Active immunization against murine TNFalpha peptides in mice: generation of endogenous antibodies cross-reacting with the native cytokine and in vivo protection.
New lines of treatment targeting cytokines have been successfully developed recently and are now widely used in therapy. They are based on passive administration of cytokine inhibitors either soluble receptors or mAbs and the major example is TNFalpha in rheumatoid arthritis (RA). Since a few years, our group has developed a novel alternative approach targeting cytokines by using active immunization against biologically inactive but immunogenic cytokine derivatives. In the present work, we present a new aspect of this research, based on immunization against specific cytokine peptides chosen by molecular modelling. We could elicit a significant humoral response against four TNFalpha peptides by active immunization, and show that the Abs generated cross-reacted with the native cytokine with good titers as determined by ELISA. Interestingly, during coimmunization experiments with couples of peptides, one showed a clear immunodominant effect over the other. Overall, we could not show the neutralization of TNFalpha biological activity in vitro by the immunized sera, but it seems that it is not a prerequisite to observe clinical efficacy. Indeed, using the LPS/galactosamine-induced shock, we could demonstrate that one of the four peptides tested conferred a clinical protection. These results validate the feasibility and efficacy of active immunization against cytokine peptides, and confirm that active immunization against cytokines could represent in the future an alternative to passive immunization in many diseases.
Capini
C J
CJ
Centre de recherche des Cordeliers, NEOVACS, Paris, France.
Bertin-Maghit
S M
SM
Bessis
N
N
Haumont
P M
PM
Bernier
E M
EM
Muel
E G
EG
Laborie
M A
MA
Autin
L
L
Paturance
S
S
Chomilier
J
J
Boissier
M-C
MC
Briand
J-P
JP
Muller
S
S
Cavaillon
J-M
JM
Therwath
A
A
Zagury
J-F
JF
D000595:Amino Acid Sequence; D000818:Animals; D019138:Antibodies, Blocking / Q000032:analysis / Q000096:biosynthesis*; D000917:Antibody Formation / Q000276:immunology; D000918:Antibody Specificity; D003429:Cross Reactions; D015195:Drug Design; D005260:Female; D005688:Galactosamine / Q000633:toxicity; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D010446:Peptide Fragments / Q000276:immunology; D012769:Shock / Q000139:chemically induced / Q000517:prevention & control; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology*
D019138:Antibodies, Blocking; D008070:Lipopolysaccharides; D010446:Peptide Fragments; D014409:Tumor Necrosis Factor-alpha; D005688:Galactosamine