(Left). The X-idiotype antibody (blue sticks) is recognized and presented to immune cells, stimulating a destructive autoimmune response that targets insulin-producing cells. (Right) Mutation of a key residue, Tyr6 in blue, in the X-idiotype could lead to deletion of the immune cells that erroneously target insulin-producing cells in Type-1 diabetes.
A research collaboration has made early progress toward a potential vaccine for type 1 diabetes, a long-sought goal for an autoimmune disease that affects more than 1.5 million Americans.
The team, including Frederick National Laboratory computational scientist David Bell, previously discovered a new protein antibody in type 1 diabetes patients. The antibody, X-idiotype, appears to trigger an autoimmune response in which the body mistakenly attacks insulin-producing cells in the pancreas.
In the current research, published in Proceedings of the National Academy of Sciences, the scientists explored the binding properties of X-idiotype, a necessary understanding for future work on possible vaccine design.
Theirs was a two-step approach. First, they used computer modeling to mutate key X-idiotype residues and then used the simulation to measure how well the mutations bind to target cells. The computer modeling was followed by biologic studies, specifically cell proliferation and flow cytometry assays, to confirm the computer findings.
The team found that several points on the surface of X-idiotype can be mutated to change how strongly or weakly it binds to immune system proteins. The next step would be to optimize this binding for use as a potential immunotherapy for type 1 diabetes. One approach might be to gradually expose impaired X-idiotype to the immune system to encourage tolerance over time.
The ability to restore tolerance of self-antigens – as in type 1 diabetes and other autoimmune diseases – as well as tolerance of environmental allergens are major goals of research to ease the suffering caused by these disorders. Current treatments attempt only to manage symptoms or suppress immune responses.
The project was led by Ruhong Zhou of Zhejiang University in China and the Thomas J. Watson Research Center and Columbia University in New York. Bell’s collaboration with the group began while he was with IBM and continued under an outside activity agreement after he joined FNL in 2021.
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