- new approaches to RA immunotherapy
- new targets for stopping RA inflammation
- a new focus on bone erosions in RA, and
- a new strategy that might change the natural history of the disease
"There have been great strides made in the treatment and management of RA and it is crucial that we continue to financially support RA research," said Leslie J. Crofford, MD, president of REF. "We are confident that the new grantees are among the brightest and most promising researchers in their field [who] will play a critical role in moving us closer to a cure."
"Their links to RA made me shift much of my initial research focus to the PAD enzymes [partly because] my father and grandfather suffer/suffered from ankylosing spondylitis, and I know the devastating effects that arthritic disorders can have on a patient's quality of life."—Paul R. Thompson, PhD
New targets for RA immunotherapy
Gregg J. Silverman, MD, at the University of California, San Diego, will be expanding his group's studies of natural antibody treatment of inflammatory arthritis. Dr. Silverman told MSKreport.com that the REF grant will fund additional work on the murine T15 antibody. "A pilot study showed that the IgM antibody could prevent induction of collagen-induced arthritis (CIA). We are now looking at whether it can be used to treat already established arthritis in mice. "
The researchers think that the T15 antibody "dials up a natural regulatory pathway" that induces autoimmune signals within dendritic cells that mimic the anti-inflammatory effects of steroids, but in a targeted way. "We hope in about 3 years to have developed a prototypic human version of this natural antibody," Dr. Silverman said.
Song Guo Zheng, MD, at the Keck School of Medicine at the University of Southern California is studying the generation of collagen-specific CD4+Foxp3+regulatory T-cells as an adoptive immunotherapy for RA.
"[R]egulatory T-cells play an important role in the controlling the development and progress of many autoimmune diseases, [and] we believe that [manipulating them] may provide a promising therapeutic strategy. Our group has established that TGF-β can induce CD4+CD25- non-Treg cells to become induced Treg cells (iTreg), [which] share similar phenotypes and suppressive activities with nTregs. However, they seem to be stable in the inflammatory milieu. [Although] the suppressive activity of nTregs in the presence of IL-6 was ablated, iTregs, however, sustained their suppressive activity in the presence of this cytokine….nTregs become Th17 cells when stimulated with IL-6 [and] are resistant to this conversion. Conversely, they maintain the Foxp3 expression and sustain the suppressive activities in vitro and in vivo," Dr. Zheng told MSKreport.com.
Hope to stop RA inflammation
Michael B. Brenner, MD, of Brigham and Women's Hospital in Boston will continue studies on how fibroblast-like synoviocytes mediate cadherin-11 dependent inflammation in RA. These are resident mesenchymal cells of synovial joints that are now thought to be important in RA pathogenesis. Fibroblast-like synoviocytes activation leads to production of a broad array of mediators that stimulate both inflammation and tissue damage, and Dr. Brenner has suggested that these cells might represent a unique target for RA treatment.
Richard M. Pope, MD, and colleagues at Northwestern University Feinberg School of Medicine in Chicago will study endogenous toll-like receptor ligands in RA, with the goal of identifying new targets for intervention in RA. This might lead to methods for inducing apoptosis as a therapeutic approach to RA.
Shiva Shahrara, PhD, also at Northwestern University Feinberg School of Medicine, is taking a different approached based on studies of the role of IL-17 in the pathogenesis of RA.
"I became interested in IL-17 because overexpression of IL-17 in ankle joints can result in acute arthritis in mice and one of the mediators of TH-17 cells such as IL-23 play a significant role in experimental arthritis, since IL-23 knockouts are resistant to collagen induced arthritis. However, little is known about the role of IL-17 in RA. We are interested in identifying the downstream targets of IL-17 in RA synovial tissue fibroblasts and synovial fluid macrophages compared with normal controls in order to determine those genes that may be regulated in a disease-specific fashion."
Bone gets more attention
RA-related bone erosions are getting attention, thanks to REF. Ellen M. Gravallese, MD, at the University of Massachusetts Medical School, is studying the role of sFRP1 and WNT signaling in formation and repair of erosions in RA. Steven Reyburn Goldring, MD, of the Hospital for Special Surgery in New York will study bone matrix-induced osteoclast genes as potential targets for RA treatment. Xu Feng, PhD, of the University of Alabama at Birmingham, will conduct in vivo studies to validate novel therapeutic targets for arthritis bone erosion.
PAD inhibitors may be novel treatment strategy
Paul Ryan Thompson, PhD, of the University of South Carolina, Columbia, is conducting one of the more novel lines of research: inhibition of protein arginine deiminases (PADs) as a treatment strategy for RA. PADs catalyze the deimination of arginine residues to citrulline in a number of proteins including histones H2A, H3, and H4.
"Much of my current research program is focused on developing inhibitors for histone-modifying enzymes because of their role in modifying transcription….I focused on the protein arginine methyltransferases (PRMTs) because the activity of these enzymes is dysregulated in heart disease and cancer. This led me to look for enzymes that could reverse or antagonize the effects of the PRMTs, and that is when I stumbled on the PADs. Their links to RA made me shift much of my initial research focus to the PAD enzymes [partly because] my father and grandfather suffer/suffered from ankylosing spondylitis, and I know the devastating effects that arthritic disorders can have on a patient's quality of life," Dr. Thompson told MSKreport.com. His group is evaluating the efficacy of a small molecule PAD inhibitor in the CIA model of RA.
"We are trying to evaluate the efficacy of a small molecule PAD inhibitor that my lab developed in the CIA model of RA. This work is being performed in collaboration with Michael Holers lab at the University of Colorado. To date, we have had excellent data showing that this compound is effective in decreasing disease severity and several hallmarks of inflammation, " Dr. Thompson said.
Reference
1. American College of Rheumatology Research and Ed. Found. Awards New Research Grants for Rheumatoid Arthritis Research [press release]. Newswise Website. http://www.newswise.com/articles/view/543691/.
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