The experimental (in vitro) and clinical (in vivo) immunosuppressive effects of a rat IgG2b anti-human CD2 mAb, LO-CD2a/BTI-322.
BACKGROUND
CD2 is a cell surface glycoprotein expressed on most human T cells and natural killer (NK) cells, working as a cell adhesion and costimulatory molecule. The aim of this paper is to analyze the mechanism of action of a rat IgG2b anti-human CD2 monoclonal antibody (mAb) (LO-CD2a/BTI-322 mAb), which is a potent immunosuppressive agent and inducer of cell death. In vivo, this mAb is able to prevent or treat kidney allograft rejection.


METHODS
The mechanisms by which the LO-CD2a/BTI-322 mAb is able to induce inhibition of cell activation and cell death were analyzed by mixed lymphocyte reactions and by flow cytometry. After in vivo treatment, levels of circulating mAb were measured by ELISA as well as anti-rat immunization and cytokine release.


RESULTS
We show that the inhibition of cell activation induced by LO-CD2a/BTI-322 mAb after allogeneic or OKT3 stimulation is due to an Fcgamma receptor-dependent CD2 down-modulation and to T-cell depletion through an antibody-dependent cell-mediated cytotoxicity mechanism mediated by NK cells or activated monocytes. Peripheral T- and NK-cell depletion was observed after in vivo treatment with LO-CD2a/BTI322. Cytokine release (TNFalpha) was correlated with some side effects, but only after the first injection, and the effects were never severe or life threatening.


CONCLUSIONS
The correlation between the in vitro and in vivo data suggests that T-cell depletion, especially of activated cells, and inhibition of cell activation after CD2 down-modulation are the main mechanisms of action of the LO-CD2a/BTI-322 mAb.
Nizet
Y
Y
Experimental Immunology Unit, School of Medicine, University of Louvain, Brussels, Belgium.
Chentoufi
A A
AA
de la Parra
B
B
Lewalle
P
P
Rouas
R
R
Cornet
A
A
Besse
T
T
Mourad
M
M
Malaise
J
J
Squifflet
J P
JP
Bazin
H
H
Latinne
D
D
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects / Q000502:physiology; D018801:CD2 Antigens / Q000032:analysis / Q000187:drug effects / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D015536:Down-Regulation; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007166:Immunosuppressive Agents / Q000276:immunology / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D018655:Lymphocyte Count / Q000187:drug effects; D009000:Monocytes / Q000502:physiology; D016853:Muromonab-CD3 / Q000494:pharmacology; D051381:Rats; D017452:Receptors, IgG / Q000502:physiology; D012397:Rosette Formation; D013601:T-Lymphocytes / Q000166:cytology
D000911:Antibodies, Monoclonal; D018801:CD2 Antigens; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; C105249:LO-CD2a; D016853:Muromonab-CD3; D017452:Receptors, IgG