Questions & Answers

What is autoimmune disease?

Autoimmune disease is a disease that occurs when the body’s immune system attacks its own tissue, thinking it is a foreign threat.  In the case of juvenile diabetes, the immune system destroys insulin producing islet cells.  In lupus, the immune system destroys organ connective tissue.  In multiple sclerosis, nerve covering in the brain is destroyed.

Who are affected by autoimmune disease?

The 80 known autoimmune diseases affect more than 22 million Americans – affecting one in every 12 people – most of whom (75%) are women.  NIH estimates that certain of these autoimmune diseases – including type I diabetes, multiple sclerosis, lupus, and psoriasis generate annual direct medical costs of between $14.7 billion and $19.3 billion in the U.S. from these four diseases alone.  These four diseases are a small fraction of the 80 clinically distinct autoimmune diseases, which also include rheumatoid arthritis, Crohn’s disease, Sjogren’s Syndrome and Graves’ disease, among the more prevalent.

What is the “Common Cause” hypothesis?

The “Common Cause” Hypothesis predicts that many devastating autoimmune diseases have a single cause.  A growing body of new research suggests that autoimmune diseases should be regarded as one disease that is manifested as many distinct syndromes. The evidence in favor of the Hypothesis is extensive, compelling and growing.

It has been known for years that patients with autoimmune diseases are more likely to have a relative with an autoimmune disease, but they do not necessarily have the same disease.

Approximately 15% of all autoimmune patients have two autoimmune diseases and the typical family with one affected adult will have greater than 40% chance of another adult member having an autoimmune affliction.

Large genetic studies repeatedly find that autoimmune diseases can be linked to the same region of a chromosome as genes involved in training the immune system to identify “self” tissue.

It is common for one identical human twin to have an autoimmune disease and 60 – 70% of the time for their sibling not to have this condition – in fact there are many documented cases in which twins express two different autoimmune diseases!

Why is the “Common Cause” hypothesis so important?

It provides a paradigm that the central disease is autoimmunity, and accordingly, any effective cure therapy must  address and resolve the underlying autoimmune disease. Most publically and privately funded research continues to be directed at the symptoms of the disease that has lead to significant relief from the symptoms and short-term effects of many autoimmune diseases.  A cure, however, can only be achieved by stopping the autoimmune destruction.

How was type I diabetes reversed in the NOD mouse, the autoimmune model for human type I diabetes?

Both humans and the research NOD mouse have a defective immune cells (bad cells) that may be responsible for causing several autoimmune diseases.  The bad cells, which are erroneously “programmed”, mistakes the body’s normal tissue as a foreign threat and then destroys it.  The mistaken programming also leaves the bad cells vulnerable to being easily killed.

The bad cells are killed by a substance already present in the body (TNF alpha):  this substance needs to be stimulated to be abundant enough to kill the bad cells… and only the bad cells.  By killing this bad cells, the destructive autoimmune process is stopped.

After the autoimmune process was stopped in the mouse, the mouse’ pancreas was able to regenerate its islet cells, thus permanently curing diabetes. This regeneration used adult stem cells that appear to be ever-present in the pancreas.² It took 40 days for the mice to regenerate their islet cells. In a study in a similar animal model recently conducted in Canada, it took only 14 days for the islets to regenerate.³ This would imply that the pancreas is constantly producing new beta cells that are then destroyed by the bad cells.

To prevent the bad cells from being reproduced by the immune system, normal immune cells were introduced which then reeducated the immune system to stop making the bad cell.  This resulted in 92% of more than 250 mice being permanently cured of type I diabetes.  Their lifespan grew to 5 – 8 times longer than that of untreated mice.  This reeducation process also works in humans who are critically ill with autoimmune disease and who have had their immune system destroyed with radiation.⁴ Normal (genetically) matched immune cells are injected, resulting in a healthy, immune system free of all bad cells.

Several labs have shown the same defect to be present in people with Crohn’s disease ⁵, lupus ⁶, rheumatoid arthritis ⁷ and autoimmune thyroid disease ⁸. These articles lend support to the “Common Cause” hypothesis.

Is the correction of a late or end-stage diabetic NOD mouse common? How well does the NOD model reflect the human?

Many papers that use the NOD mouse for a model for diabetes, use this mouse when they are very young — 5-10 weeks of age. At this age it appears as if many if not most therapies correct the mice. The NOD mouse at 5-10 weeks of age is a pre-diabetic mouse. Up until this recent breakthrough, the already diabetic NOD mouse had not been cured. This spontaneously diabetic NOD mouse obviously represents more closely human disease – people who already have diabetes.

