N-acetyl Cysteine and Rapamycin for the Treatment of SLE via Modulation of the Cellular Response to Reactive Oxygen Species
Introduction. Systemic Lupus Erythematosus (SLE) is an autoimmune disorder involving multiple organ systems with a wide range of clinical manifestations commonly including arthritis, nephritis, neurologic disorders and hematologic disorders. SLE affects approximately 1 in 2500 people with a much higher prevalence in females than males.1 Although current drug treatment has reduced the overall mortality of SLE, little progress has been made recently to reduce SLE related mortality. Moreover, much of the mortality of SLE is related to medication side effects, including infections due to immunosuppression and cardiovascular events.2 Therefore, there is a strong desire to develop new effective drugs for SLE management. One potential target is the modulation of the cellular response to reactive oxygen species using N-acetyl cysteine (NAC) and rapamycin, drugs recognized to have oxidative stress modulatory effects.3 This review aims to examine the mechanism of action and clinical efficacy of these drugs. Methods. Peripheral blood lymphocytes (PBL) were isolated from four groups, 1) untreated SLE patients, 2) NAC treated patients, 3) rapamycin treated patients, and 4) healthy volunteer controls. The metabolome of PBLs from groups 1, 2, 4 were determined via mass spectrometry combined with a profiling platform utilizing selected reaction monitoring (SRM) that covers all major metabolic pathways.4 The T-cell population composition was determined via flow cytometry for groups 1, 3, 45 and all groups were monitored for clinical outcomes using SLE Disease Activity Index (SLEDAI).6,7 Results. SLE PBL populations had significant changes in metabolite concentrations in the pentose phosphate, glycolysis and 25 other metabolic pathways compared to healthy volunteer PBLs. Kynurenine (Kyn), a tryptophan breakdown product, was identified as a metabolite increased in SLE PBLs that directly activates mTOR4. NAC treatment effectively increased NADPH and decreased Kyn, serving as a uniquely identified mechanism of action of NAC.4 SLE PBL populations demonstrated a marked increase in proportion of DN T cells that produce IL-4 (11.2 ± 1.7% vs to 6.9 ± 0.8%) vs healthy PBL controls. IL-4 stimulates production of TH2 CD4 cells, which have an antagonistic effect on the development of anti-inflammatory FOXP3+ Treg cells. PBLs from rapamycin treated patients demonstrated diminished IL-4 production of DN T cells and increased FOXP3+ Treg cells. In clinical trials, both NAC and rapamycin proved to be clinically efficacious as both improved SLEDAI by an average of 1.6 and 5.4 points, respectively. Conclusions. The mechanisms and effectiveness of N-acetyl cysteine and rapamycin for the treatment of SLE were demonstrated.
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- Perl A, Hanczko R, Lai Z-W, et al. Comprehensive metabolome analyses reveal N-acetylcysteine responsive accumulation of kynurenine in systemic lupus erythematosus implications for activation of the mechanistic target of rapamycin. Metabolomics. 2015
- Lai Z-W, Borsuk R, Shadakshari A, et al. Mechanistic Target of Rapamycin Activation Triggers IL-4 Production and Necrotic Death of Double-Negative T Cells in Patients with Systemic Lupus Erythematosus. The Journal of Immunology. 2013
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- Lai Z-W, Hanczko R, Bonilla E, et al. N-acetylcysteine reduces disease activity by blocking mammalian target of rapamycin in T cells from systemic lupus erythematosus patients: A randomized, double-blind, placebo-controlled trial. Arthritis & Rheumatism. 2012;64(9):2937-2946. doi:10.1002/art.34502