Frequently Asked Questions

  1. What is an autoimmune disease?
  2. What is type 1 diabetes?
  3. What were the findings of the Faustman lab in relation to a therapy for type1 diabetes?
  4. What is the significance of this finding?
  5. What was the treatment used in mice?
  6. How will this be applied to humans?
  7. What is BCG? Is it safe? Why use it?
  8. Will embryonic stem cells be used in the human trials based on this research?
  9. Will adult stem cells or spleen cell transplantation be used in the human trials?
  10. Will islet cell transplantation be used?
  11. Will other immune suppressants be used?
  12. Haven't there been many compounds discovered to date that have a positive effect on non-obese diabetic (NOD) lab mice?
  13. In March 2006, three labs published their results using the Faustman lab's protocol for end-stage diabetes reversal in mice. What were the results?
  14. The three JDRF-funded groups confirmed Dr. Faustman's cure of some of the NOD mice; however, their reported success rates were lower that those reported by Dr. Faustman's in earlier studies. Why is that?
  15. What are the different cure rates found at the different institutions

1. What is an autoimmune disease?
An autoimmune disease is a disease in which the immune system malfunctions and mistakenly attacks itself. Type 1 diabetes is an autoimmune disease in which the immune system incorrectly targets, attacks and destroys a person's own insulin-producing cells. Other autoimmune diseases include lupus, Crohn's disease, multiple sclerosis, scleroderma, Sjogren's syndrome, and rheumatoid arthritis.

2. What is type 1 diabetes?
Type 1 diabetes is a chronic autoimmune disease. In autoimmune diseases, the immune system is defective and attacks or mediates an attack on the body's healthy tissue and organs. In type 1 diabetes, the immune system attacks the healthy beta cells (the cells that produce insulin) in the pancreas. When this happens, the body does not produce insulin and cannot balance its blood sugar.

3. What were the findings of the Faustman lab in relation to a therapy for type 1 diabetes?
In 2001 1 and in 2003 2, the results of the Faustman lab's experiments in end-stage diabetic mice were published. The results showed that a brief, 40-day treatment selectively eliminated the disease-causing white blood cells in end-stage diabetic mice. This treatment killed only the cells that were causing the autoimmune destruction, and not the healthy cells. These experiments also uncovered the ability of the pancreatic islets to regenerate without the introduction of any live cells once the cells that were causing the autoimmune destruction were eliminated and the autoimmune disease was stopped. The Science paper also identified a new source of adult stem cells- adult stem cells in the spleen- that could form new islets in the formerly diabetic animals. In the human trials, no spleen cells will be used.

References:

  1. Kodama S, Kuhtreiber W, Fujimura S, Dale EA, Faustman DL. Islet regeneration during the reversal of autoimmune diabetes in NOD mice. Science 2003; 302:1223-7.
  2. Ryu S, Kodama S, Ryu K, Schoenfeld DA, Faustman DL. Reversal of established autoimmune diabetes by restoration of endogenous beta cell function. J Clin Invest 2001; 108(1): 63-72.

4. What is the significance of this finding?
Current diabetes treatments attempt to replace the insulin that is either not produced or not produced in sufficient quantities by the body; they do not reverse or eliminate disease. Dr. Faustman's work represents a reversal of diabetes, rather than just a treatment for the symptoms and complications of this disease. Dr. Faustman's research suggests it may be possible to stop the destruction of insulin-producing cells as the first step in the reversal of diabetes. Not only does this research have significant implications for the future of diabetes treatment, but it also has the potential to impact the treatment of other autoimmune diseases, including rheumatoid arthritis, multiple sclerosis, Crohn's disease and lupus. Worldwide research efforts have discovered evidence of genetic and white blood cell errors in these human autoimmune diseases similar to those seen in type 1 diabetes.

