number of autoantigen-specific Th-1-cells detected in the two treated groups was not reduced, but increased in the anti-CCR5 group. Redundancy within the chemokine system may account for this lack of prevention, or the intervention may have come too late in the disease process. Furthermore, blocking Th-1 chemokine receptors in the late autoimmune process may also inhibit regulatory T-cells, thus accelerating rather than preventing the disease.

Autoimmune insulitis - regulatory T-cells - Th-1 cells - CCR2 - CCR5 - redundancy

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