10 April 2012

Reversing Type I Diabetes Without Side Effects Using Genetically Engineered Bacteria From The Gut

Type I diabetes is caused when the body's own immune system attacks its pancreatic islet beta cells (β cell) that produces insulin. This then requires the patient to have daily injections of insulin to regulate the blood glucose levels.

Insulin is a hormone that stops the use of fat as an energy source. It regulates the carbohydrate and fat metabolism of the body and cause cells in the liver, muscle and fat tissue to take glucose from the blood. Glucose when unregulated can be toxic. At low levels the body begins to break down the glycogen stored in the liver and muscles into glucose which is used as an energy source.

Patients with type 1 diabetes depend on external insulin for their survival because the hormone is no longer produced internally by the pancreas.

Insulin is required for the regulation of blood sugar levels. With type I diabetes, since the cells that produce insulin are destroyed by the immune system, Chantal Mathieu and colleagues at the University of Leuven have attempted to circumvent this response by taking advantage of the fact that the immune system accepts foreign gut bacteria. The Mathieu group engineered gut bacteria so that they produce a form of insulin, and asked if these bacteria could retrain the immune system in mice with type I diabetes to accept insulin-producing cells.

They found that these special bacteria increased the frequency of cured mice when compared to traditional methods alone, with seemingly no undesirable effects.

In the gut, humans are in intimate contact with billions of commensal bacteria that do not trigger an inflammatory response in healthy individuals, because specific characteristics of the gut immune system create a context that promotes tolerance rather than immunity toward gut-delivered β cell–specific antigens (Ags).

Video: What is Type 1 Diabetes?

Harnessing this phenomenon, Chantal's group have devised a tool for gut delivery of diabetes-relevant autoAgs, together with immunomodulators. Lactococcus lactis, a common and food-grade commensal bacterium that is non-pathogenic and non-colonizing, was genetically modified (GM) to secrete the autoAg human proinsulin alone or in combination with the tolerance-promoting cytokine IL-10. Similar live, biologically contained GM L. lactis bacteria have been applied in other diseases and are being evaluated currently in patients with mucositis.

They demonstrated that, in the context of a short course of low-dose anti-CD3, GM L. lactis secreting human pro-insulin and IL-10 can stably revert autoimmune diabetes in newly diagnosed diabetic NOD mice. Mechanistically the treatment induced Ag-specific Foxp3+ Tregs that prevented diabetes transfer and homed to the islets of Langerhans. These results demonstrate, for the first time, the potential to arrest T1D by induction of Ag-specific tolerance using a novel, safe tool for gut-delivered β cell Ags and biologically active immunomodulators in the context of clinically acceptable low doses of anti-CD3 mAbs.

Traditional methods suppress the immune system, which brings with it unfavorable consequences such as increased infections. In fact the Mathieu group confirmed that the immune system functioned in the mice following treatment. Their study provides a promising step towards the ability to reverse type I diabetes, as well as other autoimmune disorders, without incurring adverse side effects.

Experience with this bacterial delivery tool in other human diseases and its acceptance by the regulatory authorities should allow rapid translation into the T1D clinical setting.


Journal of Clinical Investigation
University of Leuven
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