CELLULAR AND MOLECULAR MECHANISMS INVOLVING IMMUNOREGULATORY LEPTIN IN THE PATHOGENESIS OF TYPE 1 DIABETES: NOVEL STRATEGIES FOR AN IMMUNE INTERVENTION

Malnutrition represents the most common cause of death for infectious diseasein the less developed countries.Nutrient deficiency and the consequentreduction of the fat mass causes immunodeficiency in animals and humans.Wehave recently identified that deficiency of leptin,the adipocyte-derivedhormone,is responsible for the immunosuppression observed during stravation.Leptin has great structural similarities with molecules produced by the immune system.Following nutritional deprivation leptin blood levels fall dueto reduction of body fat,causing impairment of the immune system function.Conversely,during autoimmune diseases such as type 1 diabetes,immune fuctionis enhanced against a self organ as pancreatic beta-cells.This processleads to destruction of those cells that produce insulin. Administrationof leptin during early phases of the autoimmune attack anticipates theonset of clinically evident diabetes in susceptible animals such as nonobesediabetic (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 understant 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.