Hypothermia and hypoglycemia induced by anti-CD3 monoclonal antibody in mice: role of tumor necrosis factor.
The possible involvement of tumor necrosis factor-alpha (TNF) in the metabolic disturbances induced by anti-CD3 monoclonal antibodies (mAb) was analyzed in DBA/2 mice injected with 50 micrograms of the anti-murine CD3 mAb 145-2C11. First, we found that 145-2C11 induces a profound hypothermia maximal between 3 h and 6 h after the injection (at 3 h: -3.0 +/- 0.1 degrees C) as well as hypoglycemia (blood glucose levels at 6 h and 24 h: 76 +/- 13 mg/100 ml and 92 +/- 22 mg/100 ml, respectively, p less than 0.001 as compared with control values). These metabolic changes are preceded by the release of TNF into the circulation (peak serum TNF levels at 2 h: 50 +/- 23 pg/ml, p less than 0.01 as compared with controls). The release of TNF induced by 145-2C11 depends on the effect of the mAb on T cells as it is not observed in athymic nude mice while lipopolysaccharide-resistant C3H/HeJ mice also display a significant rise in serum TNF (peak levels at 2 h: 59 +/- 44 pg/ml). Pretreatment of DBA/2 mice with 12 mg of rabbit anti-murine TNF antibodies completely prevents the hypothermia while the hypoglycemia is significantly attenuated. Finally, F(ab')2 fragments of 145-2C11 induce only a transient hypoglycemia (blood glucose levels at 6 h: 109 +/- 14, p less than 0.001 as compared with controls) but neither hypothermia nor significant TNF release. We conclude that TNF is a major mediator of the acute metabolic changes induced by the intact form of 145-2C11.
Alegre
M
M
Laboratoire Pluridisciplinaire de Recherche Expérimentale Biomédicale, Université Libre de Bruxelles, Belgium.
Vandenabeele
P
P
Flamand
V
V
Moser
M
M
Leo
O
O
Abramowicz
D
D
Urbain
J
J
Fiers
W
W
Goldman
M
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology*; D017252:CD3 Complex; D007003:Hypoglycemia / Q000209:etiology*; D007035:Hypothermia / Q000209:etiology*; D051379:Mice; D008815:Mice, Inbred Strains; D008819:Mice, Nude; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; D011948:Receptors, Antigen, T-Cell; D014409:Tumor Necrosis Factor-alpha