Researchers at Beth Israel Deaconess Medical Center (BIDMC) have found that a triple combination therapy consisting of both tolerance-inducing and anti-inflammatory properties is successful in abolishing adverse autoimmunity against insulin-producing cells in a mouse model of Type 1 diabetes.
The findings, which appear in the Online Early Edition of the Proceedings of the National Academy of Sciences (PNAS) this week, offer a possible new prototype for therapies to restore normal blood glucose levels in diabetes patients and suggest a previously unrecognized role for inflammation in the disease.
"Type 1 diabetes is known to develop as a consequence of autoimmune destruction of insulin-producing pancreatic beta cells," explains senior author Terry Strom, MD, Director of the Transplantation Research Center at BIDMC and Professor of Medicine at Harvard Medical School. "But in addition to the long-recognized role of T-cell-dependent immune-system-mediated islet destruction, this work reveals for the first time that a form of inflammation in fat and muscle [is also acting to] prevent insulin from disposing blood glucose into tissues that require glucose."
Formerly known as juvenile-onset or insulin-dependent diabetes, Type 1 diabetes develops when the body's immune cells attack and destroy its own pancreatic beta cells. Without beta cells, the body is unable to produce insulin, a hormone needed to convert glucose into energy. To prevent the development of serious complications, more than 21 million individuals with Type 1 diabetes , primarily children and young adults , must receive as many as three injections of insulin each day.
Previous attempts to treat existing Type 1 diabetes were primarily focused on restoring immune tolerance, which in healthy individuals is achieved when immune system cells turn off so as not to overreact and attack one's own cells. In individuals with Type 1 diabetes, the process of immune tolerance fails to work properly, thereby permitting the self-destruction of the body's beta cells.
But lead author Maria Koulmanda, MSc, PhD, director of Non-Human Primate Research in BIDMC's Transplantation Research Center, wondered if there might also be a role for inflammation in the disease process.
"We knew that in cases of type 2 [non-insulin dependent] diabetes, a form of inflammation in muscle and fat prevents insulin from triggering the transfer of glucose from the blood into important insulin-sensitive tissues," explains Koulmanda, who is also Assistant Professor of Surgery at HMS. "We thought that in addition to autoimmune destruction of insulin-producing cells, there might also be inflammation-induced insulin resistance [in type 1 diabetes.]
To test this hypothesis, the authors administered a ,cocktail, of three separate agents (rapamycin plus agonist IL-2- and antagonist-type, mutant IL-15-related Ig fusion proteins) in a NOD (non-obese diabetes) mouse model of type 1 diabetes. The therapy regimen, which included two novel immunoglobulin-fusion proteins, was aimed at both increasing tolerance and decreasing inflammation.