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facilitated full engraftment of donor hematopoietic cells and mediated
the GVL effect without causing severe acute GVHD [74] . These results
suggest that in vivo engagement of CD40 and possibly other costimula-
tory molecules may be used as a GVHD prophylaxis in the nonirradiated
parent-into-F1 HCT setting.
In many murine models of solid organ transplantation, blockade of the
CD40/CD154 pathway using an anti-CD154 mAb (MR1) has proven to be
highly effective in prolonging survival of heart, kidney, and islet allografts
[75] . While the potency of CD40/CD154 blockade in rodent models held
great promise for translating this strategy to the clinic, the disappoint-
ment lay in the high incidence of thromboses associated with anti-CD154
treatment in both primate studies and phase I clinical trials [76] . The unex-
pected complication is probably due to the expression of CD154 on plate-
lets, which promotes platelet aggregation when bound by anti-CD154 mAb
[77] . Thus, plans for future development of anti-CD154 mAbs in the clinic
have been replaced with the development of anti-CD40 mAbs in an attempt
to circumvent problems associated with anti-CD154 [78] .
In the comparison of the blockade of the CD40L versus the CD28 pathway,
studies have shown that anti-CD40L was similar to or more effective than anti-
B7 in the reduction of GVHD. However, anti-CD40L had a deleterious effect
on the GVL activity in contrast to anti-B7 mAbs blocking CD28. The inhibition
of the GVL effect was probably due to the inhibitory effects on Th1 and cyto-
toxic T cells [16] . Given the predominant roles of the CD40/CD40L and B7/
CD28 pathways in T-cell costimulation, additional studies aimed to evaluate
combinational effects of the two pathways in BMT. GVHD induced by CD28-
deficient T cells was significantly improved by treatment with anti-CD40L
[79] . Coadministration of CTLA4-Ig and anti-CD40L was more advantageous
than either treatment alone in the reduction of GVHD severity [73] . Further-
more, the coblockade of the B7 and CD40 pathways together with Sirolimus
significantly improved GVHD after haploidentical BMT in rhesus macaques
[80] . These studies provide evidence to support nonredundant roles of these
two pathways in T-cell pathogenesis under allogeneic BMT in mice.
204
OX40/OX40L pathway
OX40 (CD134) is a member of the TNFR family and is abundantly expressed
on activated but not resting T cells. Its ligand, OX40L, is expressed prefer-
entially on APCs such as B cells, dendritic cells (DCs), macrophages, and
other cell types including Langerhans cells, endothelial cells, mast cells,
and NK cells, suggesting that OX40/OX40L interactions can be involved in
many aspects of physiological responses between T cells and lymphoid and
nonlymphoid cells [81] . Costimulatory signals from OX40 to conventional
T cells promote division and survival and augment the clonal expansion of
effector and memory populations as they are being generated in response
to antigen [82] . Signaling through OX40 promotes T-cell proliferation and
cytokine secretion and induces Th1 and Th2 differentiation and develop-
ment into memory cells [83] . In line with these important modulatory func-
tions, OX40/OX40L interactions have been found to play a central role in the
development of multiple inflammatory and autoimmune diseases, making
them attractive candidates for intervention in the clinic [84] .
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