Human hyperimmune globulin protects against the cytotoxic action of staphylococcal alpha-toxin in vitro and in vivo.
Alpha-toxin, the major cytolysin of Staphylococcus aureus, preferentially attacks human platelets and cultured monocytes, thereby promoting coagulation and the release of interleukin-1 and tumor necrosis factor. Titers of naturally occurring antibodies in human blood are not high enough to substantially inhibit these pathological reactions. In the present study, F(ab')2 fragment preparations from hyperimmune globulin obtained from immunized volunteers were tested for their capacity to inhibit the cytotoxic action of alpha-toxin in vitro and in vivo. These antibody preparations exhibited neutralizing anti-alpha-toxin titers of 80 to 120 IU/ml, whereas titers in commercial immunoglobulin preparations were 1 to 4 IU/ml. In vitro, the presence of 2 to 4 mg of hyperimmune globulin per ml protected human platelets against the action of 1 to 2 micrograms of alpha-toxin per ml. Similarly, these antibodies fully protected human monocytes against the ATP-depleting and cytokine-liberating effects of 0.1 to 1 microgram of alpha-toxin per ml. Intravenous application of 0.5 mg (85 to 120 micrograms/kg of body weight) of alpha-toxin in cynomolgus monkeys elicited acute pathophysiological reactions which were heralded by a selective drop in blood platelet counts. Toxin doses of 1 to 2 mg (170 to 425 micrograms/kg) had a rapid lethal effect, the animals presenting with signs of cardiovascular collapse and pulmonary edema. Prior intravenous application of 4 ml of hyperimmune globulins per kg inhibited the systemic toxic and lethal effects of 1 mg (200 micrograms/kg) of alpha-toxin. In contrast, normal human immunoglobulins exhibited no substantial protective efficacy in vitro and only marginal effects in vivo. It is concluded that high-titered anti-alpha-toxin antibodies effectively protect against the cytotoxic actions of alpha-toxin.
Institute of Medical Microbiology, University of Giessen, Federal Republic of Germany.
S
S
Bhakdi
U
U
Mannhardt
M
M
Muhly
F
F
Hugo
H
H
Ronneberger
K D
KD
Hungerer
D000818:Animals; D001427:Bacterial Toxins / Q000633:toxicity*; D001685:Biological Factors / Q000378:metabolism; D001792:Blood Platelets / Q000276:immunology / Q000502:physiology; D002478:Cells, Cultured / Q000276:immunology; D004211:Disseminated Intravascular Coagulation / Q000097:blood / Q000401:mortality / Q000517:prevention & control; D006460:Hemolysin Proteins; D006801:Humans; D007116:Immunization, Passive / Q000379:methods; D007074:Immunoglobulin G / Q000502:physiology* / Q000627:therapeutic use; D008252:Macaca fascicularis; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D015846:Monokines; D010974:Platelet Aggregation; D013211:Staphylococcus aureus / Q000276:immunology*
D001427:Bacterial Toxins; D001685:Biological Factors; D006460:Hemolysin Proteins; D007074:Immunoglobulin G; D015846:Monokines; C021091:staphylococcal alpha-toxin