New and future immunomodulatory therapy in type 1 diabetes

Abstract

Type 1 diabetes is a common autoimmune disease that affects millions of people worldwide and has an incidence that is increasing at a striking rate, especially in young children. It results from the targeted self-destruction of the insulin-secreting β cells of the pancreas and requires lifelong insulin treatment. The effects of chronic hyperglycemia - the result of insulin deficiency - include secondary endorgan complications. Over the past two decades our increased understanding of the pathogenesis of this disease has led to the development of new immunomodulatory treatments. None have yet received regulatory approval, but this report highlights recent progress in this area.

Figure 1. Revised immunologic view of type 1 diabetes

The efficacy of agents such as CTLA4-Ig and anti-CD20 has revised previous concepts about the immunologic mechanisms of the disease. Previously, experimental data suggested that the chronic autoimmune process that leads to β cell destruction was fully matured at the time of clinical presentation and was restricted to T cell-dependent destruction of the cells. The results from these new studies suggest that antigen presentation continues at the time of diagnosis and that there may still be an opportunity to impact the immune progression with agents that can arrest this process. The colored arrows indicate the induction of an autoimmune response to different autoantigens over time. The dashed blue line represents the decrease in β cell mass over time. Treatments that are initiated at clinical presentation (second black arrow) occur after considerable loss in β cell mass. The green dashed line represents the slowed decline in β cell destruction due to an effective treatment. Prevention treatments (first black arrow) are initiated after the presentation of autoantigens, but before a decline in β cell mass. Preclinical studies in NOD mice often initiate treatment even earlier in the disease process before an autoimmune response has developed.