5. What was the treatment used in mice?
In mouse studies, Dr. Faustman's lab identified two cell protein pathways that are defective in diabetic mice:

1) MHC class I and self peptide pathway

2) TNF-alpha pathway

In end-stage diabetic mice treated with drugs for either of these two pathways, disease-causing pathogenic naive T cells and memory T cells were selectively killed. Used alone, neither compound resulted in permanent disease reversal. Used together, the autoimmune disease was reversed, allowing for islet regeneration.

6. How will this be applied to humans?
In humans, first step of translating this research involves evaluating whether bacillus Calmette-Guerin (BCG), the agent that will be tested in the first Phase I human trial, can eliminate memory T cells in type 1 diabetics by targeting the TNF-alpha pathway. Since BCG is already manufactured in clinical grade and since it has an established safety profile over a very broad dose range in humans, the clinical trial can proceed forward without large manufacturing costs and minimal risk of toxicity. The second arm of therapy will target the MHC class I and self peptide pathway. Over the next several years, the Faustman lab will more clearly define what agent within the MHC class I and self peptides will be the most effective in eliminating pathogenic naive T cells in humans. Dr. David Nathan, director of the MGH Diabetes Center and one of this country's diabetes experts, will direct the human clinical trials at MGH.

7. What is BCG? Is it safe? Why use it?
Our human clinical trial program will begin with an evaluation of bacillus Calmette-Guerin (BCG), a generic drug with an impeccable human safety profile that is currently approved for two indications- tuberculosis and cancer therapy. BCG has been administered to over four billion people since coming to market over 80 years ago. Similar to the agent we used in mouse studies (CFA), BCG causes the body to make a natural substance called TNF that helps regulate the immune system.

There is ample data to support the use of BCG in the human diabetes trials. BCG was used many years ago in early-stage diabetic mice and prevented diabetes. Unfortunately, many compounds work in early-stage NOD mice, but do not work in late-stage diabetic mice or in humans with advanced disease. BCG was also tried in the past in humans with new onset diabetes, prior to the knowledge of how BCG actually works in the body. In the human studies, one diabetic patient was cured with a single dose of BCG, but two subsequent studies with a single dose of BCG showed no benefit.

Compared to when many previous BCG trials were conducted 10 year ago, the way BCG induces one's own TNF to change disease is now mapped in animal models and in some human disease. This allows for thoughtful translation of this intervention to a human trial. We think these early trials of BCG in humans, although encouraging, could not be advanced until we understood BCG's mechanism of action (what it does) and had a way to monitor the drug's effect in the blood. Think about this: If we did not know that insulin regulated blood sugars, and if we did not know how to measure blood sugar, how could we tell whether insulin actually worked to help diabetics? In many ways, early BCG trials can be seen as similar to injecting insulin without knowing what it really does or how to measure its effects. One of our major laboratory efforts is to create a method to rapidly and precisely count the disease-causing cells in human blood and to use this test to evaluate whether BCG can eliminate these cells, and at what dose.

Only by conducting a clinical trial will we know if BCG will work. We chose to test BCG because the agent is readily available and it works in the human in a similar way (induction of TNF) as the agent we successfully used in the mouse (CFA). In addition, it is relatively easy to track the killing of the population of autoreactive T cells targeted by BCG, and we believe that this population of cells may be the one responsible for the greatest amount of damage to the islets.

8. Will embryonic stem cells be used in the human trials based on this research?
This research does not use embryonic stem cells.

9. Will adult stem cells or spleen cell transplantation be used in the human trials?
This research does not use adult stem cells. In addition, splenocytes will not be used in the human trials. In one version of Dr. Faustman's experiments, she used live spleen cells to reverse diabetes in mice. It is important to note that live spleen cells are not necessary in the human research and that they have never been proposed for the human clinical trials. One purpose of using the spleen cells in the mouse trials was to show that a subpopulation of these cells could directly regenerate the missing insulin-secreting islets. However, Dr. Faustman's experiments showed that the pancreas could also regenerate without the use of live spleen cells. In other words, it appears that islet regeneration, at least in these end-stage animal experiments, was only dependent upon disease removal- "self" healing followed.

