Persistent Suppression of Type 1 Diabetes by a Multicomponent Vaccine Containing a Cholera Toxin B Subunit-Autoantigen Fusion Protein and Complete Freund’s Adjuvant
Data presented here demonstrate multifunctional vaccination strategies that harness vaccinia virus mediated delivery of a gene encoding an immunoenhanced diabetes autoantigen in combination with complete Freund’s adjuvant (CFA) that can maintain safe and durable immunologic homeostasis in NOD mice. Systemic coinoculation of prediabetic mice with recombinant vaccinia virus rVV-CTB::GAD and undiluted or 10-fold diluted CFA demonstrated a significant decrease in hyperglycemia and pancreatic islet inflammation in comparison with control animals during 17–61 and 17–105 weeks of age, respectively. Synergy in these beneficial effects was observed during 43–61 and 61–105 wks of age, respectively. Inflammatory cytokine and chemokine levels in GAD-stimulated splenocytes isolated from vaccinated mice were generally lower than those detected in unvaccinated mice. The overall health and humoral immune responses of the vaccinated animals remained normal throughout the duration of the experiments. 1. Introduction Type 1 diabetes mellitus (T1D) is a chronic metabolic disease that is based on autoimmunity and is most frequently initiated in childhood. Initial symptoms include autoreactive lymphocyte mediated progressive destruction of the insulin-producing beta islet cells of the pancreas triggered by the innate and ultimately the adaptive arm of the body’s immune system. This early perturbation of immunological homeostasis results in a progressive loss of islet β-cell function, leading to an overall insulin deficiency and resulting in elevated blood sugar levels (hyperglycemia), increased cellular oxidative stress leading to chronic pancreatic islet inflammation, and an associated risk for development of secondary neural and circulatory health problems, resulting in amputation of the extremities, blindness, and increased probability of heart attack and stroke [1]. Type 1 diabetes incidence is steadily increasing in the western world [2]. In the United States, approximately 3 million Americans are afflicted with all forms of diabetes, of which from 15 to 20% currently suffer from T1D. Showing the extensive nature of this disease, more than 13,000 children are diagnosed with T1D in the U.S. annually. Hyperglycemia, the major manifestation of clinical diabetes, represents the final outcome of immunological processes that have progressed over a number of months in mice and years in humans. Treatments for disease prevention which focus on arresting or reversing hyperglycemia are inadequate, as islet β-cell destruction is completely asymptomatic until more than half of the
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