Reversal of T1D by Restoration of Antigen-Specific Tolerance Using Genetically Modified Bacterium in Mice

The gastrointestinal tract is an attractive route for the safe delivery of agents aimed at inducing and/or restoring immune tolerance. When delivered to cells in the gastrointestinal tract, certain types of bacteria reside there for 8 48 hours, during which time they can continuously release therapeutic amounts of biologically active proteins. Such a release profile more closely mimics the way in which natural biomolecules are released in the body, in contrast to the pharmacokinetic profile of many conventional drug products. In this study, the authors demonstrate that an orally administered common, food-grade bacterium that is non-pathogenic (L. lactis) modified to concurrently secrete whole human pro-insulin and hIL10 (a secreted soluble protein IL-10 that can suppress autoimmunity) can stably reinstate normal blood glucose control in newly diagnosed diabetic mice when introduced immediately after treating the mice with a course of low-dose systemic anti-CD3 mAb (an agent that can suppress over-active T-cells of the immune system). Combination-treated diabetic mice had higher beta cell mass and augmented levels of functional regulatory T-cells, which resided and proliferated locally in the pancreas.

Reference:

Takiishi T, Korf H, Van Belle TL, Robert S, Grieco FA, Caluwaerts S, Galleri L, Spagnuolo I, Steidler L, Van Huynegem K, Demetter P, Wasserfall C, Atkinson MA, Dotta F, Rottiers P, Gysemans C, Mathieu C. J. Clin Invest. May 2012;122(5):1717-25.

Investigators and Institutions:

This work was led by Dr. Chantal Mathieu from KU Leuven, Belgium.

Ramifications for Individuals with Type 1 Diabetes:

In the gut, immune modulatory agents (such as IL-10) are able to act locally on intestinal epithelial cells, thereby enhancing the desired expansion or maintenance of regulatory T-cells and their suppressive function essential to combating the autoimmune process. Importantly, experience with this bacterial delivery tool in other human diseases (colitis and mucositis) has shown safe us in people and its acceptance by the regulatory authorities offers great potential to allow rapid translation into the T1D clinical setting after promising pre-clinical results are established.

JDRF Involvement:

This study was funded in part by JDRF, alongside NAIMIT, which is a multi-disciplinary consortium of leading European diabetologists and immunologists.