Treatment of mice with anti-CD3 mAb induces endothelial vascular cell adhesion molecule-1 expression.
In vivo treatment of mice with anti-CD3 mAb causes polyclonal T cell activation and cytokine release. Since several cytokines are known to alter expression of MHC molecules and adhesion molecules on endothelia, we hypothesized that anti-CD3 mAb treatment should result in activation of vascular endothelia. In previous studies, we established that vascular endothelial cells in murine heterotopic cardiac grafts can develop at least 2 stable inflammatory phenotypes: cardiac allograft endothelia characteristically develop reactivity with MECA-32 mAb (undefined endothelial epitope) and M/K-2 mAb (murine vascular cell adhesion molecule-1 [VCAM-1]), whereas cardiac isografts develop reactivity with MECA-32, but not M/K-2 mAb. We now report that a single treatment of cardiac isograft recipients with the anti-CD3 mAb 145-2C11 caused expression of VCAM-1 on all cardiac isograft endothelia, including the microvascular endothelia. In contrast, expression of endothelial VCAM-1 in the native heart of the isograft recipient was limited to patchy areas of larger arteries. This patchy, arterial pattern of VCAM-1 expression was observed in lung, liver, kidney, and thymus of all mice treated with 145-2C11, whether or not they were implanted with a cardiac isograft, and was dissociated from expression of MECA-32 mAb reactivity. Hence, treatment of mice with anti-CD3 mAb causes systemic endothelial activation (VCAM-1 expression), and endothelial cells of recently implanted cardiac isografts appear to be hypersensitive to induction of VCAM-1 by anti-CD3 mAb treatment. Further studies showed that (1) treatment with 145-2C11 F(ab)'2 fragments did not induce endothelial activation, (2) intravenous pretreatment with pentoxifylline eliminated all endothelial effects of 145-2C11 treatment, (3) induction of endothelial activation by 145-2C11 mAb always paralleled the expression of adverse physiologic symptoms, and (4) mice exhibit strain-specific differences in endothelial responses to 145-2C11 treatment. We propose that anti-CD3 mAb treatment causes simultaneous activation of circulating T cells and systemic vascular endothelial cells which may facilitate systemic lymphocyte-endothelial interactions, and may explain the rapid disappearance of T cells from the circulation that is associated with anti-CD3 treatment in mouse and man.
Bergese
S D
SD
Department of Surgery, Ohio State University College of Medicine, Columbus 43210.
Pelletier
R P
RP
Ohye
R G
RG
Vallera
D A
DA
Orosz
C G
CG
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D017252:CD3 Complex / Q000276:immunology*; D015815:Cell Adhesion Molecules / Q000502:physiology*; D004730:Endothelium, Vascular / Q000737:chemistry / Q000166:cytology*; D005260:Female; D016027:Heart Transplantation / Q000276:immunology; D008213:Lymphocyte Activation / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008819:Mice, Nude; D013601:T-Lymphocytes / Q000276:immunology; D019010:Vascular Cell Adhesion Molecule-1
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D015815:Cell Adhesion Molecules; D019010:Vascular Cell Adhesion Molecule-1