A NONCOMPETITIVE P55 TNF RECEPTOR ANTIBODY ENHANCES THE SPECIFIC ACTIVITY OF LYMPHOTOXIN-ALPHA

In the present study the authors elucidated the involvement of the two TNF receptors (TNFR) in discriminating TNF and lymphotoxin-alpha (LT- alpha) effects in human SW480-beta Gal and KYM-1 cell lines. A non-com petitive p55 TNFR monoclonal antibody (MoAb) 44E strongly enhanced LT- alpha-mediated gene regulation and cytotoxicity up to the level of the responses caused by TNF. TNF-induced biological responses were only w eakly influenced by 44E. 44E did not affect both binding and the rate of dissociation of the cytokines. The combination of the two p55 TNFRM oAb 44E and Htr5 elicited strong TNF responses, while none of them wer e agonistic alone. When the p75 TNFR was blocked with Utr1, LT-alpha w as still less potent than TNF in mediating CMV promoter activation and cytotoxicity. However, the addition of 44E in the presence of Utr1 me rged the LT-alpha dose-response curves with those obtained with TNF pl us Utr1. Using antagonistic TNFR MoAb, the authors further showed that TNF functions through both TNFR types while LT-alpha mediates its eff ects largely via the p55 TNFR. These data suggest that LT-alpha is les s potent than TNF due to its lower ability to properly trigger the p55 TNFR and because of its lack of signalling through the p75 TNFR.