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NRF2 activator A-1396076 ameliorates inflammation in autoimmune disease models by inhibiting antigen dependent T cell
Christian Goess1, Sonia Terrillon1, Martha Mayo1
1AbbVie Bioresearch Center, 100 Research Drive, Worcester, MA, 01605, USA.
Abstract:
Nuclear factor (erythroid-derived 2) like 2 (NRF2) is a nuclear transcription factor activated in response to oxidative stress that induces a gene program that dampens inflammation and can limit cell damage that perpetuates the inflammatory response. We have identified A-1396076, a potent and selective NRF2 activator with demonstrated KEAP1 binding and modulation of cellular NRF2 mediated effects. In vivo administration of A-1396076 inhibits inflammation across several rodent models of autoimmunity when administered at or before the time of antigen challenge while also inducing NRF2 modulated gene transcription in the liver of the animals. It was not effective when administered after the time of antigen challenge or in a T cell independent model of arthritis induced by passive transfer of anti-collagen antibodies. A-1396076 inhibited antigen dependent T cell activation as measured by IFN-γ production in an ex vivo re-stimulation assay and following anti-CD3 challenge of MOG-sensitized mice. A-1396076 reduced costimulatory molecule expression on dendritic cells in the lungs of OVA LPS challenged mice suggesting that the mechanism of T cell inhibition was mediated at least partially by interfering with antigen presentation. These data suggest that NRF2 activation may be an effective strategy to dampen inflammation for treatment of autoimmune disease.
Insights
A novel NRF2 activator, A-1396076, effectively inhibits inflammation in rodent models of autoimmunity by modulating T cell responses and antigen presentation, suggesting potential for autoimmune disease treatment.
Area of Science:
- Immunology
- Molecular Biology
- Pharmacology
Background:
- Nuclear factor (erythroid-derived 2) like 2 (NRF2) is a transcription factor activated by oxidative stress.
- NRF2 activation initiates a gene program that reduces inflammation and limits cell damage.
- Targeting NRF2 presents a potential therapeutic strategy for inflammatory and autoimmune diseases.
Purpose of the Study:
- To identify and characterize a novel NRF2 activator, A-1396076.
- To evaluate the efficacy of A-1396076 in preclinical models of autoimmune disease.
- To elucidate the mechanism of action of A-1396076 in modulating immune responses.
Main Methods:
- In vitro characterization of A-1396076 for KEAP1 binding and NRF2 modulation.
- In vivo administration of A-1396076 in rodent models of autoimmunity (e.g., antigen challenge, MOG-sensitized mice).
- Ex vivo assessment of T cell activation (IFN-γ production) and dendritic cell costimulatory molecule expression.
Main Results:
- A-1396076 demonstrated potent and selective NRF2 activation.
- In vivo administration of A-1396076 inhibited inflammation in T cell-dependent autoimmune models when given prophylactically.
- A-1396076 inhibited antigen-specific T cell activation and reduced costimulatory molecule expression on dendritic cells.
Conclusions:
- NRF2 activation via A-1396076 is a promising therapeutic strategy for autoimmune diseases.
- The mechanism involves inhibition of T cell activation and impaired antigen presentation.
- Prophylactic administration is key for efficacy in T cell-dependent autoimmune conditions.
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