Endogenous production of cytotoxic factors in serum of BCG-primed mice by monophosphoryl lipid A, a detoxified form of endotoxin.

Monophosphoryl lipid A (MPL), a detoxified form of endotoxin, was evaluated for its ability to elicit cytotoxic factors in the serum of mice pretreated with BCG. BDF1 mice were given a priming dose of bacillus Calmette-Guerin (BCG) intravenously (i.v.). Two weeks later, these mice were challenged with MPL i.v. and their serum was tested for cytotoxicity against Lewis lung carcinoma cells growing in culture. A well-tolerated dose of MPL induced substantial serum cytotoxic activity comparable to that found after a toxic dose of endotoxin. The effective dose of MPL for eliciting serum cytotoxicity was 20 times less than the toxic dose of MPL in BCG-primed mice. No serum cytotoxicity was induced by MPL without prior treatment with BCG or in mice exposed to BCG for less than 10 days. The i.v. route of administration was superior to intraperitoneal, intrapleural, or subcutaneous routes for both BCG priming and induction of serum activity with MPL. Serum manifested TNF-like activity in that it was heat-stable, not species-specific, more effective against tumor than normal cell lines, and more effective against a TNF-sensitive than a TNF-resistant cell line. We conclude that MPL is an effective, well-tolerated biological response modifier that triggers production of cytotoxic factors in serum of mice with an activated reticuloendothelial system.