Thanks to UCSF immunologists including Jeff Bluestone, PhD and Todd Brusko, PhD, a paradigm shift in thinking has occurred regarding the immune system’s role in type 1 diabetes. Previously, the goal was to suppress the immune system so insulin-producing beta cells weren’t destroyed.
It is now believed that beta cell destruction occurs because of an imbalance in the immune system. This imbalance occurs when uncontrolled, autoreactive effector T cells (Teff) outnumber the protective regulatory T cells (Tregs) – cells that are involved in helping the body to suppress immune responses, inflammation and tissue destruction plus “tolerate” its own cells.
The Bluestone Lab has rapidly advanced research on the beneficial effect of increasing the numbers of Tregs to correct the immune imbalance -- to stop beta cell destruction and to possibly reverse disease. After a few years of successfully isolating and expanding Tregs in animal models, the team expects to launch the first human clinical trials utilizing an individual’s own Tregs for treating type 1 diabetes and autoimmunity.
Amy Putnam, a staff research associate in the Bluestone Lab, has created the optimal expansion protocol based on culturing highly purified Tregs with anti-CD3/anti-CD28 coated microbeads and IL-2. Tregs, defined as CD4+ CD127lo/-CD25+, can be expanded an average of 1,500-fold over a two-week period while retaining high levels of FOXP3 – a transcription factor required for proper development and function of Tregs. By infusing expanded, “personalized” Tregs back into the patient, it is hoped that the immune system will be back in balance, beta cell destruction will discontinue, and type 1 diabetes may even be reversed.
Even though the team is excited to launch their first human clinical trials, they are looking to the future as well. They hope to create “designer” antigen-specific Tregs capable of recognizing diabetes autoantigens at the site of the inflammatory attack, in order to stop beta cell destruction.