The search for a cure to diabetes has been a focused effort by hundreds of scientists for nearly thirty years. Basic scientific discovery has contributed to many significant advancements in this quest. Many improvements in diabetes care have emerged, and much human suffering has been spared. But no previous research has achieved the cure of a fully insulin dependent diabetic mouse, recently attained by a group of scientists at MGH - a discovery that holds the hope that a cure for this terrible disease can be found.
In a major breakthrough, published in the Journal of Clinical Investigation in July 2001, Dr. Faustman and her colleagues at MGH have cured diabetic (NOD) mice, for the first time ever. That is, they have devised a treatment which restored normal blood glucose levels permanently. This was achieved with a 40-day treatment program, which is entirely different from any previously attempted, was based on previous discoveries in Dr. Faustman's laboratory on the nature of the autoimmune response.
In her previous work, Dr. Faustman has identified a singular immune T cell defect in diabetic mice that is responsible for the destruction of insulin producing beta cells. This T cell defect is due to a genetically identifiable trait, and it is because of this defect that the cells can be mature inappropriately to attack the beta cells and become autoreactive T cells. Luckily, this same defect also results in a flaw that allows these T cells to be singled out and destroyed. That is, the cells are more susceptible to the effects of a signaling protein, known as TNF-alpha, which initiates the process of apoptosis, or cell suicide. A second part of the treatment prevents the redevelopment of the disease producing autoimmune T cells. Immune cells from another tissue-matched individual are able to re-educate the T-cells to recognize the pancreatic beta cells as "self", effectively re-educating the immune system, and preventing autoimmune cell formation and beta cell destruction. The natural process of beta cell regeneration then cured the diabetes in the mouse experiments. This process of destroying the defective T cells and preventing their recurrence is described as immunomodulation.
The MGH research team has considerable evidence that this T cell defect found in diabetic mice is physiologically identical to that found in diabetic humans. Defective T cells were in all of the 100 Type 1 diabetic patients that have been screened to date and none of the healthy control subjects. Furthermore, the severity of the T cell defect seems to be directly proportional to the age of diabetes onset. The younger the patient, the greater degree of T cell defect.
The next step in this research is to develop a laboratory assay for rapid and accurate analysis of defective cells in patient blood samples, suitable for use in a clinical study. This assay will enable physicians to identify patients who are likely to benefit from the treatment and can also be used to provide evidence of the success of the treatment. This step will be accomplished through the collaboration of Dr. Faustman with Dr. David Nathan, an internationally recognized clinician and clinical investigator in the field of diabetes.
In a second major breakthrough, another team of MGH researchers led by Dr. Joel Habener, announced their exciting discovery of stem cells within the pancreatic islets in March 2001. This discovery is of vital importance for the cure of long term Type 1 diabetes (when the natural supply of pancreatic stem cells may have died out) and is also likely to benefit those with Type 2 diabetes. Stem cells are immature cells that can proliferate indefinitely and provide a source of cells that can mature into many cell types, including beta cells, a normal process that replaces cells that have naturally died out. Other research suggests that these stem cells may survive in the pancreas for some years after the onset of frank insulin dependency, still maturing into beta cells only to be immediately destroyed by autoreactive T cells.
Thus, if the autoimmunity is eliminated, as in the mice experiments, the patients may cure themselves with the residual beta stem cells. In many diabetic patients, however, all of the pancreatic stem cells may have been used up after only 3-5 years of disease. Thus, beta cell replacement therapies are likely to be required for the cure of the vast majority of established Type 1 diabetic patients. Pancreatic islet transplantation is one possible therapy but it is widely appreciated that the supply of human islets for transplantation will never meet the existing need. In addition, after islet transplantation, the patients need to take immunosuppressive drugs to prevent rejection throughout their life. An alternative therapy is to transplant beta cells. In this case, the cells surface can be treated to prevent rejection (another major discovery from Dr. Faustman's laboratory) and no immunosuppression is necessary.
Stem Cells (light shade) in a
Pancreatic Islet
The team of investigators at MGH have isolated these stem cells and found that they will proliferate rapidly outside of the body, in cell culture. They are also able to make them differentiate into beta cells by the addition of certain hormones and growth factors, and have implanted them into mice without rejection. One essential hormone needed for their differentiation into beta cells is GLP-1, which was first discovered by Dr. Habener and his colleagues several years ago.
In this work, the MGH team has identified a source of new human beta cells which may, in the future, be given to patients after their autoimmunity has been reversed. Before that can happen, the investigators will have to develop methods to isolate and grow pancreatic stem cells in quantity and to guide their development into beta cells more efficiently. Then these cells must effectively reverse diabetes in animal models before they can be considered as a suitable treatment for humans.
Conclusion
It is a leap of faith for any research team to proclaim that that a cure for Type 1 diabetes is in sight. A modifying statement saying the cure may be in sight would be more prudent, of course. But such a modifier would not reflect the enthusiasm the MGH Diabetes Center investigators are trying to contain over these discoveries.
Adding to the confidence behind these discoveries is the growing realization that the defective T cell believed to cause Type 1 diabetes, may in fact also cause other autoimmune diseases such as lupus, rheumatoid arthritis, and multiple sclerosis. The implications that may emerge from this research may extend well beyond diabetes alone. It may come to pass that the cause of many devastating autoimmune diseases have one cause that could be likened to having a loaded gun. The gun (defective T cell selection), selects different targets to destroy in different people, for reasons not yet understood. But what is important about this research is that there appears to be a way to disarm and remove the gun, permanently.
The multidisciplinary scientific team of the MGH Diabetes Center have arrived at a seldom seen position of being able to look into the future and see how these complimentary discoveries that may lead to a permanent cure to Type 1 diabetes, and possibly other autoimmune diseases.
MGH biomedical research as a whole attracts more NIH funding than any hospital in the country. In fact, the MGH Diabetes Program has attracted significant NIH and foundation support; current annual funding exceeds $13 million. Some of their most significant work, however, has been conducted "at the margin", without direct NIH funding support. If at all, it has been supported directly by philanthropic gifts.
The day has now come when philanthropic support may make the difference that will bring a cure for type 1 diabetes to human clinical trials. It is not an accident that lightning has struck, not once, but twice at the Diabetes Center at MGH. For the moment, please allow yourself to be open to the possibility that a cure for Type 1 diabetes - - for those who now have it and who are likely to become afflicted - - will be available with further research to bring the discoveries in mice to new medical treatments.
Source:
http://www.mgh.harvard.edu/depts/dia...e1research.htm