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Immune interferon, available at high specific activity through recombinant DNA technology, is known to activate macrophages to intra- and extracellular cytotoxicity. We now report that murine recombinant IFN-gamma activates macrophages to cytotoxicity also when applied in vivo. Furthermore, recombinant IFN-gamma can protect mice in vivo against the intracellular bacterial pathogen Listeria monocytogenes in a local as well as in a systemic infection model. The role of T lymphocyte-produced lymphokines in acquired resistance to facultative intracellular pathogens and their possible involvement in novel immunotherapy are discussed.

Priming of macrophages from both murine and human sources by recombinant immune interferons from Escherichia coli (r-IFN-gamma s) and activation by lipopolysaccharide (LPS) resulted in the production of tumor necrosis factor (TNF). r-IFN-gamma alone did not induce TNF production by macrophages; for this to occur, the second signal provided by small amounts (nanograms) of LPS was required. The small amounts of LPS alone were insufficient to activate the macrophages for TNF production. Priming by r-IFN-gamma was not necessary when larger amounts of LPS were employed, although an enhancement of yield resulted. Priming could also be demonstrated in vivo. Inoculation of r-IFN-gamma into mice resulted in increased yields of TNF following LPS challenge 12 hours later.

A syngeneic model system for the study of tumor metastases and cell-mediated immunity is described. The system consists of two related, chemically induced murine lymphomas, the non-metastasizing parental line Eb and i t s metastasizing variant ESb. A n unrelated, chemically induced tumor (MDAY) i s included for specificity controls. Serological typing revealed that both Eb and ESb were of T lymphoid origin and expressed the H-2K and H-2D molecules of the host strain DBA/2. By various electron microscope techniques, morphological differences were observed between the t w o cell lines. I n comparison t o Eb cells, ESb tumor cells had a more polymorphic nucleus with many invaginations of the nuclear envelope and a more prominent expression of microvilli on the cell surface. A n in vitro organ culture test for tumor invasiveness, presented here for the f i r s t t i m e In a syngeneic murine system, revealed that ESb but not Eb tumor cells had the ability t o attach t o and invade normal tissue. Accordingly, ESb tumor cells showed higher malignancy in vivo. This was apparent from their higher tumorigenicity and their ability t o disseminate and metastasize and t o kill recipient mice more quickly. Upon histological examination of the local primary tumors a striking difference was noticed with regard t o the degree of infiltration by host-derived mononuclear cells, mostly histiocytes. The non-metastasizing tumor Eb was heavily infiltrated while tumor ESb contained only a few of these cells. The differences between the tumor lines ESb and Eb are considered i n the light of their possible relevance for metastases in general. The etiology of the t w o tumors i s discussed in particular with respect t o their relatedness.Metastasis, the spread of malignant cells from a primary site to distant organs, represents one of the most intriguing problems in the pathogenesis and treatment of cancer (see Willis, 1973;Fidler and Kripkie, 1977; Carter, 1978). While primary tumors in many instances can be removed surgically it is the subsequent development of metastases which often cannot be prevented and is responsible for most therapeutic failures (Krokowski, 1978). In spite of its importance, relatively little is known about the processes which either lead to or prevent formation of tumor metastases. One reason for this is that experimental tumors in animals are often not suitable for the study of metastasis: they either do not metastasize or they grow so fast that they kill the host before metastases can develop (Kim, 1970;Mellgren, 1976 The majority of experimental tumors induced by either tumor viruses or chemical carcinogens and maintained by long-term transplantations usually express immunogenic tumor-associated transplantation antigens (TATA) against which syngeneic animals can be successfully immunized. When similar immunization procedures were applied to humans, a significant protective effect was observed only occasionally (see Terry and Windhorst, 1978). The meager success in cancer patients of specific immunotherapy prot...