Abstract 15075: An Immunologic Mechanism and Treatment for Type 1 Diabetic Atherosclerosis
Introduction: Type 1 Diabetes (T1D), a classic autoimmune disease, is an independent risk factor for atherosclerosis with CD40 being a major contributor to both diseases. We described a unique CD4+ T cell population initially in T1D that expresses CD40; over time we termed those cells Th40. Th40 cells are significantly expanded in peripheral blood of T1D patients, as well as being necessary and sufficient to cause T1D in mice. In multiple cell types of human coronary atherosclerotic lesions, CD40 or its ligand CD154 are expressed and blocking CD40/CD154 interaction confers a favorable fibrous cap phenotype, abrogates atherosclerosis, and limits neointimal formation and restenosis. Successful human trials at targeting the ligand CD154 in other diseases, were hampered by embolic events due to normal CD154 action in thrombus stabilization.
Results: We have found that Th40 cells are similarly expanded in ApoE deficient mice, a mouse model for atherosclerosis. These cells are found within plaque in large numbers. They not only overexpress interferon gamma (INFγ) but, in turn, INFγ feeds back upon the Th40 cell, causing proliferation. When INFγ is blocked, expansion of Th40 cells cease. We developed a novel small therapeutic peptide (KGYY15) that targets the CD40 molecule directly and Th40 cells specifically. Results of this novel method of direct targeting show a reduction of Th40 cells within target organs, reduction of overall plaque formation (p<0.05) and INFγ production. Furthermore, there is a significant reduction in number of early and advanced atherosclerotic lesions (p<0.05) with plaque composition of the advanced lesions demonstrating a trend toward increased collagen content and decreased necrotic core area; a stable plaque phenotype.
Conclusions: While hyperglycemia is studied world-wide as one factor increasing risk of atherosclerosis in diabetes, we have found an autoimmune mechanism which can, at minimum, augment the risk in T1D, if not be a primary reason for the aggressive atherosclerosis. These findings are ongoing evidence of the importance of inflammatory pathways in atheroma formation and most importantly, demonstrate a novel, effective method of treatment.
Author Disclosures: M. Yussman: Ownership Interest; Modest; OP-T-Mune, Inc. Denver. D. Wagner: Ownership Interest; Significant; OP-T-Mune, Inc. Denver. G. Vaitaitis: None. D. Waid: Ownership Interest; Modest; OP-T-Mune, Inc., Denver.
- © 2016 by American Heart Association, Inc.