Anti‐interferon‐γ (IFN‐γ) antibodies were found to protect mice against pathological changes induced by injection of anti‐CD3 antibody: incidence of diarrhea, severity of hypothermia and mortality rates were dramatically reduced. In anti‐IFN‐γ antibody‐treated mice, IFN‐γ blood levels were significantly reduced at 1.5 h post anti‐CD3 challenge, but more elevated levels were found from 4 to 24 h. This rebound‐like IFN‐γ response coincided with more profound hypoglycemia. Tumor necrosis factor and interleukin (IL)‐6 levels were not affected by anti‐IFN‐γ treatment. Exogenous IFN‐γ, administered within 3 h (but not later) of the anti‐CD3 challenge made the syndrome worse. Furthermore, inter‐mouse strain differences in sensitivity to the anti‐CD3 syndrome correlated with the ability of the strain to produce IFN‐γ. Anti‐IL‐6 antibodies provided only marginal protection against hypothermia and mortality, but did markedly reduce hypoglycemia. Levels of biologically active IL‐6 in serum were not influenced by anti‐IL‐6 antibody treatment during the first few hours after anti‐CD3 challenge, but were significantly increased at later times.

The data provide evidence that endogenous IFN‐γ is a critical element in the early phase of the anti‐CD3 syndrome; endogenous IL‐6, while possibly being involved in hypoglycemia, seems of lesser importance for the outcome of the syndrome.