British and Taiwanese scientists have described a novel approach to the treatment of autoimmune rheumatoid arthritis (RA), using an already approved DNA-methylation inhibitor (DMI), which was shown to effectively treat active inflammatory disease in animal models.
Among the different DMIs tested, one agent in particular, decitabine (Dacogen; Otsuka Pharmaceuticals), was found to generate robust regulatory T cells (Tregs) with the capacity to maintain long-term remission.
"We are not the first group to demonstrate that decitabine can effectively treat active inflammatory RA in animal models," noted study leader Richard Williams, a professor in the Kennedy Institute of Rheumatology at the University of Oxford, U.K.
"However, ours is the first study to show that decitabine selectively eliminates T effector cells expressing the equilibrative nucleoside transporter 1 (ENT1) in active arthritis and generates induced Treg cells that could maintain remission from arthritis."
Importantly, decitabine's ability to maintain long-term remission was shown to be dependent on indoleamine 2,3-dioxygenase (IDO).
"IDO is known to be important for the generation of Tregs and we showed in IDO gene knockout (KO) mice that remission was not sustained in the absence of IDO, which reinforces the role of Tregs in maintaining remission," said Williams.
Chronic inflammatory diseases, such as RA, are characterized by an imbalance between pathogenic T effector cells and fully functional Tregs, of which there is a marked deficit.
DNA-methylation inhibitors have been shown to promote regulatory T-cell responses and, in the new study reported in the May 11, 2021, online edition of Proceedings of the National Academy of Sciences, the authors evaluated the potential of these agents to ameliorate disease in chronic and acute mouse models of RA.
"The chronic and acute animal models of RA were collagen-induced arthritis (CIA) and antigen-induced arthritis (AIA), respectively," Williams told BioWorld Science.
"The CIA model, which is widely considered the best model of RA, was used to test three nucleoside-derived inhibitor agents, zebularine, procainamide and decitabine, and one non-nucleoside-derived inhibitor, psammaplin A."
Among these different drugs, the cytosine analogue decitabine was shown to be the most effective, rapidly achieving a sustained therapeutic effect that was dependent on IDO and associated with expansion of induced Tregs, particularly at the site of disease activity.
"The therapeutic effect of decitabine was very rapid, which we attributed to elimination of T effector cells," said Williams, adding, "Treg cells act locally, so it is particularly important that we found induced Treg cells at the site of disease activity."
Treatment with decitabine, which is approved by the U.S. FDA for myelodysplastic syndromes in adults, was also demonstrated to cause apoptosis of proinflammatory T helper 1 (Th1) and Th17 cells in active arthritis in a highly selective manner.
"Decitabine was shown to cause apoptosis of activated Th1/Th17 cells but not naive T cells, which is important, because if you eliminate naive T cells you induce immunosuppression," said Williams.
Decitabine was further shown to selectively target T effector cells expressing ENT1, which generates robust regulatory T cells with the ability to suppress immune-driven inflammation.
The researchers also demonstrated in mice that short-term treatment with decitabine resulted in the generation of a population of Tregs that were able to suppress active arthritis upon adoptive transfer.
"'We treated arthritic mice with 1 mg/kg of decitabine for 4 days starting from the day of disease onset in the CIA model and from the day 10 after immunization for the AIA model," explained Williams.
"Adoptive transfer involves the transfer of cells from donors into recipients and in our systems, we transferred Treg cells from the arthritic mice treated with decitabine into the recipient arthritic mice by intravenous injection."
Collectively, these findings demonstrate that decitabine treats active inflammatory disease effectively and generates robust regulatory T cells with the IDO-dependent capacity to maintain remission.
Because it had previously been approved by the FDA, theoretically "decitabine could go into RA patients now, but there may be safety concerns which might be acceptable in cancer, but not in nonfatal diseases like RA," said Williams.
Nevertheless, "while our study demonstrates that DMIs may be able to re-establish tolerance in autoimmune disease, the downside is that they are likely to have off-target effects. Therefore, we intend to study more selective epigenetic drugs in the future."