Abstract
Proteins containing citrulline, a post-translational modification of arginine, are generated by peptidyl arginine deiminases (PAD). Citrullinated proteins have pro-inflammatory effects in both innate and adaptive immune responses. Here, we examine the therapeutic effects in collagen-induced arthritis of the second generation PAD inhibitor, BB-Cl-amidine. Treatment after disease onset resulted in the reversal of clinical and histological changes of arthritis, associated with a marked reduction in citrullinated proteins in lymph nodes. There was little overall change in antibodies to collagen or antibodies to citrullinated peptides, but a shift from pro-inflammatory Th1 and Th17-type responses to pro-resolution Th2-type responses was demonstrated by serum cytokines and antibody subtypes. In lymph node cells from the arthritic mice treated with BB-Cl-amidine, there was a decrease in total cell numbers but an increase in the proportion of Th2 cells. BB-Cl-amidine had a pro-apoptotic effect on all Th subsets in vitro with Th17 cells appearing to be the most sensitive. We suggest that these immunoregulatory effects of PAD inhibition in CIA are complex, but primarily mediated by transcriptional regulation. We suggest that targeting PADs is a promising strategy for the treatment of chronic inflammatory disease.
Highlights
But 10 times more potent against PAD27
To examine the therapeutic potential of BB-Cl-amidine in vivo we used the drug in a treatment protocol, that is, after the onset of arthritis
We have shown that the second generation peptidyl arginine deiminases (PADs) inhibitor, BB-Cl-amidine, reversed joint inflammation both clinically and histologically in collagen-induced arthritis at a dose of 10 mg/kg, with a partial response at 1 mg/kg
Summary
But 10 times more potent against PAD27. The PAD inhibitor Cl-amidine was shown to have a modest anti-inflammatory effect, when given prophylactically at high doses[8]. We use a therapeutic, rather than prophylactic, treatment protocol, which is more relevant for translation into human disease. We demonstrate that BB-Cl-amidine reverses immune-mediated joint inflammation in a pre-clinical mouse model of arthritis. By targeting PAD enzymes, BB-CL-amidine reduces citrullination which is induced during inflammatory conditions such as arthritis. BB-CL-amidine-treatment decreases Th1 and Th17 responses in vivo while Th2 responses are supported. We report a novel treatment for immune-mediated pathologies in which the balance between Th17 and Th2 cells is disturbed
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