Drug insight: New immunomodulatory therapies in type 1 diabetes.

Animal models and human studies have provided strong evidence that the immune response that causes type 1A diabetes is initiated against a limited array of antigens but acquires breadth and depth until beta-cell mass has been critically compromised. Two recent trials confirmed the ability to identify relatives at risk for development of diabetes, but were unsuccessful in preventing disease. Treatment of at-risk individuals with oral insulin, which is postulated to be an antigen in the disease, did however show efficacy in a subgroup of these subjects, suggesting that antigen-specific prevention approaches might be successful in the right group of subjects at the right time. Earlier trials showed that the natural progression of disease can be altered with conventional immune suppression but these approaches have been supplanted by tolerance-induction strategies. Anti-CD3 monoclonal antibodies have shown efficacy in preventing the loss of insulin production over the first 2 years of disease without chronic immune suppression. The mechanisms are novel, and appear to involve induction of immune regulation by the monoclonal antibody. Ultimately, preservation and even improvement in beta-cell mass is the goal of therapy. The means needed to achieve this will depend on the timing and mechanisms of the immune intervention and might require combinations of agents.