Quick non-expert takes on research about insulin-dependent diabetes
Mixing up a cure. Last week Prevention Bio asked the Food & Drug Administration to approve teplizumab for people at high risk of type 1 diabetes (T1D). Teplizumab will be the first drug to delay the onset of the disease among people at high risk, as shown in a phase 2 clinical trial.
The drug is a monoclonal antibody that targets CD-3, a receptor protein that can activate T cells expressing the CD-8 receptor. Those cells are thought to be the main players attacking insulin-producing beta cells in pancreatic islets and triggering T1D. Exactly how teplizumab works, and on whom, is very much under study.
To date, more than 2100 clinical trials have tried to stop T1D, notes a Biomolecules review published in December by Gabriel Brawerman and Peter Thompson of the University of Manitoba in Winnipeg. Almost all of the trials, understandably enough, aimed to fiddle with the immune system.
However, “a growing body of evidence supports the idea that beta cell dysfunction is just as critical as the autoimmune process, and that T1D is also a disease of the beta cells/islets,” Brawerman and Thompson write. “Thus, a new emphasis on beta cell drug therapies could be an exciting avenue to reduce beta cell death, restore beta cell function and avert T1D onset.”
“The classic view is that autoreactive T cells mistakenly destroy healthy (‘innocent’) beta cells,” say Bart Roep of the City of Hope in Los Angeles and colleagues in a December Nature Reviews Endocrinology paper. “We propose an alternative view in which the beta cell is the key contributor to the disease.”
Researchers led by Decio Eizirik of the Indiana Biosciences Research and Université Libre de Bruxelles continued the theme last week in a Science Advances paper. “There is increasing evidence that the target tissues of these diseases are not innocent bystanders of the autoimmune attack but participate in a deleterious dialog with the immune system that contributes to their own demise, as shown by our group and others in the case of T1D,” the scientists declare.
Eizirik’s team examined gene expression in the tissues under autoimmune attack in T1D, lupus, multiple sclerosis, and rheumatoid arthritis. Among their findings, the scientists pinpointed a number of genes that are highly expressed in the tissues for some or all of these conditions, many of these genes related to local inflammation. Moreover, more than 80% of the top risk genes show changes in expression among the tissues at risk rather than among immune cells. “These observations suggest that future research on autoimmune diseases should focus on both the immune system and the target tissues, and on their dialog,” they conclude.
So, combining beta cell therapies with immunotherapies indeed will be a promising avenue of research. “However, the use of combination therapies would not be without its challenges in the clinic,” Brawerman and Thompson write. “Each of the therapies alone present a distinct set of risks for adverse side-effects… A further limitation to implementing combination therapy in T1D could stem from the unpredictability of the effects of the one therapy on the other cell type.”
“Our understanding of T1D will continue to evolve and be refined due to advancements in experimental tools and approaches,” the Manitoba biologists conclude. “But progress will also depend on the willingness to challenge dogma and long-held assumptions about T1D.” 1/9/21