Checkpoint inhibition 'unleash' inflammatory markers, hurdles in giant cell arteritis
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More thorough understanding of giant cell arteritis disease processes has shed light on how immune checkpoint inhibitors may be exacerbating this and other immune-mediated conditions, according to a presenter here.
Cornelia M. Weyand, MD, PhD, professor of rheumatology and immunology at Stanford University, suggested that the GCA disease process involves abnormalities in both the innate and the adaptive immune system.
Issues with the innate immune system manifest in extravascular manifestations, with elevations seen in a number of biomarkers and cytokines like erythrocyte sedimentation rate (ESR)/C-reactive protein (CRP). Conversely, abnormalities in the adaptive immune system can lead to the vascular complications of GCA.
“The vascular part of GCA is really the part that scares the patient and us,” Weyand said. “This makes us respond with therapy and interventions.”
The key issue is seen in blood vessel walls, according to Weyand. “Nature has gone out of its way to make sure the blood vessel wall is an immune-privileged site, meaning it has no inflammatory cells,” she said.
When the T cells and macrophages of GCA disease process are inflamed at those sites, this can be problematic and difficult to treat. “The vascular components seem to be chronic and persistent,” Weyand said. “This is very hard to treat because once the disease has built its nest, it is not so easy to leave that nest.”
With all of this in mind, Weyand raised what she believes is a key question in vasculitis as it pertains to the advent of immune checkpoint inhibition. “Is autoimmune disease a consequence of not enough immune checkpoint signaling?” she said.
In patients who have the vascular and extravascular complications of GCA, a signal of immune checkpoint deficiency can be observed, according to Weyand. “In a normal aorta, there is plenty of expression of PDL-1,” she said. “When the aorta is affected with GCA, there is a clear reduction in PDL-1.”
This is important because vasculitides like GCA can be notoriously difficult to diagnose and manage, according to Weyand. Having a clear biomarker would make the life of a rheumatologist easier and likely improve outcomes for this disease.
Weyand and her group went on to design a mouse model investigating checkpoint inhibition in mice who had been given GCA. In short, when these mice were given a checkpoint inhibitor, mild inflammation in the vasculature became very aggressive. “If we break the immune checkpoint, all the inflammatory cytokines jump up,” she said, noting expression of interferon-gamma, interleukin-(IL)-17a and IL-21, among other inflammatory markers. “Checkpoint inhibition also unleashes T cell immunity.”
As Weyand and her group dug deeper into immune processes in their mouse model, they observed that CD28 had “beneficial effects on the remodeling of the artery,” she said. “The thickness of the intima is positive on this intervention.”
While there is considerable work to be done to develop and refine this potential treatment strategy, Weyand believes it could be a first step in providing relief for patients with this complicated and therapeutically challenging condition. “There is hope on the horizon,” she said.
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Weyand CM. Immune Checkpoints in Vasculitis. Presented at: Congress of Clinical Rheumatology-East annual symposium; August 12-15, 2021 (hybrid meeting).
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