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

Active anti-tumour necrosis factor (TNF)- immunization with the kinoid of TNF- (TNF-K) induces polyclonal anti-TNF- antibodies and ameliorates arthritis in human TNF- (hTNF-) 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- 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 (IFXw015); TNF-K plus weekly IFX for 4 weeks (TNF-K+IFX); and weekly IFX for 4 weeks (IFXw04); PBS. Animals were killed at week 16. Anti-hTNF- antibody titres and clinical and histological scores were compared. All TNF-K immunized mice (TNF-K and TNF-K+IFX) produced anti-hTNF- antibodies. Titres were higher in TNF-KversusTNF-K+IFX (P<0 center dot 001) and correlated inversely with histological inflammation (R=0 center dot 78; P=0 center dot 0001) and destruction (R=0 center dot 67; P=0 center dot 001). TNF-K+IFX had higher histological inflammation and destruction versusTNF-K (P<0 center dot 05). A receiver operating characteristic (ROC) analysis of anti-hTNF- 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 center dot 05). In a model of TNF--dependent arthritis, protection from articular damage by TNF-K correlates with the titres of induced anti-hTNF- 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- antibody production. These results are relevant for future development of active anti-TNF- immunization in human disease.