Controlling the Residual Inflammatory Risk in Type 1 Diabetic Atherosclerosis

Abstract Prevention trials with statins reduce the relative risk of cardiovascular (CV) events by 10 to 40%. This leaves a ‘residual risk’ of 60–90% for which the CANTOS trial (IL1β inhibition) provided proof of concept that targeting inflammation reduces CV event rates; unfortunately, it did not change rates of type 1 diabetes (T1D) and infections in T1D patients were higher. A major molecular driver of auto-inflammation in both diseases is the CD40/CD154 inflammatory dyad with unique T cell subset, CD3+CD4+CD40+ (TH40 cell) known to be significantly expanded in T1D subjects. Normalization of the aberrant contact dependent interaction of this dyad has shown efficacy in animal models using antibody to CD154, reversing T1D and rate of atherosclerosis, but unfortunately has deleterious side effects when given in humans. We measured TH40 cells in T1D subjects with high calcium scores (a measure of atherosclerotic burden) and those with low calcium scores. Additional to the higher percentage of TH40 cells compared to controls, we have found a statistically significant elevation in in INFg production in the high calcium score cohort, indicating a more pathogenic state of these cells. We designed peptides capable of binding directly to the CD40 receptor, which have been shown to reverse T1D in animals. Peptide was administered to ApoE−/− mice, a model of atherosclerosis. Immunohistochemical staining demonstrated significant reduction in plaque as well as smooth muscle and collagen content. In-vitro analysis of TH40 mouse splenic cells showed modulation in IL2, INFγ and IL17, all potent cytokines of atherosclerosis. This new information relays promise for a more directed diagnostic and therapeutic target for T1D related atherosclerosis.