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. 2013 Apr;172(1):54-62.
doi: 10.1111/cei.12040.

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

L Semerano  1 , J Biton, L Delavallée, E Duvallet, E Assier, N Bessis, E Bernier, O Dhellin, G Grouard-Vogel, M-C Boissier
Affiliations

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

L Semerano et al. Clin Exp Immunol. 2013 Apr.

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.

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Figures

Figure 1
Figure 1
Study protocol and arthritis scores. All treatments were started at week 0 (black arrow). The tumour necrosis factor-α-kinoid (TNF-K) group (orange diamonds) received three immunizations with TNF-K at weeks 0, 1 and 4 of the experiment. The phosphate-buffered saline (PBS) control group (pink squares) received three injections of PBS at weeks 0, 1 and 4. The infliximab (IFX)w0–15 group (purple triangles) received weekly injections of IFX from weeks 0 to 15. The association group TNF-K + IFX (green circles) received three immunizations with TNF-K at weeks 0, 1 and 4 and weekly injections of IFX from weeks 0 to 4. The IFXw0–4 group (blue squares) received weekly injections of IFX from weeks 0 to 4. The clinical score curves report the mean ± standard error of the mean of the clinical scores for each group at each observation.
Figure 2
Figure 2
(a,b). Box-and-whisker plot with all data (arithmetic mean of all articular site scores for each mouse) plotted for each treatment group of histological inflammation (a) and destruction (b) scores [haematoxylin-eosin (HE) staining], compared for each group. All groups had lower scores than the phosphate-buffered saline (PBS) control group. The tumour necrosis factor-α-kinoid (TNF-K) group had significantly lower scores versus the PBS, infliximab (IFX)w0–4 and TNF-K + IFX groups for both inflammation and destruction scores. *P < 0·05 versus PBS; **P < 0·05 versus PBS and IFXw0–4; ***P < 0·05 versus PBS, IFXw0–4 and TNF-K + IFX. Representative examples (c–j) of histological section for each treatment group stained, respectively, with safranin O (c–f) for cartilage–proteoglycan depletion and with haematoxylin and eosin (g–j) for articular inflammation and destruction. The TNF-K and the IFXw0–15 groups show good protection from cartilage and proteoglycan depletion (c,d) and from histological inflammation (g,h). The PBS group displays marked cartilage depletion (f) and synovial inflammation and destruction (j). In some mice in the TNF-K + IFX group, moderate cartilage depletion (e) and synovial inflammation and destruction (i) were detected.
Figure 3
Figure 3
Anti-human tumour necrosis factor (hTNF-α) antibody titres in tumour necrosis factor-α-kinoid (TNF-K) (a) and TNF-K + infliximab (IFX) (b) groups as detected by enzyme-linked immunosorbent assay (ELISA). The graph shows antibody titres in the three different blood samples for each mouse. The TNF-K group had higher titres than TNF-K + IFX (P < 0·01). A receiver operating characteristic (ROC) curve analysis on the geometric mean of anti-hTNF-α antibody titres for each mouse identified the value of 4211 as the cut-off value to discriminate between the two groups (dotted line). Nine mice in the TNF-K group and four mice in the TNF-K + IFX groups had higher anti-hTNF-α titres than the cut-off.
Figure 4
Figure 4
(a,b) Tumour necrosis factor-α-kinoid (TNF-K)-treated mice [TNF-K and TNF-K + infliximab (IFX) groups]: correlation (with scatter diagram and regression line) between the geometric mean of TNF-K-induced anti-hTNF-α antibody titres and histological inflammation scores (a), and histological destruction scores (b) for each individual mouse. (c,d) IFX-only treated mice (IFXw0–15 and IFXw0–4 groups): correlation between the geometric mean of IFX trough serum levels and histological inflammation scores (c) and histological destruction scores (d) for each individual mouse.
Figure 5
Figure 5
Box-and-whisker plot with all data (arithmetic mean of all articular site scores for each mouse) plotted of histological inflammation (a) and destruction (b) scores [haematoxylin-eosin (HE) staining] categorized on the basis of anti-human tumour necrosis factor (hTNF-α) antibody production: higher (1) or lower (0) than the cut-off value of anti-hTNF-α antibody geometric mean that best allows to discriminate between TNF-K and TNF-K + infliximab (IFX) groups (4211) (see Fig. 4). Mice with higher anti-hTNF-α antibody titres had both lower inflammation and destruction scores. *P < 0·05.
Figure 6
Figure 6
Binding of infliximab to tumour necrosis factor-α-kinoid (TNF-K) (direct antigenicity).
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