Biology Reference
In-Depth Information
COSTIMULATORY MOLECULES PLAY PIVOTAL ROLES IN EXPERIMENTAL GVHD
A major role for GVHD initiation in rodent models has been ascribed to CD28/
CTLA-4 (CD152):B7 interactions which consists of both a positive (CD28/B7)
and an inhibitory (CTLA-4:B7) pathway (reviewed in chapter 10). Another B7
supergene family member, ICOS (inducible costimulator) (CD278), binds the
ligand B7h (CD275) expressed on host APCs and thereby promotes T-effector
responses. Blockade or absence of ICOS on donor T cells diminishes gut and
liver GVHD
[51,52]
. Other costimulatory molecules with potent implication
in GVHD include OX40 (CD134), CD40L (CD154), 4-1BB (CD137) and gluco-
corticoid-induced tumor necrosis factor receptor (GITR).
INHIBITORY PATHWAYS THAT DOWNREGULATE GVHD
In response to tissue injury and activated T cells, inhibitory pathways are
upregulated in an attempt to protect the host against injury. CTLA-4 and pro-
grammed death-1 (PD-1; CD279) are upregulated on donor T cells during
acute GVHD and serve to dampen the immune response. Both also are pri-
marily expressed in the cytoplasm of activated T cells and CD4
+
CD25
+
Treg cells
(reviewed in references
[6,15]
). In rodents, selective blockade of CTLA-4:B7
interactions accelerated acute GVHD lethality. Thus, an ideal reagent for inhib-
iting GVHD would be one that selectively blocks CD28/B7 blockade or absence
of PD-1 on donor cells accelerates GVHD and is associated with increased IFN-
γ production
[53]
. Conversely the future development of molecules that signal
via PD-1 or its downstream pathways may prove useful in inhibiting GVHD. In
addition to surface molecules, the intracellular tryptophan catabolic pathway,
indoleamine 2,3-dioxygenase, induced by IFN-γ in GVHD target organs espe-
cially in the GI tract, diminishes T effector cell destruction via local mecha-
nisms that result in both an increased donor T-cell apoptosis and decreased
proliferation
[54-56]
. Activation of indoleamine 2,3-dioxygenase or provision
of tryptophan catabolites has been shown in rodent models to reduce GVHD.
7
Translating data on costimulatory molecules for GVHD prevention into the
clinic turns out to be much more difficult. Data on a limited number of patients
suggest that costimulatory blockade accomplished by adding CTLA4-Ig to an
in vitro
mixed lymphocyte reaction culture resulted in donor anti-host hypo-
responsive T cells that supported relatively rapid T-cell immune recovery and
a seemingly low propensity to cause acute GVHD when added to a haploi-
dentical stem cell graft
[57,58]
. More broadly directed
in vitro
methodologies
have been recently devised to depleted alloreactive T cells and such meth-
odologies have been applied to studies in a limited number of patients
[59]
.
The new CTLA4-Ig derivative of Abatacept, Belatacept, which preferentially
blocks CD28/B7 interactions, is highly efficient in the treatment of rheuma-
toid arthritis and psoriasis and in preventing acute solid organ graft rejection,
but has not been tested to date for acute GVHD prophylaxis
[60]
.
Acute GVHD and T-cell subpopulations
CONVENTIONAL T CELLS
Using new methods such as green fluorescent protein marking or biolumi-
nescence technology, it has been reported that T cells can undergo a mas-
sive and much earlier than previously thought expansion in lymph nodes
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