Type 1 Diabetes (T1D) affects an ever growing population. While this disease typically has been associated with juveniles, the disease in adult populations is rapidly increasing. The defining clinical component is insulin loss, which occurs because of sustained inflammation in the islets. At present there is no means to prevent or reverse insulin loss. A major inflammatory pathway in T1D that contributes to insulin loss is the CD40 ? CD154 dyad. CD40 is expressed on a wide array of cells and when engaged by CD154 creates localized inflammation. This pathway is decisive in T1D; blocking the interaction prevents diabetes onset and reverses hyperglycemia in new onset diabetic mice. We discovered that CD40 provides a link between mouse and human during T1D. We discovered that NOD mice increase CD40 expression, including on a sub population of T cells during diabetes development. Those cells, termed Th40, not only expand in number as diabetes develops but Th40 cells are singularly capable of transferring T1D to scid recipients. In a translational approach, we discovered that Th40 cells become prominent in human T1D patients, regardless of the age, HLA haplotype, auto-antibody status, or duration of disease. Like in the mouse model, Th40 cells start at low percentages but increase as human subjects progress to T1D and remain at high levels even up to 40 years after diagnosis. New onset as well as long ? term diabetic patients have highly expanded numbers of Th40 cells when compared to non-autoimmune, or type 2 diabetic controls. A portion of TrialNet defined Pre-T1D subjects also have expanded Th40 cell numbers, suggesting that these cells become pathogenic over time, depending upon CD40 expression. Controlling CD40 therefore will be therapeutically advantageous. Methods to control CD40 have relied upon monoclonal antibodies or randomly generated, small organic molecules. Both those options have failed clinically. Importantly antibodies or Fab? fragments have never reversed hyperglycemia. We developed a series of peptides derived from the CD154 protein sequence that target CD40 binding sites. These peptides do not function like antibodies and unlike the random generated organic molecule approach, have high specificity for CD40. In preliminary work we determined that some of the peptides prevent diabetes onset in NOD mice and one of the peptides (thus far) reversed hyperglycemia in new onset diabetic mice. The goals of this grant are to address the mechanism(s) of action of these peptides: focusing on Th40, and CD40 expressing antigen presenting cells. Translationally, we proposed that the peptides alter human Th40 cells, rendering them susceptible to regulation.
The role of CD40 during inflammation is understood; however how to safely control CD40 ? mediated auto-inflammation is not. Current approaches use dangerous monoclonal antibodies. We created a set of peptides that target CD40 directly. This grant explores the mechanism of action of those peptides in type 1 diabetes development.
