Denise Faustman, MD, PHd
The Faustman Lab at work

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General Overview and Questions About the Early Research at the Faustman Lab

  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 than those reported by Dr. Faustman in earlier studies. Why is that?
  15. What were the different cure rates in mice at the different institutions?
  16. The lab has published several papers related to the spleen. Why are you interested in the spleen?
  17. What is the status of the “JoinLeeNow” campaign?

Looking for questions and answers about the Faustman Lab's clinical trials? Read frequently asked questions about the clinical trials.

Questions and Answers About the Early Research at the Faustman Lab

1. What is an autoimmune disease?
An autoimmune disease is a disease in which the immune system mistakenly attacks the body’s own tissues and cells. Type 1 diabetes is an autoimmune disease in which the insulin-producing cells of the pancreas are the target of the immune attack. 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 type 1 diabetes, the immune system attacks the healthy insulin-producing beta cells of the pancreas. When this happens, the body is no longer able to produce enough insulin to regulate blood sugar levels which can lead to serious, life-threatening consequences.Approximately 1 million Americans have type 1 diabetes, many of whom are young children.

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 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 autoimmune destruction 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.

The lab has also shown that humans with type 1 diabetes have disease-causing T cells that are similar to those found in diabetic mice3. Based on this finding, they hypothesized that using a therapeutic approach in humans similar to the approach that reversed diabetes in mice might be effective. A human clinical trial program to test one part of this approach is currently being conducted.


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.
  3. Ban L, Zhang J, Wang L, Kuhtreiber W, Burger D, Faustman DL. Selective death of autoreactive T cells in human diabetes by TNF or TNF receptor 2 agonism. Proc Natl Acad Sci USA. 2008; 105 (36): 13644-9.

4. What is the significance of this finding?
Current diabetes treatments attempt to replace the insulin that is not sufficiently produced 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 or re-educated. 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, the first step of translating this research involves evaluating whether bacillus Calmette-Guerin (BCG), an inexpensive generic drug, can eliminate memory T cells in type 1 diabetics by targeting the TNF-alpha pathway in humans. 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 with minimal risk of toxicity. A Phase I study was recently completed, demonstrating that BCG vaccination was safe in type 1 diabetics. A Phase II trial is being planned, with fundraising efforts ongoing to meet the $25.2 million total cost

7. What is BCG? Is it safe? Why use it?
Our human clinical trial program began in 2008 with an evaluation of the safety of bacillus Calmette-Guerin (BCG) vaccination in type 1 diabetics. BCG is a generic drug with an impeccable human safety profile that is currently approved for two indications- tuberculosis prevention and bladder 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. Our FDA-approved Phase I human clinical study successfully demonstrated the safety of BCG vaccination in humans with type 1 diabetes.

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, some diabetic patients achieved remission with a single dose of BCG (Shehadeh et al. Lancet 1994), but two subsequent studies with a single dose of BCG showed no benefit.

Compared to when many previous BCG trials were conducted over a decade 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 was 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 to eliminate one population of disease-causing cells in human type 1 diabetes. We chose to test BCG because the agent is readily available and it works in humans in a similar way as the agent we successfully used in the mouse (CFA)— by inducing TNF, leading to the destruction of the disease-causing memory T cells. 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?
The human research does not use adult stem cells or spleen cell transplant. 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 not 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 islet-destroying white blood cells and do not harm the healthy 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" mice that are 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 hastened the return to normal blood sugars. Our work was the first to show that a targeted type 1 disease removal therapy was sufficient to permit impressive islet self regeneration. We have never had a clinical protocol where we intended to inject live splenic stem cells into a human.

Independent work by Tran et al.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 Sjögren’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 Sjögren’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. Published data from Oxford, England also shows that avian spleens can be coaxed in culture into insulin-secreting cells, thus confirming the spleen as a source of islets.5 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 until the BCG protocols can fully and completely remove the underlying immune disease and all options for spontaneous regeneration can be observed. 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 SD, Kodama S, Lodde BM, Szalayova I, Key S, Khalili S, Faustman DL, Mezey E. Reversal of Sjogren's-like syndrome in non-obese diabetic mice. Ann Rheum Dis 2007;66(6):812-4.
  5. Robertson SA, Rowan-Hull AM, Johnson PR. The spleen--a potential source of new islets for transplantation? J Pediatr Surg 2008;43(2):274-8.

