IMMUNOMODULATORY AND IMMUNOTHERAPEUTIC PROPERTIES OF RECOMBINANT GAMMA-INTERFERON AND RECOMBINANT TUMOR-NECROSIS-FACTOR IN MICE

Abstract

These studies were designed to examine the immunomodulatory and immunotherapeutic properties of recombinant murine interferon gamma (rM IFN-.gamma.) and recombinant human tumor necrosis factor (rH TNF). We report that rM IFN-.gamma. activated murine natural killer cells and macrophages in a dose-dependent manner in vivo. The rM IFN-.gamma., which demonstrated a bell-shaped therapeutic response curve, must be administered at specific doses and schedules to produce optimal therapeutic activity. Optimal activity was observed after i.v. administration of 50,000 U/animal rM IFN-.gamma. three times per week. In contrast, rH TNF produced its major therapeutic activity in the treatment of metastatic disease after i.v. but not i.p. administration. The therapeutic effects of rH TNF were as great in these in vivo systems as those of rM IFN-.gamma.. Furthermore, rH TNF had additive therapeutic activity when administered in conjunction with suboptimal doses of rM IFN-.gamma.. Unlike rM IFN-.gamma., rH TNF did not activate natural killer cells in vivo or in vitro but did augment in vivo and in vitro macrophage tumoricidal activity. It also had synergistic cytostatic properties with rM IFN-.gamma. for some murine tumor cell lines in vitro. High levels of rH TNF were readily detected in the serum with a half-life of approximately 30 min after i.v. administration. In contrast, only minimal serum TNF activity occurred after i.p. administration, suggesting that i.v. administration may more efficiently facilitate systemic therapeutic activity. In summary, rH TNF and rM IFN-.gamma. have therapeutic activity for metastatic disease as individual agents and additive therapeutic activity when used in combination. Furthermore, it appears that in addition to therapeutic potentials as cytostatic agents, the immunomodulatory properties of rH TNF have a role in its therapeutic properties.