Previous and current research
The pathogenesis of diabetes mellitus hinges on the loss of pancreatic islet beta cells which in type 1 diabetes is mediated by autoimmunity. We have studied how autoimmunity develops in the course of the disease in children, the target beta cell antigens and epitopes, and the factors that predispose to autoimmunity. We showed that autoimmunity develops most frequently around 1 to 2 years of age and that the proinsulin prohormone is a primary target antigen in this age period. This age period is rich in new environmental exposures, but as we showed, it is also the immune system that is susceptible to activation at this age. Our studies have demonstrated that autoimmunity can pre-stage clinical disease and that rate of progression to disease after onset of autoimmunity is determined by genes associated with immune response and that rate of progression can be programed by perinatal events including mode of delivery. We have also identified an important role of cytokine involved in T cell homeostasis such as IL-7 in the development and expansion of autoreactive T cells and are pursuing studies that may lead to therapeutic approaches to interfere with this mechanism.
Our ongoing research is focused on trying to understand how environmental cues alter the fate of autoreactive T cells and on the one side lead to their activation and persistence that eventually causes beta cell destruction, and on the other side will lead to their deletion or regulation. We have developed technology that allows us to monitor T cell receptor and gene expression at the single cell level to allow us to monitor fate over time in individuals and to determine in vitro effects of environment on T cell fate. We are using this technology to assess the effects of mucosal insulin treatment on children in efforts to prevent islet autoimmunity and type 1 diabetes in clinical trials that we conduct.
Future prospects and goals
- Identify the mechanisms of autoreactive T effector and T regulatory cell expansion in man that can be harnessed to re-instate self immune tolerance.
- Understand how environment alters immune response to change the susceptibility for type 1 diabetes associated autoimmunity.
- Primary antigen-based therapies in infants for prevention of type 1 diabetes.