Background. Blockade of the B7/CD28 costimulation pathway with the fus
ion protein, CTLA4-Ig, has been shown to prolong allograft survival in
numerous rodent models, suggesting that this pathway is functionally
important in the allograft rejection response. This pathway is complex
and consists of at least the B7-1, B7-1a, B7-1cyt II, and B7-2 molecu
les on the antigen-presenting cell and CD28 and CTLA4 molecules on the
T cell. Methods. The intragraft transcript expression of the B7 molec
ules and their counterreceptors was defined using reverse transcriptas
e-polymerase chain reaction in the vascularized mouse cardiac allograf
t model. In addition, the functional significance of these molecules w
as investigated both in vitro in the mixed leukocyte response (MLR) an
d in vivo in the vascularized mouse cardiac allograft model. Results.
Intragraft expression of B7-1, B7-1a, B7-1cyt II, B7-2, CD28, and CTLA
4 transcripts is up-regulated in allografts when compared with both no
rmal untransplanted hearts and syngeneic transplants at between 5 and
12 days after transplant. Both anti-B7-1 and anti-B7-2 monoclonal anti
bodies alone inhibited T-cell proliferation in the MLR, however, equiv
alent maximal inhibition was obtained by a combination of these agents
or by CTLA4-Ig. Likewise, in the mouse cardiac allograft model, both
anti-B7-1 and anti-B7-2 modestly prolonged graft survival. However, an
increased survival was obtained with either a combination of anti-B7-
1 and anti-B7-2 or CTLA4-Ig. Blockade of the B7/CD28 pathway in the ML
R using T cells from CD28 knockout mice had no effect on the prolifera
tive response. Likewise, blockade of the B7/CD28 pathway did not effec
t the rate of rejection of cardiac allografts by CD28 knockout recipie
nts. Conclusions. These data suggest that both B7-1 and B7-2 have an i
mportant role in allograft rejection in the mouse vascularized cardiac
allograft model.