Exogenous and endogenous tumour necrosis factor therapy.

Although tumour necrosis factor (TNF) is known as a tumoricidal cytokine, it is also important in maintaining homoeostasis in living organisms by inducing an inflammation-like state. We consider that this monokine may also regulate ontogenesis in animals, because we found that a considerable amount of TNF is secreted by mouse embryonal cells at various stages of development. We named the inflammation-like state in which the TNF concentration was high 'ontogenic inflammation'. Induction of endogenous TNF in the adult body as in ontogenic inflammation should restore homoeostasis in patients suffering from chronic diseases including tumours. We have established several methods for inducing sufficient endogenous TNF to cause tumour regression in patients. For more efficient tumour therapy by ontogenic inflammation, the localization of TNF around tumour lesions was found to be critical. By using a newly constructed rTNF-S, which, like endogenous TNF, has a broader cytotoxic spectrum and fewer side effects than conventional rTNF, we developed a new therapy--exogenous/endogenous TNF therapy (EET therapy). With this therapy, exogenous and endogenous TNF can be targeted to and localized in tumours where they act synergistically. Our results suggest that ontogenic inflammation may be important, even in adults, for maintaining homoeostasis. The appropriate application of ontogenic inflammation should also be effective in treating other diseases, such as rheumatism.