Abstract
Type 1 diabetes in mice is characterized by autoimmune destruction of insulin-producing pancreatic β-cells. Disease pathogenesis involves invasion of pancreatic islets by immune cells, including macrophages and T cells, and production of antibodies to self-antigens, including insulin. Activation of the inflammatory reflex, the neural circuit that inhibits inflammation, culminates on cholinergic receptor signals on immune cells to attenuate cytokine release and inhibit B-cell antibody production. Here, we show that galantamine, a centrally acting acetylcholinesterase inhibitor and an activator of the inflammatory reflex, attenuates murine experimental type 1 diabetes. Administration of galantamine to animals immunized with keyhole limpet hemocyanin (KLH) significantly suppressed splenocyte release of immunoglobulin G (IgG) and interleukin (IL)-4 and IL-6 during KLH challenge ex vivo. Administration of galantamine beginning at 1 month of age in nonobese diabetic (NOD) mice significantly delayed the onset of hyperglycemia, attenuated immune cell infiltration in pancreatic islets and decreased anti-insulin antibodies in serum. These observations indicate that galantamine attenuates experimental type 1 diabetes in mice and suggest that activation of the inflammatory reflex should be further studied as a potential therapeutic approach.
Highlights
Type 1 diabetes is associated with substantially increased rates of morbidity and mortality, accounting for costs exceeding $14.9 billion in health care costs in the U.S each year [1,2,3,4,5,6,7,8,9,10,11]
Cytokines were measured by multiplex enzyme-linked immunosorbent assay (ELISA) (Quansys), and immunoglobulin G (IgG) antibodies were measured by ELISA
Plates were coated with 20 μg/mL keyhole limpet hemocyanin (KLH) antigen in phosphate-buffered saline (PBS) (Life Technologies) overnight, followed by blocking with 1% bovine serum albumin (BSA) in PBS for 2 h
Summary
Type 1 diabetes is associated with substantially increased rates of morbidity and mortality, accounting for costs exceeding $14.9 billion in health care costs in the U.S each year [1,2,3,4,5,6,7,8,9,10,11]. It is characterized by decreased insulin secretion and severe hyperglycemia, which can lead to ketoacidosis, coma and death. Anti–B-cell antibodies (rituximab), anti-CD3 antibodies (otelixizumab and teplizumab) targeting T cells and the Diamyd vaccine (GAD immunotherapy) have all failed to meet endpoints in recent clinical trials [24,25,26,27,28,29,30]
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