Type 1 diabetes mellitus is a metabolic disorder characterized by elevated blood glucose levels as a result of decreased insulin secretion. Its pathophysiology involves the destruction of β-pancreatic cells, with an absolute insulin deficiency and permanent dependence on exogenous insulin. The cause in 90% of cases is considered autoimmune, as determined by the presence of anti-islet antibodies (ICA), glutamic acid decarboxylase antibodies (anti-GAD antibodies), and anti-insulin antibodies, and about 10% of cases are idiopathic. These antibodies are elevated during years of evolution of the disease and spontaneously follow a downward curve [15
]. There is no medical treatment available at present to alter this evolution of the disease.
The prevalence of diabetes mellitus for all age groups worldwide was estimated to be 2.8% in year 2000 and is projected to be 4.4% by 2030 [15
]. It is quite clear that the statistics show a growing disease without curative treatments, which develops into serious complications and justifies research and development of alternative therapeutic strategies.
The clinical picture refers to the classical triad of polyphagia, polyuria, and polydipsia, accompanied by an emaciated nutritional status and hyperglycemia.
Ketoacidosis, a major complication in many patients, is evidenced by dehydration, acidic respiration, nausea, and vomiting [18
Recently it was demonstrated that different types of stem cells, including mesenchymal stem cells, have properties allowing them to regulate the function of immune cells. The therapeutic use of mesenchymal stem cells in autoimmune diseases is being studied in different pre-clinical and clinical experiments in adults and children [19
]. In addition, other studies showed that mesenchymal cells also secrete peptides that act as modulating factors for local micro-immunity [28
]. The molecules secreted by mesenchymal cells are predominantly anti-inflammatory in nature. Mesenchymal cells play a central role in immunologic homeostasis and several studies have shown that mesenchymal cells (
MSCs) can secrete specific peptides, such as hepatocyte growth factor, that can contribute to the creation of a local immunosuppressive environment. Similarly, transforming growth factor-1 is also involved in T cell suppression by working with hepatocyte growth factor in promoting the allo-escaping phenotype [31
]. Di Nicola et al showed that neutralizing antibodies to hepatocyte growth factor and transforming growth factor-1 restored the proliferative response in mixed lymphocyte reactions [31
]. Other suggested factors include interferon (INF), tumor necrosis factor, and interleukin (IL)-2 [32
]. Interleukin-10 also seems to be constitutively expressed by MSCs and has a well documented role in T cell regulation and in the promotion of the suppressor phenotype by antagonizing the action of IL-12 during induction of the inflammatory immune responses.
We believe that bone marrow stem cell transplantation directly into the liver parenchyma provides conditions similar to the culture media, where the implanted cells stay in contact for more than 4 days, the same as a culture medium, and may stimulate the cellular differentiation and modulation of the immune system.
The implanted bone marrow cells could stimulate the secretion of hepatocyte growth factor and other chemokines, which could modulate the action of antigen-presenting cells and lymphocytes and may reverse the production of antibodies, as described in the preclinical experiments.
We observed a reduction in anti-islet (ICA) and GAD antibodies, which remained during the follow-up at 12 months, and noted that the negative results for antibodies is associated with increased C peptide, decreased requirement for daily insulin dose, and decreased concentrations of glycosylated hemoglobin (HbA1c).
At 12 months, in Patient 1 we observed a small increase in anti-insulin antibody, which we consider insignificant since it only reaches 20% of the level observed before cell treatment. The patient who was treated with insulin only (Control case/Patient 3) showed positive and continuously increasing antibodies and decreased C-peptide measurements, which continued to increase in daily insulin dose. However, the daily insulin requirement was lower in patients treated with stem cells (Patients 1 and 2). Clearly, the bone marrow stem cells implantation in 2 consecutive patients had an effect on the production of pancreatic antibodies, pancreatic function, and metabolic control after 12-month follow-up.
The proposed treatment is easy to perform and has no ethical issues. No complications were observed during the implantation procedure or 12 months of follow-up. We believe that the cell implantation clearly influenced the suppression of anti-islet antibody and reversed its effects. The exact mechanism of action of stem cells is unclear but we could not determine any other means of change in antibody levels.
This therapeutic method appears to be an effective alternative for the treatment of recently diagnosed type 1 diabetes. Despite the small number of patients treated, the results, which are unprecedented in the history of medicine, are very impressive. This information should be verified in clinical studies attempting verify our results, which could mean a cure for type 1 diabetes mellitus.