Improvement of collagen-induced arthritis by active immunization against murine IL-1beta peptides designed by molecular modelling.
Interleukin-1beta (IL-1beta) is a crucial cytokine in inflammation processes and has been implicated in the pathogenesis of several chronic inflammatory diseases. Strategies designed to blocking IL-1beta by passive administration of inhibitors (mAbs, IL-1 receptor antagonist) have previously demonstrated efficacy in rheumatoid arthritis (RA). Using molecular modelling, we have defined three murine IL-1beta peptide regions characterized by their close proximity to the receptor. Synthetic peptides corresponding to these regions, in cyclic and linear form, were delivered as immunogens in Swiss mice, resulting in significant levels of autoantibodies directed against the native murine IL-1beta cytokine as determined by ELISA and by an assay for neutralization of IL-1beta biological activity. More importantly, one of the cyclic peptides showed a protective effect against inflammation and articular destruction in DBA/1 mouse collagen-induced arthritis, a model of RA. The high rate of success observed for active immunization against cytokine peptides in vivo suggests that the in silico approach to autoantigen design may be a promising avenue for the development of anti-cytokine immunotherapeutics.
Bertin-Maghit
Sébastien M
SM
Laboratoire d' Oncologie Moléculaire, 2 place Jussieu, Tour 53, 75005 Paris, France.
Capini
Christelle J
CJ
Bessis
Natacha
N
Chomilier
Jacques
J
Muller
Sylviane
S
Abbas
Aïcha
A
Autin
Ludovic
L
Spadoni
Jean-Louis
JL
Rappaport
Jay
J
Therwath
Amu
A
Boissier
Marie-Christophe
MC
Zagury
Jean-François
JF
D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D001842:Bone and Bones / Q000187:drug effects* / Q000473:pathology; D003094:Collagen; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000008:administration & dosage* / Q000737:chemistry; D007596:Joints / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008811:Mice, Inbred DBA; D008958:Models, Molecular; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry; D012795:Sialoglycoproteins / Q000494:pharmacology
C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D010455:Peptides; D012795:Sialoglycoproteins; D003094:Collagen