Tumor Necrosis Factor a Potency Efficacy Noncorrelation

Anti-TNF therapy of inflammatory (112), oncological (113), and autoimmune

(114) diseases illustrates a complex scenario in which in vitro and in vivo data sometimes seem to contradict one another. For example, in a recent study by Egberts et al., although inhibition of TNF-a with infliximab or etanercept only marginally affected proliferation and invasiveness of pancreatic ductal adeno-carcinoma cells in vitro, both reagents exerted strong antitumoral effects in vivo

(115). Noncorrelation was also observed by Teng et al., who demonstrated that TNF-producing and TNF-nonproducing tumor cells grow at similar rates in vitro but form different-sized tumors in vivo (116). The authors proposed several explanations for this lack of correlation, including the possibility that tumor cells when grown in vivo, rather than in vitro, were directly susceptible to the secreted TNF or that secondary mediators induced by TNF had an effect on the tumor cells (116). Alternatively, the mechanism of inhibition could be indirect and related to TNF effects on the blood vessels or other nonmalignant stromal components, including inflammatory cells that may be activated by TNF to destroy the tumor (116). Earlier work by Bromberg et al. addressed the discrepancy between the in vivo and in vitro activities of anti-TNF antiserum by proposing the following three possibilities: (i) TNF is important for in vivo cellular communication, but different arrays of cells and cytokines juxtaposed in culture are able to activate cells in the relative absence of TNF, (ii) low-level TNF-TNF receptor interactions may be of higher affinity than the Ab and override the inhibitory effect, and/or (iii) TNF is most important during priming events, therefore anti-TNF will be most effective during the afferent, priming events in immunity (which are strongly inhibited in vivo) that encompasses initial, low-affinity interactions with Ag; conversely, most in vitro assays represent secondary or high-affinity primary responses that seem to produce either relatively low quantities of TNF and/or other cytokines that can activate T cells in the absence of TNF, including IL-1a and IL-6 (117). In contrast to all of the above noncorrelative studies, Waterston et al. employed the B16F10 murine melanoma model to investigate the role of TNF in promoting metastasis (118). TNF autovaccination was able to generate high-titer anti-TNF autoantibodies whose in vitro inhibition of TNF function correlated well with in vivo inhibition of metastasis (118).

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