Active immunization to tumor necrosis factor-alpha is effective in treating chronic established inflammatory disease: a long-term study in a transgenic model of arthritis.
BACKGROUND
Passive blockade of tumor necrosis factor-alpha (TNF-alpha) has demonstrated high therapeutic efficiency in chronic inflammatory diseases, such as rheumatoid arthritis, although some concerns remain such as occurrence of resistance and high cost. These limitations prompted investigations of an alternative strategy to target TNF-alpha. This study sought to demonstrate a long-lasting therapeutic effect on established arthritis of an active immunotherapy to human (h) TNF-alpha and to evaluate the long-term consequences of an endogenous anti-TNF-alpha response.


METHODS
hTNF-alpha transgenic mice, which spontaneously develop arthritides from 8 weeks of age, were immunized with a heterocomplex (TNF kinoid, or TNF-K) composed of hTNF-alpha and keyhole limpet hemocyanin after disease onset. We evaluated arthritides by clinical and histological assessment, and titers of neutralizing anti-hTNF-alpha antibody by enzyme-linked immunosorbent assay and L929 assay.


RESULTS
Arthritides were dramatically improved compared to control mice at week 27. TNF-K-treated mice exhibited high levels of neutralizing anti-hTNF-alpha antibodies. Between weeks 27 and 45, all immunized mice exhibited symptoms of clinical deterioration and a parallel decrease in anti-hTNF-alpha neutralizing antibodies. A maintenance dose of TNF-K reversed the clinical deterioration and increased the anti-hTNF-alpha antibody titer. At 45 weeks, TNF-K long-term efficacy was confirmed by low clinical and mild histological scores for the TNF-K-treated mice. Injections of unmodified hTNF-alpha did not induce a recall response to hTNF-alpha in TNF-K immunized mice.


CONCLUSIONS
Anti-TNF-alpha immunotherapy with TNF-K has a sustained but reversible therapeutic efficacy in an established disease model, supporting the potential suitability of this approach in treating human disease.
Delavallée
Laure
L
EA4222, Li2P, University of Paris 13, 74 rue Marcel Cachin, 93000, Bobigny, France. laure.delavallee@univ-paris13.fr
Semerano
Luca
L
Assier
Eric
E
Vogel
Géraldine
G
Vuagniaux
Grégoire
G
Laborie
Marion
M
Zagury
Daniel
D
Bessis
Natacha
N
Boissier
Marie-Christophe
MC
D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood / Q000276:immunology*; D001169:Arthritis, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology* / Q000494:pharmacology
D057134:Antibodies, Neutralizing; D014409:Tumor Necrosis Factor-alpha