Biology Reference
In-Depth Information
Although a bivalent anti-CD28 mAb provides a costimulation to T cells
in vitro,
several of those mAbs were as immunosuppressive as the B7
blockade in rodent models of GVHD
[20,29]
and therefore behaved like
antagonists. These Abs actually induced
in vivo
a selective depletion of T
lymphocytes that recognized alloantigens by an IFN-γ-dependent apop-
tosis mechanism
[30]
. They could enhance T-cell migration
in vitro
and
induce the migration of memory but not naïve T cells to extralymphoid
tissue independent of TCR-derived signals or homing receptors
[31]
. The
mouse anti-rat CD28 mAb JJ319 was reported to stimulate T-lymphocyte
activation
in vitro,
but it down-modulated the CD28 receptor on the T-cell
surface and acted as an antagonist
in vivo
. Consequently, JJ319 was func-
tionally antagonist
in vivo
and efficient in GVHD by blocking the expansion
of alloreactive T cells and promoting their apoptosis after a few divisions
[32,33]
.
SUPERAGONISTIC ANTI-CD28 ABS
Inhibition of GVHD with anti-CD28 mAb proved to be superior to the treat-
ment with anti-B7 Ab. To add complexity to the involvement of the CD28
pathway in GVHD, studies have also utilized superagonistic anti-CD28 Abs,
which were defined by their capacity to cause a strong activation and prolif-
eration of naïve T lymphocytes in the absence of antigenic stimulation
[23]
.
These molecules reduce GVHD mostly by preferential targeting of Tregs over
conventional T cells, thus preserving the GVT reaction
[34,35]
. A combina-
tion of CD28 stimulation plus rapamycin was also shown to prevent acute
GVHD in animal models, confirming previous data suggesting that Tregs
require CD28 costimulation to maintain their suppressive functions
[36]
.
200
The clinical translation to block the B7/CD28/CTLA4 pathway for the treat-
ment of GVHD in humans has been scarce, partially because of the com-
plexity of this system and limited availability of clinical-grade reagents. One
proof-of-concept study demonstrated that pretreatment of donor marrow
with CTLA4-Ig during
ex vivo
culture with irradiated mononuclear cells
from the patient reduced the risk of acute GVHD after haploidentical BMT
[37]
. The rationale of this approach was to induce anergy of the alloreactive
donor T cells, while preserving the GVT effect.
B7h/ICOS pathway
The inducible costimulator (ICOS) is a CD28 homolog and is expressed in
activated CD4
+
and CD8
+
T cells
[38,39]
. The ICOS ligand, known as B7h or
B7RP-1, is structurally related to B7 molecules but does not bind to either
CD28 or CTLA4. B7h is expressed at low levels on B cells, dendritic cells,
macrophages, and parenchymal cells including vascular endothelial cells,
but its expression is rapidly upregulated by inflammatory cytokines such as
IFN-γ and TNF-α and by CD28 costimulation
[39]
. Analogous to the YMNM
motif on CD28, ICOS contains a YMFM motif that is phosphorylated upon
ligation and activates PI3-kinase
[40]
. A 2009 study provided evidence that
ICOS can execute its function beyond activation of PI3-kinase
[41]
. Engage-
ment of ICOS by B7h enhances T-cell proliferation and cytokine production
preferentially in Th2 polarization
[42]
. CD28 and ICOS play distinct roles in
T-cell differentiation, with the CD28 signal responsible for T-cell activation
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