The basic biological mechanisms that underpin autoimmune disorders are finally coming to light. Researchers in Boston’s Longwood medical area — a neighborhood where the streets are flanked by hospitals, research institutions and academic centers — are setting the stage for a new wave of future therapies that can prevent, reduce or even reverse symptoms of disease.
Inside the lab of Michael Carroll, PhD, scientists are working to understand how and why immune cells start to attack the body’s own tissues; it turns out the immune system’s B cells compete with each other in true Darwinian fashion. On the way to this discovery, the lab has flushed out new potential drug targets that could ease autoimmune symptoms — or stop them entirely — by “resetting” the body’s tolerance to itself.
Carroll’s team has also drawn some of the first links between chronic inflammation, synapse loss and neuropsychiatric disease in lupus.
The implications for a link between inflammation and synapse loss go beyond lupus because inflammation underpins so many diseases and conditions, ranging from Alzheimer’s to viral infection and even to to chronic stress. In which case, are we all losing synapses to some varying degree? Carroll plans to find out.
Meanwhile, Sun Hur, PhD, and members of her lab are digging deep on a genetic variant and its link to pediatric inflammatory autoimmune disorders like Aicardi-Goutieres syndrome.
“We’ve found that chronic inflammation and autoinflammatory disorders can originate from genetic mutations to MDA5 that cause it to misrecognize ‘self’ as ‘non-self,’ essentially launching the immune system into self-attack mode,” said Hur.
As a result, MDA5 inhibitors have surfaced as an attractive candidate to alleviate inflammation caused by autoinflammatory disorders.
Biologics-based therapies on the horizon
Taking a different approach to modulating the immune response, Hidde Ploegh, PhD, is investigating the use of engineered red blood cells to re-train the immune system.
“Given the broad acceptance and safety profile of red blood cell transfusions, [this strategy] promises a lack of adverse effects,” Ploegh said.
In models of autoimmune diseases in mice, Ploegh’s team has already demonstrated that transfusions of engineered cells can prevent and even reverse the clinical signs of type 1 diabetes and a multiple-sclerosis-like condition.
But that’s far from being the only creative workaround to diabetes that’s being explored by researchers in Boston. Diane Mathis, PhD, and Christophe Benoist, MD, PhD, are studying how the gut microbiome impacts the health of the immune system. Some of their latest findings raise fascinating questions about whether early-life antibiotics and inadequate germ exposure could play a role in type 1 diabetes — and if fecal transplants could someday reduce diabetes risk.
“Avoiding or at least minimizing antibiotic treatment in infants and pregnant women during critical periods of development may be a good idea,” Mathis said.
Across the street, Paolo Fiorina, MD, PhD, has yet another approach to type 1 diabetes, employing pre-treated blood stem cells to reverse hyperglycemia.
Using a cell-based therapy, his approach would involve restoring a lost immune checkpoint molecule called PD-L1 (also gaining interest as a target in cancer treatment) to diabetic blood stem cells. In mice, an intravenous infusion of the treated cells curbed the autoimmune attack on islet cells in the pancreas, curing almost all indivi
duals of diabetes in the short term. A third of them even maintained normal blood sugar levels indefinitely.
“There’s really a re-shaping of the immune system when you inject these cells,” Fiorina said.
One of many, many of one with an autoimmune disorder
At the bedside, multi-disciplinary teams are working in real time to understand their most complex patients and how best to treat them. Although more than 23 million Americans are living with an autoimmune disorder, some people remain undiagnosed while others share their diagnosis with a select few.
Take 4-year-old Vanessa, for example, who was the sixteenth child in U.S. to be diagnosed with a condition called DADA2, caused by deficiency of an enzyme known as ADA2.
Vanessa, who is a patient of Boston Children’s Hospital, has had strokes and two massive cerebral hemorrhages that threatened her life. Why? Because her immune system is attacking her own blood vessels.
Now, while Vanessa is on an anti-inflammatory drug regime that’s keeping her symptoms at bay, her parents are partnering with physician-scientists to better understand how ADA deficiency relates to immune health.
“ADA is an enzyme, but what it really does has yet to be demonstrated convincingly,” said Pui Lee, MD, a rheumatologist at Boston Children’s Hospital who helps care for Vanessa.
In 2016, Vanessa’s mother Katherine Bell co-founded a foundation that will host its second international DADA2 conference this summer. The first conference led to at least four independent medical collaborations to study the condition.
“This is just the beginning,” said Bell.
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