Research Tracks Possible Benefit of Src-like Adaptor Protein

A study recently submitted for publication has demonstrated that manipulating T-cell receptor complex–mediated signaling can prevent the development of autoimmune arthritis in mice and may lead to new human therapies without the drawbacks associated with existing treatments.

The lead researcher on this project is Leonard Dragone, MD, PhD, assistant professor of pediatric rheumatology at the University of Colorado Denver School of Medicine and National Jewish Health and a recipient of an ACR Research and Education Foundation (REF) Within Our Reach: Finding a Cure for Rheumatoid Arthritis research grant. Dr. Dragone and his fellow investigators seek to understand how to manipulate T-cell signaling—or the activation and differentiation of T cells—to affect rheumatoid arthritis (RA) susceptibility.

A protein called Src-like adaptor protein, or SLAP, is known to regulate TCR signaling, so Dr. Dragone and his colleagues have been experimenting with mice bred to have both SLAP deficiency and inflammatory arthritis in an attempt to understand how TCR signaling influences the pathogenesis of RA. Their research has shown that SLAP deficiency prevented chronic arthritis in their subjects.

“We’re only a year in to the study, but we’ve already had some exciting discoveries,” Dr. Dragone says.

Unlike past studies with mouse models, the arthritis prevention in this study was not the result of alterations in the development of arthritogenic T cells in the thymus. Instead, the success of Dr. Dragone’s research comes from an increased number and enhanced function of regulatory T cells, which increases the ability to suppress arthritogenic T cells and thus prevent arthritis.

“We intend to define the signaling events that lead to the enhanced numbers and increased function of Tregs in our model,” Dr. Dragone says. “We hope that the information gained by these studies could ultimately be translated to future human therapies. Therapies that result from our studies could prevent arthritis without completely defeating the immune system. That’s the problem with our current therapies. They’re like a sledgehammer to the immune system, making patients susceptible to a host of other illnesses.”

Dr. Dragone said he’s grateful the Within Our Reach grant has allowed this research to continue. “We were poised to begin, and the funding from the Within Our Reach program allowed us to move forward,” he says. “As one of only two pediatric rheumatologists to have been awarded a Within Our Reach grant, I feel very fortunate. I’m very grateful because pediatric rheumatologists are underrepresented in research, and funding from the Within Our Reach [campaign] has provided me with an opportunity to develop my research program.”

An oral presentation of the most recent findings from this research will presented at the ACR/ARHP Annual Scientific Meeting in Atlanta on November 10.