Abstract
Autoimmune disease has presented an insurmountable barrier to restoration of durable immune tolerance. Previous studies indicate that chronic therapy with metabolic inhibitors can reduce autoimmune inflammation, but it remains unknown whether acute metabolic modulation enables permanent immune tolerance to be established. In an animal model of lupus, we determined that targeting glucose metabolism with 2-deoxyglucose (2DG) and mitochondrial metabolism with metformin enables endogenous immune tolerance mechanisms to respond to tolerance induction. A 2-week course of 2DG and metformin, when combined with tolerance-inducing therapy anti-CD45RB, prevented renal deposition of autoantibodies for 6 months after initial treatment and restored tolerance induction to allografts in lupus-prone mice. The restoration of durable immune tolerance was linked to changes in T cell surface glycosylation patterns, illustrating a role for glycoregulation in immune tolerance. These findings indicate that metabolic therapy may be applied as a powerful preconditioning to reinvigorate tolerance mechanisms in autoimmune and transplant settings that resist current immune therapies.
Highlights
Systemic lupus erythematosus (SLE) is an autoimmune disease that is characterized by inappropriate B and T cell collaboration leading to T cell activation and autoantibody production [1]
Anti-CD45RB promotes regulation of the B and T lymphocyte compartment that is resisted in the SLE123 mouse
We previously established that SLE123 mice resist transplant tolerance induced by a monoclonal antibody (MB23G2) that targets cell surface phosphatase CD45RB [27]
Summary
Systemic lupus erythematosus (SLE) is an autoimmune disease that is characterized by inappropriate B and T cell collaboration leading to T cell activation and autoantibody production [1]. In healthy individuals in the absence of immune insult or infection, the majority of T cells remain in an unreactive, naive state This state is marked by relatively reduced metabolic requirements, fulfilled by low levels of mitochondrially driven oxidative phosphorylation (OXPHOS) to produce ATP [6]. CD4+ T cells from murine models and humans with SLE demonstrate exaggerated mitochondrial OXPHOS and glycolysis compared with healthy controls [8, 9]. It is unclear whether enhanced CD4+ T cell metabolism leads to spontaneous activation or whether heightened metabolism represents the activated state of CD4+ T cells actuated via some other mechanism. Enhanced metabolism is functionally related to the pathogenesis caused by CD4+ T cells in SLE
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