Another body of literature describes reversing diabetes in NOD mice using bone marrow transplantation. Others have reversed the disease using powerful immune suppressing drugs, and have only followed the mouse progess for a few months. These approaches have severe limitations to otherwise healthy humans because of the many associated dangers. The discussed reversal of diabetes in critically ill diabetic mice was without transplantation or immune suppression, with the mice living well beyond their peer’s lifespan. This is believed to more closely mimic human diabetics who already have the disease.

Are islet transplant centers being closed?

Several islet transplant centers around the US have had difficulty replicating the successes of the Edmonton Protocol and this has resulted in the closure of several islet transplant programs including a large portion of the Harvard Islet Center and the NIH Islet program.  It is becoming increasingly evident that transplanted islets are still vulnerable to autoimmune destruction, in spite of powerful immune suppressing cocktails.

Is the use of embryonic stem cells close to being used to provide a supply of islet cells for transplantation into humans?

No. The field of embryonic stem cells faces enormous hurtles to overcome before these cells can be used in humans.  The two key challenges to overcome are making the stem cells differentiate into specific viable cells consistently, and controlling against unchecked cell division once transplanted. Solid data of stable, functioning islet cells from embryonic stems cells in animals has not been seen.

Is there any evidence that islet cells will regenerate after the autoimmune attack response is halted?

There are indications that the insulin being produced by transplanted patients may be being produced by the pancreas and not the transplanted islet cells ⁹.  This work is as yet unpublished, but it may eventually show that insulin producing islet cells have regenerated in humans with diabetes.

There is a growing body of research indicating regeneration in animals and humans. In addition, Dr. Douglas Melton, in a paper released on May 6^th in the Journal Nature, shows that even in normal adult mice, without any diabetes and without any introduced fetal or adult precursor cells, pancreatic islets once again re-grow. ¹⁰ This new work shows that even in non-diabetic animals the islets turn over and self-renewal occurs.

Are there other clinical trials underway that are testing a cure for type I diabetes in humans?

The following clinical trials that at all relate to reversing type I diabetes, as found on the National Institutes of Health web site http://www.clinicaltrials.gov are:

1.    Interferon-Alpha for Diabetes Mellitus Type 1 (early onset)

2.    Evaluation of a Diabetes Vaccine in Newly Diagnosed Diabetics (early onset)

3.    Safety and Pharmacokinetics (PK) of hOKT3g1 (Ala-Ala) in Type 1 Diabetes Mellitus (T1DM)

4.    hOKT3gamma1 (Ala-ala) for the prevention of human islet allograft failure (transplantation)

5.    Islet Transplantation for patients with Type 1 diabetes and stable renal allografts using steroid sparing immunosuppression (transplantation)

6.    Ingested Interferon Alpha: Prolongation or Permanence of the “Honeymoon” Phase in Newly Diagnosed Type 1 Diabetes Mellitus (early onset)

7.    Effect of AC2993 with or without Immunosuppression on Beta Cell Function in Patients with Type I Diabetes (transplantation)

8.    Safety, Tolerability, Immunological and Clinical Efficacy of Multiple Subcutaneous Doses of AVE0277 in Latent Autoimmune Diabetes in Adults (LADA) (early onset)

None of these trials are attempting to address established diabetes without transplantation and immune suppression.

How far along  is the effort to try this intervention in  humans?

The blood assay, which measures the death of the bad cells when exposed to BCG, is being perfected.  We can determine if BCG works, and at what dose and frequency, only by being able to count cell death as a “bio-marker”.  Through the tandem work of ADRF and the Iacocca Foundation, the equipment needed to process a high number of blood samples for the clinical trial has been secured. It will take several months to automate the blood assay process and then the trial will be ready to test BCG in humans. BCG will be tested in many adults and children with type I diabetes over the course of the following one to two years.

Who can participate in the trial?

The protocol that will apply to human subjects is being finalized and will be posted by NIH at the appropriate time.

Are pharmaceutical companies interested in this discovery?

If this clinical trial demonstrates the role of BCG or another compound in reversing type I diabetes and confirms the mechanism for this reversal, the stage will be set for an inexpensive and permanent cure for several autoimmune diseases.  This could jeopardize a multi-billion dollar autoimmune disease medication market.  As officials at a major pharmaceutical company stated, “We don’t know how to price a cure.”

In short, the pharmaceutical industry and peer review research special interests are not demonstrating enthusiasm for this work.

Citations

1.                   Journal of Clinical Investigation, July 2001,
2.                   Science, November 2003
3.                   Nature Biotechnology Volume 21;Number 7 July:2003
4.                   Arthritis Rheum 1999 Nov;42(11):2281-5
5.                   Nature 2001 May 31;411(6837):599-603
6.                   J Immunol 1999 Aug 1;163(3):1682-9
7.                   J Immunol 2001 Dec 15;167(12):6821-6
8.                   Eur J Immunol 2002 Apr;32(4):1021-8).
9.                   NIH, Harlan D.
10.                 Nature (England), May 6 2004, 429(6987) p41-6