ENDOGENOUS D-FACTOR ACTIVITY PARTIALLY MEDIATES THE TOXIC BUT NOT THETHERAPEUTIC EFFECTS OF TUMOR-NECROSIS-FACTOR

We have earlier shown that passive immunization against differentiatio n-inducing factor/leukemia-inhibitory factor (D factor) activity impro ves the survival of endotoxemic mice, suggesting that D factor may con tribute to the systemic toxicity associated with tumor necrosis factor (TNF). In the current experiments, TNF induced D-factor gene expressi on in various tissues of non-tumor-bearing female C57B1/6 mice. passiv e immunization against D-factor significantly improved survival after a lethal TNF challenge in both non-tumor-bearing (p(2) < 0.02) and tum or-bearing mice (p(2) < 0.01). In mice bearing 10-day s.c. MCA 105 sar comas, D-factor antibody alone had no effect on tumor growth as compar ed with control IgG. Tumor regression and regrowth in mice treated i.v . with TNF was not affected by pre-treatment with D-factor antibody, a s compared with pre-treatment with IgG. However, TNF-treatment-related mortality was abrogated by pre-treatment with D-factor antibody (0% v s. 36% for IgG-pre-treated controls). These results indicate that endo genous D-factor activity contributes to the toxicity but not to the an ti-tumor effects of TNF therapy. With renewed interest in the use of T NF for the treatment of patients with cancer, improved understanding o f the role of D factor in mediating the effects of TNF may have import ant clinical benefits. (C) 1995 Wiley-Liss, Inc.