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For rheumatoid arthritis that’s resistant to current treatments, two emerging therapies are showing positive results in research underway at The Ohio State University Wexner Medical Center.
“Even with all the advances in rheumatoid arthritis therapy, there are still patients who do not respond as we would hope,” says Wael Jarjour, MD, director of the Ohio State Division of Rheumatology and Immunology in the Department of Internal Medicine. “That is why we continue to look for new approaches.”
Scientists recently published the results of two separate studies.
Inhibition of BET proteins to reduce inflammation
Bromodomain and extra-terminal (BET) protein is required for gene transcription. It’s known that when the BET protein transcription is suppressed, inflammation is reduced.
A study led by immunologist Susheela Tridandapani, PhD, and Dr. Jarjour shows for the first time that BET inhibition downregulates expression of antibody-mediated responses. The work was published in the International Journal of Molecular Sciences in April 2023.
Fcγ receptors (FcγRs) expressed on myeloid cells bind to immunoglobulin G immune complexes. When FcγRs recognize autoantigen-antibody complexes, inflammation occurs. This causes tissue damage and can escalate the inflammatory response.
“What we showed is that BET inhibition suppresses the expression of these receptors,” Dr. Tridandapani says. “This would mean that these cells cannot phagocytose and cannot create inflammation.”
A mouse model of collagen-induced arthritis further showed that BET inhibition significantly reduced FcγR expression in the spleen and the clinical response in this murine model.
These results suggest that BET inhibition affects not only general inflammatory responses but also FcγR expression and function.
In the animal model, mice given the BET inhibitor showed reduced footpad swelling. When the monocytes from these mice were tested, they also showed reduced FcγR expression. However, this is a correlation, and not a cause-and-effect response, Dr. Tridandapani says.
“Future studies must show a cause and effect,” she says. “We have to use knockout animal models that don’t express the gamma receptors.” Such research should reveal more information about how to combine the BET protein with another compound for effective delivery into cells to enhance receptor suppression.
Dr. Tridandapani says a substance must be found that can regulate these receptors while not impacting a whole plethora of genes.
Therapeutic effects of gingival mesenchymal stem cells and their exosomes
Gingival mesenchymal stem cells are easily harvested from the tissue that envelopes the necks of erupted teeth. These cells are known to possess immunomodulatory properties. Extensive studies reveal their potential for cell-based therapeutics for several autoimmune disorders.
In a study led by Dr. Jarjour and his lab, healthy gingival mesenchymal stem cells and their exosomes were used to treat mice with a chimeric model of rheumatoid arthritis. The work was recently published in Arthritis Research & Therapy.
At the start of the published research, mice received an implant of human cartilage from a subject with degenerative arthritis.
“When these mice receive an infusion of synovial cells from patients with rheumatoid arthritis, these synovial cells act in an aggressive way and invade the cartilage and damage it like they do in a human,” Dr. Jarjour says.
However, when some of these mice were treated with the gingival stem cells, they showed significant therapeutic effects that suppressed the inflammation, according to Dr. Jarjour.
Researchers also isolated exosomes made by these cells. When the exosomes were injected into arthritic mice, those subjects also showed benefits.
While the cell-based therapy showed better results than the exosome injection, there is much more research to be done, Dr. Jarjour says. Ongoing studies will explore:
- Effective dosage for the exosome treatment
- The exact genes the exosomes target to produce the anti-inflammatory effects
Being able to identify one or two genes that haven’t been studied could open new avenues for therapeutic targets.
“There is still room for improvement,” Dr. Jarjour says. “There are always new approaches not being considered, and we need to keep exploring new areas to improve the lives of our patients.”
