It is generally believed that an effective cure for type 1 diabetes will require two substantial scientific advances. First, in order to restore the pancreas' ability to produce insulin, new islet beta cells must be provided, either by transplanting cells from a healthy donor or by encouraging the growth and/or function of the diabetic patient's own cells. Second, to protect the new beta cells, no matter what their origin, it is necessary to repair the breakdown in immunological tolerance that precipitated the anti-islet attack in the first place.
In a widely discussed paper that appeared in Science in 2003, Dr. Denise Faustman and her colleagues reported successful achievement of both of these advances, resulting in the "cure" of a substantial fraction of severely diabetic NOD mice, the most popular animal model of human type 1 diabetes. Their method entailed giving diabetic mice a temporary islet transplant from a genetically identical mouse, administering a single injection of an immuno-stimulatory compound called Complete Freund's Adjuvant (CFA), and repeatedly injecting a large number of spleen cells taken from genetically different mice. It was thought that the islets served to keep the animals with diabetes healthy long enough for the other treatments to have their effects, that the CFA eliminated the autoimmune attack on the islets, and that the spleen cells somehow gave rise to insulin-producing cells, presumably beta-cells, ultimately leading to islet regeneration.
"The compound CFA has been used to modulate diabetes in NOD mice for a number of years in a variety of experimental contexts, so its effect was not very surprising. However, the notion that adult spleen cells from one mouse could give rise to new islets in the pancreas of another mouse was a novel and exciting one," said Diane Mathis, Ph.D., who led the Joslin study along with Christophe Benoist, M.D., Ph.D. Drs. Benoist and Mathis head Joslin's Section on Immunology and Immunogenetics, hold the William T. Young Chair in Diabetes Research, and are Professors of Medicine at Harvard Medical School.
Therefore, many research teams were interested in extending the potentially important findings of Dr. Faustman and her colleagues by defining the precise cellular and molecular mechanisms involved. As a necessary first step, the researchers needed to reproduce the results published in the 2003 Science paper. Unfortunately, this did not prove possible, as reported in three papers appearing in the March 24, 2006, issue of Science from groups based at Joslin Diabetes Center in Boston, Washington University in St. Louis and the University of Chicago, working entirely independently. For example, the Joslin team was not able to replicate the original findings even though it strove to match as closely as possible the published methods, and also incorporated supplementary details from more extensive protocols provided by the authors. In short, like the study of Dr. Faustman and colleagues, the three new studies resulted in a substantial fraction of severely diabetic NOD mice being "cured" of their hyperglycemia as well as their autoimmunity against beta cells. However, none of the teams found any evidence that new islet cells emanating from donor spleen cells were the source of the insulin responsible for the reversal of diabetes. Rather, even though severely diabetic, the host mice kept a substantial number of residual beta cells, and the recovered islets were all of host, rather than donor spleen cell, origin.
"Given recent reports from several groups that beta cells in adult mice can undergo active cell division, the most likely explanation for islet recovery in the 'cured' mice is that when the autoimmunity was suppressed, beta-cell growth was permitted -- or even promoted -- exceeding death of the beta cells," said Dr. Benoist. "An additional possibility is that eliminating the inflammation improved the function of the residual beta cells."
"The obvious implication from these new results, given that CFA is a reagent that can potentially alter the immune system, is that the donor spleen cells might not be an essential element of the Faustman protocol," Dr. Mathis said. "The original study did not report a control group in which spleen cells were left out of the treatment protocol. Both the Joslin and Washington University groups did include this important control, and found that CFA alone (plus the temporary islets) was as effective as the full protocol with its multiple injections of spleen cells. This finding again argues that the 'cure' of diabetes afforded by the Faustman protocol did not involve donor spleen cells giving rise to host islet beta cells."
Should the effectiveness of CFA alone demonstrated in these new studies prompt a reconsideration of the analogous reagent Bacille Calmette-Guerin (BCG), in isolation, to treat people with diabetes? BCG is a component of some human vaccines, like the vaccine agent used against tuberculosis, and the Faustman group has proposed using it as a treatment for type 1 diabetes. Three BCG trials large enough to be informative have previously been performed and failed to show any positive effect. "A likely explanation for the difference in results is that the injection of CFA into the footpad of mice and the injection of BCG under the skin of humans are actually radically different interventions, the former provoking a massive inflammatory response throughout the body, a procedure that is difficult to contemplate in a patient context," Dr. Benoist explained. "It should also be kept in mind that the mice were also treated with an islet transplant, the precise role of which has not really been explored. Lastly, it might be relevant that BCG has been reported to increase the incidence or accentuate the course of diabetes in humans in certain contexts."
Other participants in the study include Junko Nishio, M.D., Ph.D., Jason L. Gaglia, M.D., and Christopher Campbell, all of Joslin, and Stuart E. Turvey, M.D., Ph.D., formerly of Joslin and now of Children's Hospital, Vancouver, British Columbia, Canada.
The Joslin study was funded by a research grant from the Juvenile Diabetes Research Foundation International, and by fellowships from the American Diabetes Association and the National Institutes of Health.
About Joslin Diabetes Center
Joslin Diabetes Center, dedicated to conquering diabetes in all of its forms, is the global leader in diabetes research, care and education. Founded in 1898, Joslin is an independent nonprofit institution affiliated with Harvard Medical School. Joslin research is a team of more than 300 people at the forefront of discovery aimed at preventing and curing diabetes. Joslin Clinic, affiliated with Beth Israel Deaconess Medical Center in Boston, the nationwide network of Joslin Affiliated Programs, and the hundreds of Joslin educational programs offered each year for clinicians, researchers and patients, enable Joslin to develop, implement and share innovations that immeasurably improve the lives of people with diabetes. As a nonprofit, Joslin benefits from the generosity of donors in advancing its mission. For more information on Joslin, call 1-800-JOSLIN-1 or visit www.joslin.org.
Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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