Anti-IL-23 therapy inhibits multiple inflammatory pathways and ameliorates autoimmune encephalomyelitis

Area of Science:

• Immunology
• Neuroscience
• Autoimmune Diseases

Background:

• Interleukin-23 (IL-23) is a cytokine linked to pathogenic T cells driving autoimmune diseases.
• IL-23-dependent T cells produce IL-17 A, IL-17 F, IL-6, and TNF, but not IFN-gamma or IL-4.
• T-bet and STAT1 are not essential for initial IL-17 production, but T-bet is optimal for IL-23-stimulated IL-17 production.

Purpose of the Study:

• To investigate the clinical efficacy of targeting the IL-23 immune pathway.
• To determine if blocking IL-23 function with anti-IL-23p19 antibodies can inhibit experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis.

Main Methods:

• Generation of anti-IL-23p19-specific antibodies.
• Testing the efficacy of anti-IL-23p19 antibodies in a preclinical EAE animal model.
• Measurement of cytokine and mRNA levels (IL-17, IFN-gamma, IP-10, IL-6, TNF) in serum and CNS.
• Assessment of proteolipid protein (PLP) epitope spreading and disease relapse.

Main Results:

• Anti-IL-23p19 treatment significantly reduced serum IL-17 levels.
• CNS expression of IFN-gamma, IP-10, IL-17, IL-6, and TNF mRNA was decreased by anti-IL-23p19 treatment.
• Therapeutic intervention during active EAE inhibited PLP epitope spreading and prevented disease relapse.

Conclusions:

• Targeting IL-23 via anti-IL-23p19 antibodies is a viable therapeutic strategy for autoimmune diseases.
• Blocking IL-23 effectively inhibits multiple inflammatory pathways crucial for central nervous system (CNS) autoimmune inflammation.
• This approach shows promise for treating conditions like multiple sclerosis by reducing inflammation and preventing disease recurrence.