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Production of Tumor Necrosis Factor in Nude Mice by Muramyl Peptides Associated with Bacterial Vaccines¹

Department of Pharmacology and Therapeutics, College of Medicine, University of South Florida, Tampa, Florida 33612 [Y. N., L. C.], and Laboratory of Immunopharmacology, C. N. R. S. UA-579, Institut Biomedical des Cordeliers, 75270 Paris 06, France [M. P., F. P.]

Gram-negative vaccines can elicit the production of tumor necrosis factor (TNF) in mice primed by muramyl dipeptide (MDP) or by its lipophilic derivative MDP-dipalmitoyl glycerol (MDP-GDP). In mice pretreated with MDP and particularly with MDP-GDP, Bordetella pertussis vaccine was shown to be more effective than typhoid vaccine. The time course of TNF production in the blood did not indicate any difference between the effect of MDP or of MDP-GDP. In both cases the cytotoxic activity reached maximal levels by 2 h after injection of the bacterial preparations and returned to normal values between 3 and 5 h after the challenge. In nude mice, high titers of circulating TNF were also produced by combined treatment with MDP-GDP and bacterial vaccine. Moreover, in tumor-bearing mice the association of MDP or of MDP-GDP to a bacterial vaccine induced a strong hemorrhagic necrosis, whereas each treatment alone was inactive. It was also found that mice were less sick when they were primed with MDP-GDP than with MDP, and when TNF was elicited by B. pertussis instead of lipopolysaccharide. Moreover, nude mice appeared more resistant to shock and to hemoconcentration than normal mice.

¹ This work was supported in part by a grant from the American Cancer Society (IM-506).

² To whom requests for reprints should be addressed, at H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, P.O. Box 280179, Tampa, FL 33682-0179.

Received 3/17/88. Revised 6/ 8/88. Accepted 7/15/88.