Posted on | April 12, 2012 | No Comments
Type 1 diabetes melllitus (T1DM) is an autoimmune disease characterised by immune-mediated destruction of insulin-producing beta-cells in the pancreas. The incidence of T1DM in childhood is increasing at about 3% per year. T1DM is the most common metabolic disease in the young. In Europe, about two million people (around 0.5 % of the population) and several million people world-wide suffer from this disease. At present, T1DM cannot be prevented or arrested in its course and lifelong insulin therapy is needed for survival. Still, chronic complications, such as eye disease, kidney disease and vascular disease, affect lifespan and in particular quality of life. Since it carries such a significant chronic disease burden, T1DM has become a major public health concern worldwide, emphasizing the urgent need for safe and effective intervention and prevention strategies.
The true cause of T1DM remains elusive, but an autoimmune destruction of the insulin-producing beta-cell in the pancreas lies at the basis and finding ways to interfere with this immune system, aimed as restoring tolerance in a specific way towards the beta-cell without interfering with the immune defences of the subject opens the way for prevention of this disease. To date, several interventions have been assessed in patients with T1DM and treatment with antibodies directed against a marker of T lymphocytes, anti-CD3, have been the most promising. However, till now, solid evidence on the applicability of this intervention in a safe and acceptable way in patients is lacking.
The group at the University of Leuven (KU Leuven) has been involved in studies on prevention and intervention in T1DM, extending from bench to bedside. Prof. C. Mathieu leads a basic science laboratory specialised in in vitro studies and animal models of type 1 diabetes, and is head of the clinical Endocrinology department, where over 1000 patients with T1DM are being treated. In that clinical department, several clinical studies on diabetes therapies are currently taking place.
The laboratory is part of several research networks, funded by national and international agencies, amongst which the JDRF (Juvenile Diabetes Research Foundation), FWO (Fonds Wetenschappelijk Onderzoek Vlaanderen), and the European Commission. The latter supports a network on Immune Intervention in T1DM (NAIMIT), in the context of Framwork 7.
The work published on April 9th in the Journal of Clinical Investigation, is the fruit of a collaboration of several groups within the NAIMIT consortium, amongst which the company Actogenix, inventors of ActobioticTM, live biologically-contained genetically-modified Lactococcus lactis, able to deliver proteins and peptides of choice in the gut. The paper reports on the ability of ActoBioticTM (which secrete both the auto-antigen pro-insulin and the immune-modulatory cytokine interleukin-10 (IL-10), to arrest progression of diabetes in an animal model of T1DM, when administered in combination with a low dose of anti-CD3 antibody (5 days). When newly diagnosed, overtly diabetic NOD mice were treated with this regimen, a stable remission could be induced, lasting stably for weeks after therapy was interrupted. Extensive immune phenotyping of the mice revealed increased local regulatory T-cell frequencies which not only accumulated in the pancreatic islets, but also suppressed in an autoantigen-specific way. Cured mice remained responsive to disease-unrelated antigens, arguing against excessive immunosuppression.
Considering the fact that these findings report on reversal of overt diabetes, without immune suppression, but with restoration of antigen-specific tolerance via the gut, these findings are of the utmost clinical relevance, as translation to the human setting is easily realizable.