New Horizons Discovered for GCA Treatment

New Horizons Discovered for GCA Treatment

January 2011
By Cornelia Weyand, MD, PhD

New research from Stanford University has identified three molecules that play a role in the abnormal immune responses of GCA. The discovery may lead to more effective ways of measuring disease activity and new GCA therapies.

“This opens a whole new world of biology for vasculitis,” says the study’s principal investigator, Cornelia Weyand, a professor of medicine at Stanford. “Patients come and see us and we have very limited means to tell them whether the disease is well-controlled or not. Currently, we use very non-specific lab tests — the sedimentation rate, CRP — to estimate disease activity. Imaging blood vessels and their walls has been disappointing so far in telling us whether the inflammation is still going on or whether it has stopped. We need much better tools.”

Assessing Disease Activity
Her research may have uncovered that “better wrench”. Studying artery tissue samples from patients who underwent temporal artery biopsy, researchers looked for genes that were expressed at very high levels in the lesions. They noticed that the samples showed high levels of NOTCH-1, JAGGED-1 and DELTA-1 molecules. NOTCH is the receptor on the T cell surface and JAGGED and DELTA are expressed on partnering cells.

“We showed that NOTCH sits on the T cells and when it binds with DELTA or JAGGED the T cells are activated and become tissue-destructive,” she explains. “We also saw that these NOTCH-expressing T cells are circulating in the blood of the patients where we can find them for diagnostic testing.”

The discovery will help researchers better understand how GCA comes about and what it does to the blood vessel. Weyand will continue to investigate whether NOTCH-positive cells can be used to find out how active the disease is in a blood sample.

Blocking Inflammation
The study findings may provide clues for ways of interfering with the inflammation response. “We know less how to stop vascular wall inflammation once it has begun,” Weyand admits. “We need to discover disease-typical cells and their products that allow us to disrupt the inflammation and do this without paralyzing the overall immune system. Essentially, all of the therapies we have right now cannot distinguish between the ‘bad’ inflammation in the arteries and the ‘good’ inflammation that protects us from harm.”

Weyand’s work puts researchers one step closer to solving that riddle. The team implanted human arteries in mice, induced vasculitis and tried various ways of blocking activation of the NOTCH molecule in an attempt to suppress inflammation.

“When we inject cells from a patient with GCA [into the mouse], those cells will initiate the inflammation,” Weyand explains. “Giving the medication very early in the disease essentially stopped the disease process. Giving it late in the disease still had excellent therapeutic effects.”

Getting Solid Support
The ground-breaking study was made possible by a grant from VF.

”The Vasculitis Foundation has emerged as an important force in supporting studies into the pathogenesis of vasculitis,” Weyand asserts. “Understanding what goes wrong in the immune system of vasculitis patients, developing new tools in measuring these abnormalities in a blood sample and, above all, paving the way for new treatments that are not broadly suppressive for the immune system but specifically target ‘bad’ inflammation are tightly connected. Diagnosing and treating disease without knowing how it comes about is like driving in the dark without the headlights on. Research is the process of switching on the headlights and finding the right direction. The Vasculitis Foundation has the potential to become the major driver of ‘switching on the headlights’.”


Vasculitis Foundation

The Vasculitis Foundation is the international organization for patients with vasculitis, their families, friends and the health care professionals who care for them.