Active immunization against IL-23p19 improves experimental arthritis.
BACKGROUND
IL-23 is a pro-inflammatory cytokine essential for the differentiation of Th17 lymphocytes, a subtype of T lymphocyte implied in auto-immunity. IL-23 shares a subunit with IL-12, IL-12/23p40, and comprises a specific subunit, IL-23p19. We previously demonstrated that active immunization against entire TNF-α and against peptides of IL-1β was protective in animal models of rheumatoid arthritis. The aim of this study was to evaluate the effect of peptide-based vaccines targeting the IL-23p19 subunit in collagen-induced arthritis (CIA).


METHODS
Using bioinformatics, the murine IL-23p19 subunit was modeled and two peptides were defined in the receptor interacting domain. Each peptide was coupled to keyhole limpet hemocyanin (KLH) to obtain two vaccines IL23-K1 and IL23-K2. Both vaccines were used for immunizations in incomplete Freund adjuvant (IFA) in groups of DBA/1 mice. Control groups received KLH or PBS at the same dates. CIA was induced by two subcutaneous injections of bovine type II collagen (CIIb), and the development of disease assessed during the next two months. Anti-CIIb and anti-IL-23 antibody levels were assessed by ELISA. Pro- and anti-inflammatory cytokines mRNA were quantified by qRT-PCR in the spleen and the synovium. T-cell populations in the spleen were evaluated by FACS analysis.


RESULTS
The clinical scores showed that mice treated with IL23-K1 developed less arthritis than negative controls (p<0.05). Mice immunized with IL23-K1 produced more anti-IL-23 antibodies than those immunized with IL23-K2 (p<0.001). mRNA quantification showed that the IL23-K1 immunization led to an increase of IL-10 in the spleen (p<0.05 vs. KLH), without any effect on IL-17 level. Histological examination showed that IL23-K1 strongly protected against joint destruction and inflammation (p<0.01 vs. KLH and p<0.001 vs. PBS). T-cell populations in the spleen were not modified by IL-23 modulation.


CONCLUSIONS
These data show that targeting IL-23p19 through a vaccination strategy is protective in CIA. This specific targeting of IL-23 might constitute a promising therapeutic approach to explore in rheumatoid arthritis.
Équipe Génomique, Bioinformatique et Applications, Chaire de Bioinformatique, Conservatoire National des Arts et Métiers 292, rue Saint-Martin, 75003 Paris, France. rratsima@gmail.com
Rojo Anthony
RA
Ratsimandresy
Emilie
E
Duvallet
Eric
E
Assier
Luca
L
Semerano
Laure
L
Delavallée
Natacha
N
Bessis
Jean-François
JF
Zagury
Marie-Christophe
MC
Boissier
D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D000917:Antibody Formation; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000276:immunology / Q000628:therapy*; D001665:Binding Sites; D016207:Cytokines / Q000276:immunology; D005260:Female; D005620:Freund's Adjuvant / Q000494:pharmacology; D006433:Hemocyanins / Q000494:pharmacology; D053760:Interleukin-23 Subunit p19 / Q000276:immunology*; D008055:Lipids / Q000494:pharmacology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009500:Neutralization Tests; D017434:Protein Structure, Tertiary; D011817:Rabbits; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014611:Vaccination; D022223:Vaccines, Subunit / Q000276:immunology*
D057134:Antibodies, Neutralizing; D016207:Cytokines; D053760:Interleukin-23 Subunit p19; D008055:Lipids; D022223:Vaccines, Subunit; C114843:incomplete Freund's adjuvant; D005620:Freund's Adjuvant; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin