PRODUCTION OF TUMOR-NECROSIS-FACTOR BY HUMAN-CELLS IN-VITRO AND IN-VIVO, INDUCED BY GROUP-B STREPTOCOCCI

Tumor necrosis factor alpha (TNFalpha) has been implicated as one of t he major mediators of the gram-negative septic shock syndrome. In our studies, group B streptococci (GBS) induced the production of TNFalpha by human mononuclear cells in a dose- and time-dependent manner. Huma n mixed mononucleor cell cultures exposed to an encapsulated (657.6 +/ - 71.3 pg/ml; n = 30 preparations) or an unencapsulated transposon mut ant of type III GBS (755.8 +/- 54.7 pg/ml; n = 9) produced similar amo unts of TNFalpha. Isolated monocytes and culture-derived macrophoges p roduced higher amounts of TNFalpha (1565 +/- 211 and 1790 +/- 928 pg/m l respectively) in response to GBS than did mixed mononuclear cell cul tures. In response to GBS, mixed mononuclear cells from neonates produ ced significantly more TNFalpha (729.1 +/- 45 vs 520.3 +/- 47.2 pg/ml; p = 0.004) than did cells from adults. Examination of specimens from patients with neonatal GBS disease revealed detectable levels of TNFal pha (7 to 424 pg/ml) in the serum of 5 of 10 patients with sepsis, in 5 of 5 urine samples from infants with sepsis, and in the cerebrospina l fluid of 1 patient with meningitis. These results suggest both a maj or role for TNFalpha in the pathogenesis of human neonatal GBS sepsis and shock and a potential role for immunotherapy directed against this cytokine in this fulminant neonatal bacterial infection.