LEPTIN, METABOLIC STATE AND NATURAL REGULATORY T CELLS: CELLULAR AND MOLECULAR BASIS FOR A NOVEL IMMUNE INTERVENTION IN TYPE 1 DIABETES

Malnutrition represents the most common cause of death for infectious disease in the less developed countries.Nutrient deficiency and the consequent reduction of the fat mass causes immunodeficiency in animals and humans. We have recently identified that deficiency of leptin,the adipocyte-derived hormone,is responsible for the immunosuppression observed during stravation. Leptinhas great structural similarities with molecules produced by the immune system. Following nutritional deprivation leptin blood levels fall due to reduction of body fat,causing impairment of the immune system function. Conversely,during autoimmune diseases such as type 1 diabetes,immune fuction is enhanced against a self organ as pancreatic beta-cells. This process leads to destruction of those cells that produce insulin. Administration of leptin during early phases of the autoimmune attack anticipates the onset of clinically evident diabetes in susceptible animals such as nonobese diabetic (NOD) mice,by increasing the immune response against beta-cells. Furthermore,other autoimmune diseases such as multiple sclerosis and reumathoid arthritis present increased production of leptin during the disease onset. Therefore,given the dramatic effect of leptin and nutritional status on immune function we plan to study leptin's role in the pathogenesis of type 1 diabetes to identify novel safe and effective therapeutic strategies to treat type 1 diabetes. We have available leptin-receptor-deficient mice;these mice will allow us to understand whether in the absence of leptin signaling diabetes develops or not. Consequently,administration of leptin antagonists should allow to prevent or treat diabetes. These studies could be effective to develop novel immunotherapeutic strategies for type 1 diabetes and rejection after beta-cell islet transplantation.