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Abstract Number: 3107

Switching from Anabolic to Catabolic Metabolism – a Novel Immunomodulatory Therapy in RA

Zhen Yang1, Yi Shen1, Eric L. Matteson2, Ebru Hosgur1, Jison Hong3, Jorg Goronzy4 and Cornelia M. Weyand1, 1Medicine: Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA, 2Rheumatology, Mayo Clinic, Rochester, MN, 3Medicine/Immunology & Rheumatology, Stanford University, Palo Alto, CA, 4Medicine/Division of Immunology & Rheumatology, Stanford University School of Medicine, Stanford, CA

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: cytokines, metabolism and rheumatoid arthritis (RA), ROS, T cells

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Session Information

Date: Tuesday, November 15, 2016

Session Title: T Cell Biology and Targets in Autoimmune Disease - Oral Session

Session Type: ACR Concurrent Abstract Session

Session Time: 4:30PM-6:00PM

Background/Purpose:  Inflammatory activity in RA relies on numerous anabolic processes; including cellular proliferation, cell trafficking, secretion of proinflammatory cytokines and release of antibodies. Lasting reversal of inflammation would require to correct such anabolic processes; ideally in the pinnacle pathogenic drivers of RA, HLA-class II-restricted CD4 T cells. CD4 T cells in RA patients are metabolically reprogrammed due to a lack of the catabolic enzyme phosphofructokinase 2 (PFK2) and an excess in the anabolic enzyme glucose-6-phosphate dehydrogenase (G6PD). It is insufficiently understood how metabolic reprogramming affects disease-relevant T cell effector functions and whether this metabolic defect is amendable to therapeutic intervention.

Methods:  Patients with seropositive and clinically active RA as well as age-matched healthy controls were enrolled. For molecular and functional studies, the population of naïve CD4+CD45RA+ T cells was activated through TCR crosslinking. Metabolites and reactive oxygen species (ROS) were measured after 72 hr, cytokine production after 7 days. Arthritogenic activity was quantified by adoptive transfer into NSG mice carrying human synovium. To reset the cells’ metabolic homeostasis, the following small molecule reagents were applied in vitro and/or in vivo: the G6PD inhibitor 6-amino-nicotinamide (6-AN), the gamma-glutamylcysteine synthetase (γ-GCS) inhibitor Buthionine-sulph-oximine (BSO), and the 1,4-naphthoquinone analog Menadione.

Results:  Compared to healthy control T cells, RA T cells produced more NADPH (p<0.05), had lower ROS (p<0.001) and higher intracellular glutathione levels (p<0.05), indicative of excess glucose shunting into the pentose-phosphate pathway. Functional consequences included: higher cellular proliferation (p<0.01), faster cell-cycle passage (p<0.001), earlier naïve-to-memory conversion (p<0.05) and preferential Th1 and Th17 lineage commitment (p<0.05). G6PD inhibition restored intracellular ROS level, corrected the cell-cycle behavior and suppressed IFN-γ production. In human synovium-NSG chimeric mice, RA T cells promptly invaded into the synovial tissue (p<0.001), where they produced IFN-γ and IL-17 and stimulated production of TNF-α, IL-1β and IL-6. Treatment with BSO or Menadione corrected the metabolic abnormalities and suppressed inflammatory activity in the synovial tissue.

Conclusion:  T cells in RA patients are biased towards anabolic metabolism, resulting in excessive biomass generation, hyperproliferation and secretion of proinflammatory effector molecules. The underlying molecular mechanisms involve the gain in NADPH and the shift of the redox balance towards reductive elements. Pharmacologic interventions that restore oxidant signaling are highly effective in normalizing the cell-cycle behavior of affected T cells and in suppressing synovial inflammation.


Disclosure: Z. Yang, None; Y. Shen, None; E. L. Matteson, None; E. Hosgur, None; J. Hong, None; J. Goronzy, None; C. M. Weyand, None.

To cite this abstract in AMA style:

Yang Z, Shen Y, Matteson EL, Hosgur E, Hong J, Goronzy J, Weyand CM. Switching from Anabolic to Catabolic Metabolism – a Novel Immunomodulatory Therapy in RA [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/switching-from-anabolic-to-catabolic-metabolism-a-novel-immunomodulatory-therapy-in-ra/. Accessed April 17, 2021.
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