Metabolic preconditioning in CD4+ T cells restores inducible immune tolerance in lupus-prone mice
Christopher S. Wilson, Blair T. Stocks, Emilee M. Hoopes, Jillian P. Rhoads, Kelsey L. McNew, Amy S. Major, Daniel J. Moore
Christopher S. Wilson, Blair T. Stocks, Emilee M. Hoopes, Jillian P. Rhoads, Kelsey L. McNew, Amy S. Major, Daniel J. Moore
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Research Article Transplantation

Metabolic preconditioning in CD4+ T cells restores inducible immune tolerance in lupus-prone mice

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.

Authors

Christopher S. Wilson, Blair T. Stocks, Emilee M. Hoopes, Jillian P. Rhoads, Kelsey L. McNew, Amy S. Major, Daniel J. Moore

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Figure 7

Metabolic intervention improves lupus pathology and tolerance to transplanted islets.

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Metabolic intervention improves lupus pathology and tolerance to transpl...
(A) To determine whether a short therapeutic course of aCD45RB combined with 2DG/Met would improve the pathology of SLE123 mice, we treated 9-week-old mice with 2DG/met for 1 week before a standard course of aCD45RB with continued 2DG/Met. We also had a group that received 2DG/Met alone for 2 weeks. At that point, treatment was discontinued, and mice were allowed to age for 6 months before they were sacrificed and analyzed. (B and C) Kidney sections from SLE123 mice treated with triple therapy or 2DG/Met alone were stained with anti-IgG (red). There was a notable reduction in IgG deposition in mice treated with 2DG/Met and aCD45RB as compared with metabolic intervention alone. The area of red staining was quantified in these sections as shown in C and analyzed using a Student’s t test. (D) Additionally, we assessed the amount of circulating anti-dsDNA IgG. We noted a decreased in those mice treated with the triple therapy regime as compared with 2DG/Met alone. Analyzed using χ2 test. (E) To assess the capacity for durable tolerance with this triple therapy, we utilized an islet transplant model. Male and female mice 9–12 weeks old were placed on 2DG/Met 1 week before grafting MHC-disparate C3H islets under the kidney capsule. These mice received aCD45RB before metabolic therapy was discontinued. The blood glucose was tracked in these mice, as compared with B6 mice with aCD45RB or SLE123 mice that only received aCD45RB. Rejection was scored by 2 consecutive blood glucose readings of greater than 200 mg/dL. There is an increase in islet survival in SLE123 mice that received the triple therapy as compared with mice that only received aCD45RB. (B6 + aCD45RB, n = 13; SLE123 + aCD45RB, n = 8; and SLE123 + aCD45RB + 2DG + Metformin, n = 7). Scale bars: 100 μm.