Vaccine to reverse diabetes – myth or reality?

Olutayo Christopher Alebiosu

Abstract



Type 1 diabetes is caused by anautoimmune destruction of the pancreatic beta cells. Attempts to affect the disease Tprocess by prolonging residual beta cell survival at the time of onset of type 1 diabetes using immu n omo d u l a t i n g a g e n t s s u c h a s glucocorticoids, cyclosporine, and azathioprine, have been partially successful in humans. These agents must be used long term (with attendant side effects) and do not permanently preserve cell function. A century-old vaccine for preventing tuberculosis (BCG) may be the key to reversing type 1 diabetes. The BCG vaccine was first used in humans in 1921 as a vaccine against tuberculosis. More recently, its most common use has been in the treatment of bladder cancer.
Dr. Denise Faustman, the Director of the Immunobiology Laboratory at the Massachusetts General Hospital and an Associate Professor of Medicine at Harvard Medical School observed that the BCG vaccine temporarily raise levels of Tumor Necrosis Factor (TNF) – and the higher TNF levels can eliminate the damaging T cells in the blood of individuals with type 1 diabetes. TNF has been identified as a potential novel immunotherapy (Allen et al., 1999). TNF destroys insulin-autoreactive T cells, but not healthy T cells, in vitro studies of human diabetic blood samples and in the NOD mouse model.
Interventions that have destroyed insulinautoreactive T cells and boosted beneficial types of T cells have led to regeneration of insulinproducing islet cells in the pancreas of rodents with autoimmune diabetes, resulting in restoration of normoglycemia, even in advanced disease (Allen et al., 1999).
In their study (Faustman et al., 2012), Faustman's team found that two BCG injections given four weeks apart temporarily eliminated diabetescausing T cells. Patients also showed evidence of small, temporary return of insulin secretion. For the recently approved phase II of the study, 150 subjects with type 1 diabetes for 15 or even 20 years who do not suffer from any diabetic complications (such as neuropathy, retinopathy, and others) will be tested for five years to determine the dose required to potentially reverse type 1 diabetes. The subjects, aged 18 to 60, must have low but still detectable levels of insulin production. The protocol for the trial stipulates that the subjects will receive two injections, four weeks apart, of either BCG or a placebo, along with annual injections of either over the next four years.
The main goal of the trial was to determine whether activation of the innate immune system could be accomplished safely with repeated BCG vaccinations and whether this treatment would ameliorate the advanced autoimmune state of long-term type 1 diabetes. Repeated BCG vaccination at low doses was safe and well tolerated. Faustman et al (2012) found that BCG vaccination and an unexpected EBVinfection in a placebo-treated diabetic subject, both known triggers off innate immunity, caused rapid increases in circulating insulin-autoreactive Tcells that were mostly dead. The rapid release of dead insulin-autoreactive T cells supports the hypothesis, (first demonstrated in the NODmouse model of autoimmune diabetes), that BCG ameliorates the advanced autoimmune process underlying type 1 diabetes by stimulating TNF.
The later selectively kills only disease-causing cells and permits pancreas regeneration (2) as evidenced by the transient increase in C-peptide secretion we observed using an ultrasensitive Cpeptide assay.
The research report provide proof-of-principle evidence that insulin-autoreactive T cells can be specifically targeted and eliminated, though briefly even in long-standing disease with a transient restoration of C-peptide. This paves the way for either higher doses or more frequent BCG administered in future trials for patients with advanced disease to maintain or restore C-peptide levels.
For now, one can only hope that the study by Faustman et al (2012) will bring succour to the
homes of millions of people living with diabetes which are mainly in the developing world.

Keywords


diabetes

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