T-cell costimulation in graftversus- host disease and graft-versus-leukemia effect - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 198

and the ICOS signal responsible for certain effector functions [43,44] . Unlike
CD28, ICOS does not play a significant role the generation, maintenance, or
function of Tregs [45] .

In allogeneic BMT settings, an initial study using a parent-into-F1 nonirra-
diated mode showed that blocking ICOS interaction with an ICOS-specific
Ab reduces chronic GVHD by selectively suppressing the Th2 cytokines [15] .
Using myeloablative full MHC-mismatched BMT models, Taylor et al. [46]
found that ICOS blockade, achieved with ICOS −/− mice or anti-ICOS mAb
administration, resulted in significant inhibition of GVHD by reducing the
number of alloantigen-specific effector cells. Results from a separate group
indicated that ICOS blockade reduced GVHD while largely sparing GVL
activity by skewing toward Th2 differentiation, without affecting T-cell acti-
vation, proliferation, cytotoxicity, or target organ infiltration [47] . The studies
by our own group indicate that ICOS deficiency or blockade results in signifi-
cantly less GVHD morbidity and delayed mortality [19,48] . The effect of ICOS
is predominately on CD4 + T cells, and the deficiency of ICOS had no impact
on their expansion but significantly reduced their effector functions in terms
of expression in FasL and production of IFN-γ and TNF-α. Although ICOS
blockade significantly reduces acute GVHD mediated by CD4 + or total T cells,
we observed that ICOS −/− CD8 + T cells exhibited enhanced GVHD morbid-
ity and accelerated mortality associated with elevated expansion and type 1
cytokine production of CD8 + T cells, urging caution in blocking ICOS in CD8-
mediated GVHD [48] .

201

Because of interactions between the B7h/ICOS and the B7/CD28/CTLA4
pathways and the nonredundant role of CD28 and ICOS in T-cell costimula-
tion, strategies combining blockade of ICOS and CD28 have been proposed
[49] . Nanji et al. showed that combination therapy with anti-ICOS and
CTLA4-Ig prolonged islet allograft survival more significantly than either
therapy alone [50] . In allogeneic BMT settings, our study provided direct
evidence to support the blocking of CD28 and ICOS signals with sparing of
CTLA4 signals as an effective approach to prevent GVHD through manipu-
lation of the CD28 family of costimulatory molecules in vivo [19] . A more
selective CD28 blockade, rather than a B7 blockade (e.g., Belatacept and
nonactivating CD28-specific antibodies), has been produced [21,51] , and
a fully humanized antibody against human ICOS has been generated [52] .
These reagents can be used in the translation of the research findings into
clinical practice in allogeneic HCT.

PDL/PD-1 pathway

Programmed death-1 (PD-1) belongs to the CD28 family and shares ~20%
homology with CTLA4. PD-1 is expressed on activated CD4 + and CD8 + T
cells as well as on activated NK cells, B cells, and myeloid cells. Two ligands
interact with PD-1: PD-L1 (B7-H1), a member of the B7 family, is expressed
on dendritic cells and activated T cells; PD-L2 (B7-DC), is expressed on
resting monocytes. Both ligands are expressed in some nonhematopoietic
tissues, including heart, lung, kidney, pancreas, placenta, and endothelial
cells [53] .

PD-1 engagement inhibited proliferation and cytokine production by
CD4 + and CD8 + T cells after antigen stimulation in vitro, and the inhibitory