Activation and increased expression of adhesion molecules on peripheral blood lymphocytes is a mechanism for the immediate lymphocytopenia after administration of OKT3.
We investigated the mechanism by which antihuman CD3 monoclonal antibodies of the isotypes IgG2a (eg, OKT3) and IgA (eg, IXA) can induce the rapid disappearance of virtually all circulating T lymphocytes. We hypothesize that upregulation of adhesion molecules on the lymphocyte membrane contributes to this effect. However, this hypothesis is difficult to test, because of the inherent lymphocytopenia and/or shifts in lymphocyte populations between intra and extra-vascular compartments. Therefore, studies in vitro were performed, as well. Analysis of peripheral blood lymphocytes isolated at several times after addition of OKT3 or IXA to whole blood of healthy individuals showed an immediate increase in the proportion of T cells expressing NKI-L16, an activation epitope on CD11a/CD18. Likewise, an increase in CD11b/CD18 expression occurred. In parallel experiments, a transiently increased adhesion of T cells to endothelial cell monolayers was observed. This adhesion could be completely blocked by anti-CD18 or anti-CD11a monoclonal antibodies and only partly by an anti-CD11b antibody. Our data indicate that upregulation of activation epitopes of CD11a/CD18, as well as increased expression of CD11b/CD18 on T lymphocytes, may result in increased adhesion of these cells to intercellular adhesion molecule-1 (ICAM-1) and ICAM-2 on vascular endothelium. This phenomenon may, at least, partly explain the rapidly occurring peripheral lymphocytopenia observed in vivo.
University of Amsterdam, Department of Internal Medicine, The Netherlands.
S
S
Buysmann
F J
FJ
Bemelman
P T
PT
Schellekens
Y
Y
van Kooyk
C G
CG
Figdor
I J
IJ
ten Berge
D000328:Adult; D015703:Antigens, CD / Q000378:metabolism; D018821:CD18 Antigens / Q000096:biosynthesis; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000096:biosynthesis* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005260:Female; D006084:Graft Rejection / Q000517:prevention & control; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D016030:Kidney Transplantation; D019041:L-Selectin / Q000096:biosynthesis; D008231:Lymphopenia / Q000139:chemically induced*; D016177:Macrophage-1 Antigen / Q000096:biosynthesis; D008297:Male; D008775:Methylprednisolone / Q000627:therapeutic use; D008875:Middle Aged; D016853:Muromonab-CD3 / Q000009:adverse effects / Q000494:pharmacology*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
D015703:Antigens, CD; D018821:CD18 Antigens; D015815:Cell Adhesion Molecules; C065289:ICAM2 protein, human; D007166:Immunosuppressive Agents; D016177:Macrophage-1 Antigen; D016853:Muromonab-CD3; D018799:Intercellular Adhesion Molecule-1; D019041:L-Selectin; D008775:Methylprednisolone