10. Will islet cell transplantation be used?
No, islet cell transplantation will not be used. The concept of the trial is disease reversal followed by spontaneous regeneration of the islets.

11. Will other immune suppressants be used?
No. Dr. Faustman's research shows that it may be possible to create or identify compounds that only eliminate the white blood cells that are destroying the islets and do not harm the healthy white blood cells.

12. Haven't there been many compounds discovered to date that have a positive effect on non-obese diabetic (NOD) lab mice?
For those knowledgeable in the field, there are indeed over 200 ways to "cure" not yet diabetic mice (pre-diabetic). Unfortunately, this does not represent human disease where the blood sugars are elevated and the disease firmly established. Numerous interventions applied in the pre-diabetic phase can slow or halt progression to hyperglycemia; however when the immune attack has engendered sufficient beta cell damage to result in severe hyperglycemia, few of these interventions are successful. Therefore, we believe that to produce NOD mouse data that might be translated to successful human experiments, we should use protocols in end-stage NOD mice.

13. In March 2006, three labs published their results using the Faustman lab's protocol for end-stage diabetes reversal in mice. What were the results?
On March 24th, Science published three papers from three different Juvenile Diabetes Research Foundation (JDRF)-sponsored laboratories 1-3 that examined the protocol that our laboratory published in 2001 and 2003 for end-stage diabetes reversal in the NOD mouse.

Along with a body of scientific literature that supports many of our concepts, all three studies independently verified that our protocol can 'cure' end-stage diabetes in mice. By cure, we mean that the autoimmune attack was sufficiently halted to stop islet destruction and/or promote islet rescue/regeneration and that the autoimmune diabetes did not recur with long-term follow-up. Regeneration was seen and long-term normal blood sugars were achieved.

The major difference between the new results and our earlier findings is the failure of the recent studies to detect evidence that the spleen cells may play a role in islet regeneration. Our original paper in the Journal of Clinical Investigation in 2001 and our subsequent paper in Science in 2003 showed that the diabetes cure could be accelerated by the administration of adult spleen cells in mice. The delivery of a live splenic stem cell was not necessary for cure; but, rather, its delivery hurried the kinetics of returning to normal blood sugars. Our work was the first to show that a targeted type 1 disease removal therapy was sufficient to permit impressive self islet regeneration. We have never had a clinical protocol where we intended to inject live splenic stem cells into a human.

Despite the March 24th papers, we are still confident that the spleen plays a role, and independent work by Tran et al. at the NIH 4 confirms our findings that the spleen can contribute to the colonization of the pancreas. Tran et al. evaluated our protocol to see if it would be effective in diabetic mice that also had Sjogren's syndrome, an autoimmune disease affecting the moisture-producing glands. The researchers found that our protocol could be used to reverse two forms of established autoimmune disease in mice (type 1 diabetes and Sjogren's syndrome) with a success rate of diabetes reversal close to 100%. Unlike the March 24th papers, the NIH group found that the spleen did contribute in part to regeneration of the pancreas and the salivary glands. The results of Tran et al. lead us to conclude that the failure to detect a role of the spleen cells in the JDRF-funded reports reflects difficulties in lineage tracing and/or differences in the experimental methods applied. Most researchers working in this field believe that pancreas regeneration after disease removal can occur by many mechanisms.

Whatever the origin of the insulin-secreting beta cells of the islets, the treatment protocol we described enables the permanent restoration of normoglycemia in at least 45% (based on the March 24th papers) of fully treated diabetic NOD mice. The unique efficacy of this intervention in halting destructive beta cell autoimmunity and restoring normoglycemia merits continued efforts to understand the underlying mechanisms, refine the treatment, and determine whether it is applicable to the treatment of human type 1 diabetes. Ultimately, the source of the regeneration is less important at this time than the simple fact that regeneration and/or rescue can occur and that this restores normoglycemia. The final outcome is that the animals in the studies have- from their own pancreases- insulin that regulates the blood sugar. There is no intent of spleen cell transplants for human patients. Dr. Faustman and colleagues hope there is sufficient regeneration and rescue to not require any transplant.

