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Determination of the Relative Potency of an Anti-TNF Monoclonal Antibody (mAb) by Neutralizing TNF Using an In Vitro Bioanalytical Method
Published on: September 16, 2017
Successful tumour necrosis factor (TNF) blocking therapy suppresses oxidative stress and hypoxia-induced
Monika Biniecka1, Aisling Kennedy, Chin T Ng
1Translation Rheumatology Research Group, Dublin Academic Medical Centre, The Conway Institute of Biomolecular and Biomedical Research, St. Vincent’s University Hospital, Elm Park, Dublin 4, Ireland.
Introduction:
To examine the effects of tumour necrosis factor (TNF) blocking therapy on the levels of early mitochondrial genome alterations and oxidative stress.
Methods:
Eighteen inflammatory arthritis patients underwent synovial tissue oxygen (tpO(2)) measurements and clinical assessment of disease activity (DAS28-CRP) at baseline (T0) and three months (T3) after starting biologic therapy. Synovial tissue lipid peroxidation (4-HNE), T and B cell specific markers and synovial vascular endothelial growth factor (VEGF) were quantified by immunohistochemistry. Synovial levels of random mitochondrial DNA (mtDNA) mutations were assessed using Random Mutation Capture (RMC) assay.
Results:
4-HNE levels pre/post anti TNF-α therapy were inversely correlated with in vivo tpO(2) (P < 0.008; r = -0.60). Biologic therapy responders showed a significantly reduced 4-HNE expression (P < 0.05). High 4-HNE expression correlated with high DAS28-CRP (P = 0.02; r = 0.53), tender joint count for 28 joints (TJC-28) (P = 0.03; r = 0.49), swollen joint count for 28 joints (SJC-28) (P = 0.03; r = 0.50) and visual analogue scale (VAS) (P = 0.04; r = 0.48). Strong positive association was found between the number of 4-HNE positive cells and CD4+ cells (P = 0.04; r = 0.60), CD8+ cells (P = 0.001; r = 0.70), CD20+ cells (P = 0.04; r = 0.68), CD68+ cells (P = 0.04; r = 0.47) and synovial VEGF expression (P = 0.01; r = 063). In patients whose in vivo tpO(2) levels improved post treatment, significant reduction in mtDNA mutations and DAS28-CRP was observed (P < 0.05). In contrast in those patients whose tpO2 levels remained the same or reduced at T3, no significant changes for mtDNA mutations and DAS28-CRP were found.
Conclusions:
High levels of synovial oxidative stress and mitochondrial mutation burden are strongly associated with low in vivo oxygen tension and synovial inflammation. Furthermore these significant mitochondrial genome alterations are rescued following successful anti TNF-α treatment.
Insights
Tumour necrosis factor (TNF) blocking therapy reduces oxidative stress and mitochondrial DNA mutations in inflammatory arthritis patients. Successful treatment correlates with improved oxygen levels and reduced disease activity.
Area of Science:
- Rheumatology
- Molecular Biology
- Cellular Biology
Background:
- Inflammatory arthritis is characterized by synovial inflammation and oxidative stress.
- Tumour necrosis factor (TNF) plays a key role in inflammatory processes.
- Mitochondrial dysfunction and DNA alterations are implicated in chronic inflammation.
Purpose of the Study:
- To investigate the impact of TNF-blocking therapy on mitochondrial genome integrity and oxidative stress markers in inflammatory arthritis.
- To assess the relationship between in vivo tissue oxygen levels, oxidative stress, and mitochondrial DNA mutations.
- To evaluate the correlation between these molecular changes and clinical disease activity.
Main Methods:
- Synovial tissue biopsies from 18 inflammatory arthritis patients were analyzed before and after three months of anti-TNF-α therapy.
- Measurements included synovial tissue oxygen tension (tpO(2)), disease activity score (DAS28-CRP), lipid peroxidation (4-HNE), T/B cell markers, VEGF, and mitochondrial DNA (mtDNA) mutations via RMC assay.
- Immunohistochemistry and RMC assay were employed for molecular quantification.
Main Results:
- Anti-TNF-α therapy responders showed significantly reduced 4-HNE expression, inversely correlated with improved tpO(2) levels.
- High 4-HNE levels correlated with increased disease activity scores (DAS28-CRP, TJC-28, SJC-28, VAS) and elevated immune cell markers (CD4+, CD8+, CD20+, CD68+) and VEGF.
- Patients with improved tpO(2) post-treatment exhibited significant reductions in mtDNA mutations and DAS28-CRP.
Conclusions:
- Elevated synovial oxidative stress and mtDNA mutations are linked to reduced oxygen tension and inflammation in arthritis.
- Successful anti-TNF-α therapy effectively rescues these mitochondrial genome alterations.
- These findings highlight the role of mitochondrial health in inflammatory arthritis and the therapeutic potential of anti-TNF agents.
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