A HUMAN TUMOR-NECROSIS-FACTOR P75 RECEPTOR AGONIST STIMULATES IN-VITRO T-CELL PROLIFERATION BUT DOES NOT PRODUCE INFLAMMATION OR SHOCK IN THE BABOON

Tumor necrosis factor (TNF) is a potentially useful adjunct to antican cer therapies. However, the clinical utility of TNF has been limited b y generalized toxicity and hypotension. Recently, studies have begun t o dissect the individual proinflammatory and immunologic responses tha t result from TNF binding to its two cellular receptors, p55 and p75, in an attempt to develop TNF receptor agonists with reduced systemic t oxicity. To evaluate a p75 receptor selective TNF mutant (p75TNF), TNF and p75TNF were administered to healthy anesthetized baboons. Intrave nous infusion of the p75TNF produced nolle of the hemodynamic changes seen after the infusion of TNF. Infusion of p75TNF also failed to indu ce the plasma appearance of interleukins 6 and 8. However, p75TNF enha nced in vitro baboon thymocyte proliferation to concanavalin A, and in fusion of p75TNF resulted in increased soluble p55 and p75 receptor pl asma concentrations. Local skin necrosis and tissue neutrophil infiltr ation were seen after subcutaneous injections of TNF and p55TNF. Subcu taneous injection of p75TNF did not result in skin necrosis but did re sult in a modest dermal infiltration of lymphocytes and macrophages. T he findings suggest that p75TNF may stimulate T cell proliferation wit hout the systemic and local toxicity seen with TNF.