References:

  1. Nishio J, Gaglia JL, Turvey SE, Campbell C, Benoist C, Mathis D. Islet recovery and reversal of murine type 1 diabetes in the absence of any infused spleen cell contribution. Science 2006; 311(5768): 1775-80.
  2. Suri A, Calderon B, Esparza TJ, Frederick K, Bittner P, Unanue ER. Immunological reversal of autoimmune diabetes without hematopoietic replacement of {beta} cells. Science 2006; 311(5768): 1778-80.
  3. Chong AS, Shen J, Tao J, et al. Reversal of diabetes in non-obese diabetic mice without spleen cell-derived beta cell regeneration. Science 2006; 311(5768): 1774-5.
  4. Tran S, Kodama S, Mezey EM. Treatment success and regenerative mechanisms influenced by age of NOD mice and target organ of autoimmune attack. (Abstract #1202-P). In: 66th Session of American Diabetes Association; 2006; Washington, DC: American Diabetes Association; 2006. p. A283.

14. The three JDRF-funded groups confirmed Dr. Faustman's cure of some of the NOD mice; however, their reported success rates were lower that those reported by Dr. Faustman's in earlier studies. Why is that?

Success rates in animal and clinical studies are based on many variables. The success rates reported by the three March 24th Science articles ranged from 30-40%. There are probably many reasons why this rate is lower than that reported in other studies using our protocols and in our own papers. In part, disease reversal appears tightly linked to the control of blood sugars during the treatment process. In our 2001 paper 1, the cure rate for end stage mice was only 20% if tight blood sugar control was not achieved during the 40-day treatment interval. In contrast, when tight blood sugars were achieved, the cure rate at 40 days reached over 80%. In a study by Tran et al. 2, our protocol had a success rate close to 100%. In addition, a group of Japanese researchers has also confirmed our approach (disease elimination followed by regeneration) for reversing diabetes in the type 1 diabetic mouse 3, with a 71% response rate.

In addition to blood sugar control, the different success rates may also reflect intervention at different stages in diabetes progression or differences in the age of the mice. Finding these answers will require further study.

References:

  1. Ryu S, Kodama S, Ryu K, Schoenfeld DA, Faustman DL. Reversal of established autoimmune diabetes by restoration of endogenous beta cell function. J Clin Invest 2001; 108(1): 63-72.
  2. Tran S, Kodama S, Mezey EM. Treatment success and regenerative mechanisms influenced by age of NOD mice and target organ of autoimmune attack. (Abstract #1202-P). In: 66th Session of American Diabetes Association; 2006; Washington, DC: American Diabetes Association; 2006. p. A283.
  3. Okubo Y, Kanazawa Y, Oikawa Y, Miyazaki JI, Shimada A. Islet hypertrophy observed in "reversed" diabetic NOD mouse after pancreatic beta cell line administration (Abstract #1193-P). In: ADA 66th Scientific Sessions; 2006 June 9-13, 2006; Washington, DC: ADA; 2006. p. A281.

15. What are the different cure rates found at the different institutions?

Cure Rates Using the Kodama et al. Protocol for Type 1 Diabetes Reversal in the NOD Mouse

Author
(Year)		 Institution Cure Rate
 Endogenous
Islet
Regeneration		 Exogenous Islet
Regeneration
(Spleen cell contribution)
Kodama et al
(2003)		 Harvard/MGH 85-92% Yes Yes
Tran et al.
(2006)		 McGill/Grigham and
Women's/NIH		 100% Yes Yes
Okubo et al.
(2006)		 Keio University/Osaka
University - Japan		 75% Yes N/A
Nishio et al
(2006)		 Harvard/Joslin 40% Yes No
Suri et al
(2006)		 Washington University
in St. Louis		 20-30% Yes No
Chong et al
(2006)		 University of Chicago
University of Illinois		 40% Yes No





All material copyright 2006

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