InFocus,Vol. 12 No. 4, December 2004
--In the March 2004 issue of InFocus, there was a brief description of this research being carried out by Denise Faustman, M.D., Ph.D., Associate Professor of Medicine, Harvard Medical School, Massachusetts General Hospital-East (partially funded by AARDA). Here is a condensed update.
Denise Faustman, M.D., Ph.D., and colleagues at Massachusetts General Hospital (MGH) have made significant progress by curing type 1 diabetes in laboratory mice. They are now preparing to test their breakthrough findings in humans.
The MGH team unique approach corrects the problem at its source by identifying and selectively eliminating only the faulty cells of the immune system that mistakenly destroy healthy insulin-producing beta cells. This line of attack allows the body to regrow or regenerate healthy insulin-producing beta cells that can function normally without the subsequent threat of autoimmune destruction--a true permanent and lifelong correction of type 1 diabetes, at least in a mouse.
Investigators elsewhere have verified the MGH team research, and the Federal Drug Administration and the MGH have approved plans for a clinical trial to correlate the mouse model findings to type 1 diabetes in humans. The study is being directed by David Nathan, M.D., an internationally recognized investigator who heads MGH Diabetes Research Center.
In people with type 1 diabetes, a defective white blood cell produced by the immune system is unable to distinguish between healthy cells and foreign invaders such as bacteria and viruses. When called into action by a perceived threat, the defective cell attacks and destroys insulin-producing beta cells of the pancreas.
The destructive process is the result of flawed immune cells that are unable to produce protein fragments called self-peptides that are responsible for informing the immune system what is and is not a real health threat. The lack of self-peptides is similar in other autoimmune diseases, in which different tissues are erroneously damaged (e.g., in Crohn disease it is the gastrointestinal track; in multiple sclerosis, the nerve covering; in rheumatoid arthritis, the joint tissue).
The MGH team breakthrough involved two steps. The first step was to eliminate the destructive immune cell. The ability to identify the destructive immune cell (taken from blood samples) makes it open to attack; and a naturally occurring substance already present in mice and humans, called TNF-alpha, is effective in killing these harmful cells. Ironically, drugs that curb the expression of TNF-alpha are used commonly in the clinic to suppress inflammation, which is ineffective as a long-term treatment or cure for type 1 diabetes. Dr. Faustman research suggests that increasing the production of TNF-alpha is a more promising strategy for the autoimmune disease.
Once the destructive cell was eliminated, the mice began regenerating insulin-producing beta cells. In Dr. Faustman study, the regeneration process took 40 days; in another similar study in Canada, it took only 14 days. What this suggests is that the pancreas is always producing beta cells which are immediately destroyed by the defective immune cell. >P>The next step was to retrain the immune system to work properly. After Dr. Faustman destroyed the harmful cell with TNF-alpha, the second step consisted of injecting the treated mice with healthy blood cells taken from the spleens of other mice. These normal cells are able to present the self-peptides that instruct the immune system to attack only the harmful invader and not healthy tissue. This resulted in the mice "new" immune system being retrained to stop making the defective cell, effectively eliminating the harmful autoimmune response and cutting the mice diabetes.
Dr. Faustman two-step approach takes only a matter of weeks to carry out and requires no anti-rejection drugs or harvesting of scarce tissue--in contrast to other potential diabetes solutions such as islet cell transplantation. In addition to is profound implications for people with type 1 diabetes, the benefits of this pioneering research may extend to millions of others who suffer from rheumatoid arthritis, multiple sclerosis, Crohn disease, lupus, Graves disease, and a host of other autoimmune disorders. In principle, the approach is the same for each disease: disarm the harmful autoimmune response that is causing tissue damage and retrain the immune system to respond only to legitimate threats.
In bridging the gap from mouse model to human trial, the truth is that findings in animal studies do not automatically translate to medical breakthroughs for humans. The basic questions are: can flawed human immune systems be stimulated to respond like those of the diabetic mice and, if so, can the technique be applied safely?
To answer these questions, Dr. Faustman and Dr. Nathan have mapped out a series of steps designed to create a "smart" human clinical trial, one that ensures a clear understanding of how the therapy works and how its safety and efficacy can be carefully monitored.
Once trial standards are developed, the stage is set for testing the safety and effectiveness of the new therapy in people with diabetes. Initially, a limited number of volunteers will be vaccinated with BCG, a drug used safely and commonly to prevent tuberculosis and, in larger doses, to treat bladder cancer. The reason for using BCG is that it stimulates the production of TNF-alpha in the same way as the drug that Dr. Faustman used to destroy the defective immune cell in her mouse model.
The concept of islet regeneration without the need for islet cell transplantation or embryonic stem cells opens up a way to look for better treatments for type 1 diabetes. The testing of this will also open up the opportunity to see whether the regenerative potential of humans with this disease is as robust as the middle-aged mice that regrew their islets in the pancreas after a simple disease-reversing therapy.
