Posted on | October 21, 2009 | No Comments
Natural immunomodulators as novel immunotherapies for type 1 diabetes
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, equivalent to a doubling time of 20-25 years. T1DM is the most common metabolic disease in the young. In addition, 5-10% of patients originally diagnosed as T2DM have a less severe and more slowly progressing form of T1DM, usually referred to as “Latent Autoimmune Diabetes of Adults” (LADA).
About two million people in Europe (around 0.5% of the population) and several million people world-wide suffer from this disease.
Of concern are the reports of a steady increase of T1DM over the last decades in virtually all European countries and a particular escalation in the 1-5-year age group. Since it carries a significant chronic disease burden, T1DM has thus become a major public health concern worldwide, emphasizing the urgent need for safe and effective intervention and prevention strategies. At the same time that this gloomy picture has emerged, a series of key basic and clinical scientific advances have promoted the concept that reversing autoimmunity in type 1 diabetic (T1DM) patients has become a reachable challenge through growing insight in the pathogenesis of the disease and the availability of novel tools allowing interference with the disease process.
We propose an original concept, in which natural immune modulators will be introduced in interventional approaches that will modify the immune system through an antigen-specific route to achieve beta-cell protection.
Only by intervening in an antigen specific way can one guarantee beneficial immunomodulation with minimal unwanted immune perturbation in the quest to reverse autoimmunity. In NAIMIT we propose to come to tailored interventions with minimal immune system interference in new onset T1DM, leading to beta-cell protection and restoration, based on a solid understanding of the disease pathogenesis. This will enable experimental findings to be adopted for future clinical application. To achieve these ambitious goals, we have established a multidisciplinary consortium of leading European diabetologists and immunologists from 11 academic research institutions, in co-operation with 3 SMEs developing novel technologies allowing translation of basic research results towards clinical applications.
The NAIMIT approach is integrated, moving from a specific hypothesis on the pathogenesis of T1DM, supported by present state-of-the-art research, to interventions targeting the different players in the destruction of the beta-cell. The concept of this proposal is to target the immune components using natural immunomodulators and novel technologies for their delivery, thereby modulating the immune system in a targeted fashion and to a minimal degree only. This will allow arrest of autoimmunity while avoiding undesirable side effects. Two key players of the immune system in beta-cell destruction will be targeted: the DC (WP1: Re-educating antigen-presenting cells) and the T lymphocyte (WP2: Restoring the T-cell balance). In both cell types, interventions using steroid hormones (vitamin D and glucocorticoids) will be used in order to induce tolerogenic cell types. Moreover, novel interventions using soluble TCR to target immune cells and beta-cells in an antigen-specific way (WP3: TCR-mediated immunotherapy). Novel mucosal interventions using recombinant L. lactis (ActoBiotics™) as a carrier for specific peptides in combination with cytokines (WP4: Mucosal intervention for tolerance restoration) will be studied for their potential to interfere with the immune system.
An important asset of NAIMIT is that in addition to consideration of immune cells, the role of the beta-cell in its own destruction and the pathways involved in its demise will be studied.
Particular attention will be paid to understanding the communication pathways between beta-cells and the immune system, opening new ways to arrest progression of autoimmunity and preserve beta-cell mass (WP5: Beta-cell protection and restoration). Finally, we will move towards individual tailoring of therapy. Using a pharmacogenetic approach, applicable to the designed interventions, we will evaluate the potential for individualised intervention strategies (WP6: Pharmacogenetics). The results to be obtained will not only open the door to novel intervention therapies with minimal modulation of the immune system in newly diagnosed T1DM individuals, but will also improve our understanding of the disease process.