New Article by Dr. David Ostrov – Genes and Autoimmune Diabetes

Published: February 23rd, 2018

Category: Department News, Pathology News

Dr. David Ostrov, Associate Professor in the Experimental Pathology Division, has recently published an article in JCI (The Journal of Clinical Investigation).

Genes play a significant role in autoimmune diabetes. The genes most strongly associated with autoimmune diabetes produce a protein called HLA-DQ8 (HLA-DQ plays an important role in the immune system by stimulating T cells). In patients with autoimmune diabetes, HLA-DQ8 stimulates T cells that unfortunately recognize normal proteins such as insulin.

A drug capable of blocking the unwanted activity of HLA-DQ8 would be expected to prevent autoimmune diabetes in high-risk individuals (such as those inheriting HLA-DQ8), and also delay the progression of the disease in diabetes patients.

We identified a drug capable of binding HLA-DQ8 and blocking its unwanted activity (stimulating T cells). We used the crystal structure of HLA-DQ8 as the basis for screening 139,735 compounds by structure-based molecular docking using the University of Florida Research Computing Facility (HiPerGator#3 is the most powerful computer at a US Public University). We used a program developed by UCSF (called DOCK) to identify candidate compounds that were tested for activity on cells and in animals at the University of Colorado in the lab of Dr. Aaron Michels.

Dr. Michels conducted experiments showing that an approved orally deliverable drug blocked HLA-DQ8. Since this drug has been considered safe for more than 50 years (including usage in pregnant women), a clinical trial was approved and results from Dr. Michels’ Phase 1b diabetes prevention clinical trial at the University of Colorado, Denver will be reported in a new article in the JCI.

This study has significant implications for treatment of diabetes, and also other autoimmune diseases. This study suggests that the same approach (structure-based selection of drugs that bind HLA molecules) may be adapted to prevent autoimmune diseases such as rheumatoid arthritis, coeliac disease, multiple sclerosis, systemic lupus erythematosus and others.

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