This laboratory focuses on the role of cytokine mediators in clinical conditions of importance in caring for the cancer surgical patient. Using a specific polyclonal rabbit antibody to murine tumor necrosis factor-alpha (TNF), we had previously demonstrated that TNF was partially responsible for the severe toxicity associated with interleukin-2 (IL-2) immunotherapy in mice. In a recent series of survival experiments with mice bearing pulmonary metastases, we show that TNF is also partially responsible for the anti-tumor efficacy of IL-2 therapy. The ubiquitous important nature of host-produced TNF was further demonstrated in a series of experiments with oxygen toxicity. Alveolar macrophages produced TNF in response to toxic amounts of inhaled oxygen. Antibodies to TNF protected against the toxic effect of oxygen. A specific polyclonal antibody to murine interferon-gamma (IFN) protected mice against the lethal effect of endotoxin (LPS) and also blocked the lethality and anti-tumor effects of high-dose TNF. Differentiation factor (D-factor) also called leukemia inhibitory factor, is a glycoprotein produced by macrophages in response to LPS. As we had previously demonstrated for TNF and IL-1, pretreatment with D- factor protected mice against the lethal effects of LPS. Unlike what has been seen with TNF and IL-1, the protective effects of D-factor were synergistic with small doses of TNF and IL-1. Work in progress demonstrates that a specific antibody to D-factor is also protective against the lethality of LPS.
