In vivo soluble tumor necrosis factor receptor release in OKT3-treated patients. Differential regulation of TNF-sR55 and TNF-sR75.
Administration of monoclonal antibodies to CD3 triggers acute and massive release of several cytokines, including tumor necrosis factor alpha (TNF-alpha), essentially T cell-derived. This cytokine release is responsible for the spontaneously reversible acute clinical syndrome observed in most OKT3-treated patients. We found that the first OKT3 injection in human renal allograft recipients led to the release in significant amounts of soluble TNF receptors (TNF-sR55 and TNF-sR75) that are considered main natural inhibitors of TNF bioactivity. As for OKT3-induced TNF-alpha, peak TNF-sR levels were observed 1 hr postinjection, and this release was limited to the first monoclonal antibody injection. A distinct regulation of OKT3-mediated release of TNF-sR75 and TNF-sR55 was observed, since (1) in clear contrast with OKT3-mediated TNF-sR75 induction, TNF-sR55 release was completely blocked by a high dose of corticosteroids prior to OKT3 injection and (2) secretion of TNF-sR75 but not TNF-sR55 correlated with immunoreactive TNF-alpha release. In hemodialyzed patients prior to transplantation and OKT3 treatment, a condition characterized by chronic TNF-alpha release, TNF-sR efficiently block TNF bioactivity. In contrast, the system is overwhelmed by the massive acute TNF-alpha release that follows the first OKT3 injection: in such a condition TNF-sR looses its capacity to counteract TNF bioactivity.
Herbelin
A
A
U 25 INSERM, Association, Claude Bernard, Hôpital Necker, Paris, France.
Chatenoud
L
L
Roux-Lombard
P
P
De Groote
D
D
Legendre
C
C
Dayer
J M
JM
Descamps-Latscha
B
B
Kreis
H
H
Bach
J F
JF
D000305:Adrenal Cortex Hormones / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000961:Antilymphocyte Serum / Q000494:pharmacology; D001682:Biological Availability; D004797:Enzyme-Linked Immunosorbent Assay; D006084:Graft Rejection / Q000517:prevention & control; D006801:Humans; D016030:Kidney Transplantation / Q000276:immunology; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D012995:Solubility; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism / Q000493:pharmacokinetics
D000305:Adrenal Cortex Hormones; D000911:Antibodies, Monoclonal; D000961:Antilymphocyte Serum; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha