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Department of Environmental and Molecular Toxicology and Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331
CD154 (CD40 ligand, gp39) interaction with its receptor CD40 has
been shown to be critically important for the generation of
cell-mediated as well as humoral immunity. It has been proposed that
ligation of CD40 on APCs, presumably by activated Th cells, leads to
increased APC function as defined by up-regulation of costimulatory
molecules and enhancement of IL-12 production. In this report, we
directly examined the contribution of the CD154:CD40 pathway in a
murine model of allograft rejection. Generation of both the CTL and
alloantibody responses following injection with allogeneic P815 tumor
cells was severely compromised in CD154 knockout mice and wild-type
C57BL/6 mice treated with the anti-CD154 mAb, MR1. Splenic
production of IL-2, IFN-
, and TNF was significantly suppressed from
CD154-deficient mice, indicating a lack of T cell priming. However,
splenic cells from CD154 knockout mice induced comparable levels of
CD86 expression and IL-12 production when compared with their wild-type
littermates. The treatment of CD154-/- mice with the
agonistic anti-CD40 mAb, FGK45, generated activated APCs yet failed
to restore either the CTL or alloantibody responses to P815. Likewise,
immunization with B7-transfected P815 tumor cells failed to generate
expansion of the CTL effector population in CD154-/-
mice. These results suggest that the generation of allograft immunity
is dependent on the interaction of CD154 with CD40 but not primarily
for the activation of APCs.
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