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Abstract
Background Glucose is a primary substrate for cellular respiration. Glucose utilization increases in highly metabolic cells including activated, proliferating T cells and B cells as well as cancers. Lupus is a disorder in which autoreactive CD4 +T cell and B cells deviate from normal homeostasis by their uncontrolled proliferation and differentiation. Therapeutic limitation of glycolysis is therefore an attractive approach for attenuating such highly energetic, pathogenic processes inherent to lupus. Here we investigate the potential of the classic glycolysis inhibitor, 2-deoxyglucose (2DG), to prevent and reverse severe forms of autoimmune lupus-like disease in mice. As untoward side effects of 2DG therapy have also been reported, we further evaluate potential complications and biomarkers of 2DG therapy.
Methods For autoimmune disease studies, the following mouse models for spontaneous lupus-like autoimmune disease were utilized: NZB × NZW F1 (BWF1) females (adult onset) and BXSB.Yaa Cd8-/- Il15-/- males (acute adolescent onset). 2DG was provided ad libitum in acidified drinking water (2DG 2–6 g/L) for intervals of 8 wks. Mice were monitored longitudinally for weight loss, proteinurea, and survival. To assess potential effects of 2DG in non-diseased mice, C57BL6/J mice treated with 2DG and controls were analyzed for a series of metabolic, serum chemistry, cardiac, behavioral, immunological and histopathological phenotypes after short and long term exposure.
Results An 8 wk 2DG treatment of young BXSB.Yaa Cd8-/- Il15-/- mice prevented their development of prototypic cellular abnormalities and greatly extended lifespans. Given the strong normalizing effects of 2DG in disease prevention, we performed therapeutic interventions in which 2DG was intermittently supplied to 37 wk old BWF1 mice (figure 1A). This treatment abrogated proteinurea even in heavily diseased mice and extended the lifespan of many to beyond 80 wks of age (figure 1B and 1C). Safety assessments in C57BL6/J mice after 8 wks of treatment did not show any significant cardiac, behavioral, immunological and histopathological abnormalities. Alterations in serum chemistry analytes, including calcium and magnesium, but not markers of ketosis, were evident shortly after and persisted after 2DG exposure.
Intermittent 2DG treatment reverses ongoing autoimmune disease of aged BWF1 mice. Twenty-nine BWF1 female mice aged to 37 wks were randomized into two cohorts and monitored to >80 wks of age. (A) one cohort was treated with 2DG for 8 wks starting at 37 wks. All surviving mice were then treated at 53 wk for 8 wks with 2DG and again treated at 67–70 wks. (B) serial urine proteins. (C) overall survival.
Conclusions The results highlight the potent and remarkable normalizing effect of intermittent 2DG therapy in the prevention and treatment lupus-like autoimmune disease with differing genetic and mechanistic etiologies and in its most precipitous forms. This mode of therapy did not incur untoward side effects. We thus propose that therapeutic inhibition of early steps in glycolysis by 2DG has broad potential for the treatment of lupus as well as related autoimmune disorders.