14. The three JDRF-funded groups confirmed Dr. Faustman's cure of some of the NOD mice; however, their reported success rates were lower than 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. 2. Tran SD, Kodama S, Lodde BM, Szalayova I, Key S, Khalili S, Faustman DL, Mezey E. Reversal of Sjogren's-like syndrome in non-obese diabetic mice. Ann Rheum Dis 2007;66(6):812-4.
  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 were the different cure rates in mice 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. (2007) McGill/Brigham 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
(St. Louis)		 20-30% Yes No
Chong et al. (2006) University of Chicago/
University of Illinois		 40% Yes No

16. The lab has published several papers related to the spleen. Why are you interested in the spleen?
Those of you familiar with our research history know that, in research published in 2003, our lab identified the spleen as a potential new source of adult stem cells that could form new islets in mice had their end-stage type 1 diabetes reversed (1). Although these adult stem cells were not required for the pancreas to regenerate after a brief, non-toxic treatment to remove the autoimmune disease, the splenic cells did help speed disease reversal and regeneration when they were used (1). Similarly, recent data has shown that the spleen also contributes to pancreas regeneration in an animal model of type 2 diabetes (2).

Adult stem cells are not only found in the spleens of mice, but also in the spleens of humans and quails, as documented by new data from world-wide research (3,4). Harvesting and then culturing these adult stem cells allows for the formation of insulin-producing cells, suggesting a potential source of new islets for transplantation (4).

The stem cells of the spleen have the capacity to mature into numerous cell types. We believe this is because the adult stem cells of the human and mouse spleen express the developmental transcription factor Hox11 (5-7), a marker for early embryonic development.

Overall, our lab and others have observed the regenerative ability of the stem cells of the spleen to both directly and indirectly heal a multitude of different tissues, including the pancreas, salivary gland, bone, blood, cranial nerves, inner ear, and, most recently, the heart (1, 2, 8-14). These findings suggest that the spleen may be an important source of stem cells for future cellular therapies for a number of different diseases.

References:

  1. Kodama S, Kühtreiber W, Fujimura S, Dale EA, Faustman DL. Islet regeneration during the reversal of autoimmune diabetes in NOD mice. Science. 2003;302(5648):1223-7.
  2. Park, S, Hong, SM, Ahn IS. Can splenocytes enhance pancreatic beta cell function and mass in 90% pancreatomized rats fed a high fat diet? Life Sci. 2009;84(11-12):358-63.
  3. Dieguez-Acuna FJ, Gygi SP, Davis M, Faustman DL. Splenectomy: a new treatment option for ALL tumors expressing Hox-11 and a means to test the stem cell hypothesis of cancer in humans. Leukemia. 2007;21(10):2192-4.
  4. Robertson, SA, Rowan-Hull AM, Johson PR. The spleen—a potential source of new islets for transplantation? J Pediatr Surg. 2008;43(2):274-8.
  5. Kodama S, Davis M, Faustman DL. Diabetes and stem cell researchers turn to the lowly spleen. Sci Aging Knowledge Environ. 2005;2005(3):pe2.
  6. Lonyai A, Kodama S, Burger D, Faustman DL. Fetal Hox11 expression patterns predict defective target organs: a novel link between developmental biology and autoimmunity. Immunol Cell Biol. 2008;86(4):301-9.
  7. Kodama S, Davis M, Faustman DL. Regenerative medicine: a radical reappraisal of the spleen. Trends Mol Med. 2005;11(6):271-6.
  8. Faustman DL, Tran SD, Kodama S, et al. Comment on papers by Chong et al., Nishio et al., and Suri et al. on diabetes reversal in NOD mice. Science. 2006;314(5803):1243; author reply 1243.
  9. Macias MP, Fitzpatrick LA, Brenneise I, McGarry MP, Lee JJ, Lee NA. Expression of IL-5 alters bone metabolism and induces ossification of the spleen in transgenic mice. J Clin Invest. 2001;107(8):949-59.
  10. Derubeis AR, Mastrogiacomo M, Cancedda R, Quarto R. Osteogenic potential of rat spleen stromal cells. Eur J Cell Biol. 2003;82(4):175-81.
  11. Tran SD, Kodama S, Lodde BM, et al. Reversal of Sjogren's-like syndrome in non-obese diabetic mice. Ann Rheum Dis. 2007;66(6):812-4.
  12. Lonyai A, Kodama S, Burger D, Davis M, Faustman DL. The promise of Hox11+ stem cells of the spleen for treating autoimmune diseases. Horm Metab Res. 2008;40(2):137-46.
  13. Yin D, Tao, J, Lee DD, et al. Recovery of islet beta-cell function in streptozotocin-induced diabetic mice: an indirect role for the spleen. Diabetes. 2006:55(12):3256-63.
  14. Swirski FK, Nahrendorf M, Etzrodt M, et al. Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science. 2009;325(5940):612-6.

17. What was the “JoinLeeNow” campaign?
JoinLeeNow was the fundraising campaign created by the Iacocca Foundation to support our Phase I human clinical trial. When the funds were raised for the Phase I trial, the JoinLeeNow campaign was completed. strong relationship with the Iacocca Foundation and they continue to provide research support for our lab: http://www.iacoccafoundation.org/research/index.html.