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Blood, Vol. 94 No. 12 (December 15), 1999:
pp. 4347-4357
Downregulation of Antigen-Presenting Cell Functions After
Administration of Mitogenic Anti-CD3 Monoclonal Antibodies in Mice
Eric Muraille,
Fabienne Andris,
Bernard Pajak,
K. Martin Wissing,
Thibaut De Smedt,
Fabrice Desalle,
Michel Goldman,
Maria-Luisa Alegre,
Jacques Urbain,
Muriel Moser, and
Oberdan Leo
From the Laboratoire de Physiologie Animale, Département de
Biologie Moléculaire, Université Libre de Bruxelles,
Gosselies, Belgium; the Laboratoire d'Immunologie Expérimentale,
Hôpital Erasme, Brussels, Belgium; and the Department of
Medicine, University of Chicago, Chicago, IL.
Antibodies against CD3 are widely used as immunosuppressive
agents. Although it is generally assumed that these reagents exert
their immunomodulatory properties by inducing T-cell deletion and/or
inactivation, their precise mechanism of action remains to be
elucidated. Using a murine model, we demonstrate in this report that
administration of anti-CD3 antibodies causes the migration and
maturation of dendritic cells (DC) in vivo, as determined by
immunohistochemical analysis. This maturation/migration process was
followed by selective loss of splenic DC, which resulted in a selective
inhibition of antigen-presenting cell (APC) functions in
vitro. Spleen cells from anti-CD3-treated animals were unable to
productively stimulate naive alloreactive T cells and Th1-like clones
in response to antigen, while retaining the ability to present antigen
to a T-cell hybridoma and Th2 clones. Anti-CD3 treatment was found
to induce a selective deficiency in the ability of spleen cells to
produce bioactive interleukin-12 in response to CD40 stimulation. APC
dysfunction was not observed when nonmitogenic forms of anti-CD3
antibodies were used, suggesting that splenic DC loss was a consequence
of in vivo T-cell activation. Nonmitogenic anti-CD3 monoclonal
antibodies were found to be less immunosuppressive in vivo, raising the
possibility that APC dysfunction contributes to anti-CD3-induced
immunomodulation. Collectively, these data suggest a novel mechanism by
which mitogenic anti-CD3 antibodies downregulate immune responses.
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