title: Protection from articular damage by passive or active anti-tumour necrosis factor (TNF)-α immunotherapy in human TNF-α transgenic mice depends on anti-TNF-α antibody levels.
abstract: Active anti-tumour necrosis factor (TNF)-α immunization with the kinoid of TNF-α (TNF-K) induces polyclonal anti-TNF-α antibodies and ameliorates arthritis in human TNF-α (hTNF-α) transgenic mice (TTg). We compared the efficacy of TNF-K to that of infliximab (IFX) and of TNF-K and IFX co-administration, and evaluated whether the titres of anti-hTNF-α antibodies induced by immunization were a determinant of TNF-K efficacy. Forty-eight TTg mice received one of the following treatments: TNF-K immunization (TNF-K group); weekly IFX throughout the study duration (IFXw0-15); TNF-K plus weekly IFX for 4 weeks (TNF-K + IFX); and weekly IFX for 4 weeks (IFXw0-4); PBS. Animals were killed at week 16. Anti-hTNF-α antibody titres and clinical and histological scores were compared. All TNF-K immunized mice (TNF-K and TNF-K + IFX) produced anti-hTNF-α antibodies. Titres were higher in TNF-K versus TNF-K + IFX (P < 0·001) and correlated inversely with histological inflammation (R = -0·78; P = 0·0001) and destruction (R = -0·67; P = 0·001). TNF-K + IFX had higher histological inflammation and destruction versus TNF-K (P < 0·05). A receiver operating characteristic (ROC) analysis of anti-hTNF-α antibody titres identified the criterion cut-off value to discriminate most effectively between the TNF-K and TNF-K + IFX groups. Mice with high versus low titres had less histological inflammation and destruction (P < 0·05). In a model of TNF-α-dependent arthritis, protection from articular damage by TNF-K correlates with the titres of induced anti-hTNF-α antibodies. The co-administration of TNF-K and a short course of infliximab does not result in less articular damage versus solely TNF-K, due probably to lower anti-hTNF-α antibody production. These results are relevant for future development of active anti-TNF-α immunization in human disease.
authors.affiliation: Université Paris-13 Sorbonne Paris Cité, EA4222, Paris, France. luca.semerano@avc.aphp.fr
authors.forename: L
authors.initials: L
authors.lastname: Semerano
authors.forename: J
authors.initials: J
authors.lastname: Biton
authors.forename: L
authors.initials: L
authors.lastname: Delavallée
authors.forename: E
authors.initials: E
authors.lastname: Duvallet
authors.forename: E
authors.initials: E
authors.lastname: Assier
authors.forename: N
authors.initials: N
authors.lastname: Bessis
authors.forename: E
authors.initials: E
authors.lastname: Bernier
authors.forename: O
authors.initials: O
authors.lastname: Dhellin
authors.forename: G
authors.initials: G
authors.lastname: Grouard-Vogel
authors.forename: M-C
authors.initials: MC
authors.lastname: Boissier
mesh_terms: D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology; D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D002358:Cartilage, Articular / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D004338:Drug Combinations; D007116:Immunization, Passive; D016233:Immunotherapy, Active; D000069285:Infliximab; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D012372:ROC Curve; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000276:immunology; D014611:Vaccination
chemical_list: D000906:Antibodies; D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D004338:Drug Combinations; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab