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. A major impediment to drug development in diabetes has been the failure of therapeutics to translate from mouse to human. Mindful of this, we discovered that CD40 provides a link between mouse and human during T1D. We discovered that NOD mice, the industry standard model for T1D, 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. To address this, we developed a series of peptides derived from the CD154 protein sequence that are designed to 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 establish clinical parameters that will allow further development of a lead candidate for therapeutic development. We propose to determine how candidate peptides impact glucose tolerance testing, serum insulin levels and c-peptide levels.
Methods to control CD40 CD154 interaction have failed because heretofore they have depended upon monoclonal antibody or randomly generated organic molecules. We designed CD40 targeting peptides that prevent diabetes onset and reverse hyperglycemia in new onset diabetic mice.