Modification of the anti-CD3-induced cytokine release syndrome by anti-interferon-gamma or anti-interleukin-6 antibody treatment: protective effects and biphasic changes in blood cytokine levels.
Anti-interferon-gamma (IFN-gamma) 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-gamma antibody-treated mice, IFN-gamma 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-gamma response coincided with more profound hypoglycemia. Tumor necrosis factor and interleukin (IL)-6 levels were not affected by anti-IFN-gamma treatment. Exogenous IFN-gamma, 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-gamma. 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-gamma 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.
Matthys
P
P
Laboratory of Immunobiology, Rega Institute, University of Leuven Medical School, Belgium.
Dillen
C
C
Proost
P
P
Heremans
H
H
Van Damme
J
J
Billiau
A
A
D000818:Animals; D000906:Antibodies / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology*; D006224:Cricetinae; D016207:Cytokines / Q000097:blood* / Q000378:metabolism; D007003:Hypoglycemia / Q000209:etiology; D007035:Hypothermia / Q000209:etiology; D007371:Interferon-gamma / Q000276:immunology / Q000502:physiology*; D015850:Interleukin-6 / Q000276:immunology / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D016853:Muromonab-CD3 / Q000276:immunology* / Q000633:toxicity; D013045:Species Specificity; D013577:Syndrome
D000906:Antibodies; D017252:CD3 Complex; D016207:Cytokines; D015850:Interleukin-6; D016853:Muromonab-CD3; D007371:Interferon-gamma