In vivo T cell activation by anti-CD3 monoclonal antibody induces soluble TNF receptor release in mice. Effects of pentoxifylline, methylprednisolone, anti-TNF, and anti-IFN-gamma antibodies.
Injection of anti-CD3 is accompanied by an increase in systemic TNF, a mediator of the physiologic changes induced by anti-CD3 injection. Various mechanisms have been reported to be responsible for TNF inactivation and clearance. Recently, it has become evident that circulating soluble TNFRs (P55 and P75), which are known to increase in response to TNF inducers such as LPS, represent a natural protection mechanism against circulating TNF. Here we show that triggering the TCR by anti-CD3 injection results in a strong induction of both systemic TNF and soluble TNFR release. Maximal levels of TNF were reached after 2 h (10 ng/ml). Maximum levels of P55 (450 pg/ml) were reached between 0.5 and 8 h, whereas the highest levels of P75 were reached after 2 h (28 ng/ml). Because TNF and IFN-gamma are supposed to be involved in the pathophysiology of the anti-CD3 response, we investigated the influence of in vivo neutralization of TNF and IFN-gamma. Injection of mAb to TNF and IFN-gamma significantly reduced systemic TNF levels and both soluble TNFR levels. Two inhibitors of anti-CD3 induced TNF release; steroids and pentoxifylline both reduced TNF levels and P75 levels without affecting P55 levels. The results show that T cell activation induces both systemic TNF release and release of both soluble TNFRs. Although TNF and IFN-gamma are involved in this mechanism, their role does not seem to be crucial.
Department of Surgery, Faculty II, University of Limburg, Maastricht, The Netherlands.
M H
MH
Bemelmans
D
D
Abramowicz
D J
DJ
Gouma
M
M
Goldman
W A
WA
Buurman
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology*; D006224:Cricetinae; D005260:Female; D007371:Interferon-gamma / Q000502:physiology*; D008213:Lymphocyte Activation; D008775:Methylprednisolone / Q000494:pharmacology; D051379:Mice; D008811:Mice, Inbred DBA; D010431:Pentoxifylline / Q000494:pharmacology; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D012079:Renal Circulation; D013601:T-Lymphocytes / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D010431:Pentoxifylline; D008775:Methylprednisolone