Biology Reference
In-Depth Information
CTLA4-deficient mice show a profound post-thymic, hyperproliferative
phenotype leading to death within 3 weeks of age, which is due to massive
tissue infiltration and organ destruction
[8,9]
.
The contribution of the B7/CD28/CTLA4 pathway in GVHD has been
extensively studied in animal models. Experimental studies have shown
that proinflammatory signals generated following conditioning treatment
upregulate B7-1 and B7-2 expression in GVHD target tissues, providing
the rationale for the CD28/B7 pathway blockade in GVHD treatment. One
reagent that has been widely used to block CD28 costimulation is CTLA4-Ig,
a recombinant fusion protein containing the extracellular domain of CTLA4
linked to an IgG Fc portion. CTLA4-Ig acts as a competitive antagonist of
CD28/B7 interactions, as CTLA4 has a much higher binding affinity to B7
molecules than does CD28
[5,10]
. In
in vitro
studies using mixed-lympho-
cyte reaction assay, CTLA4-Ig could completely block T-cell proliferation
and effector function in response to alloantigen stimulation
[11]
. In
in vivo
studies using rodent bone marrow transplant (BMT) models, treatment
with CTLA4-Ig was able to alleviate GVHD, but the inhibition of GVHD was
far from complete
[12]
. Similar results were also obtained using blocking
monoclonal antibodies (mAbs) against both B7-1 and B7-2
[13-15]
. Those
studies also showed that expression of B7-1 on donor CD4
+
T cells was criti-
cal for GVHD development, and hence treatment with anti-B7 mAbs also
contributed to reducing GVHD not only by targeting B7 expression on the
APCs but also by a direct effect on CD4
+
T cells.
198
It is clear that B7/CD28 interactions are required for optimal GVL activ-
ity, because B7-1 expression on leukemic cells greatly enhanced the gen-
eration of leukemia-reactive cytotoxic T lymphocytes (CTL)
in vitro,
and
the B7 blockade
in vivo
significantly reduced the GVL activity medicated
by delayed lymphocyte infusion (DLI)
[14]
. One other study showed
that treatment with anti-B7 mAbs maintained the GVL effect in a sub-
lethally irradiated transplantation model
[16]
, which was probably due to
incomplete inhibition of alloresponse. In contrast, selective blockade of
B7/CTLA4 interactions significantly enhanced the GVL activity medi-
ated by DLI
[17]
. Further evidence shows that donor CTLA4 genotype also
affects the GVL activity in the clinic after allogeneic HCT
[18]
.
Because GVHD treatment based upon B7 blockade was far from satisfac-
tory, more studies focused on CD28. By using CD28-deficient mice, our
group and Blazar's showed that CD28
−/−
T cells had reduced ability in the
induction of acute GVHD, providing evidence that CD28 contributes to
the pathogenesis and severity of GVHD. Subsequently, both groups clearly
demonstrated that CD28 signals amplify GVHD, while CTLA4 signals inhibit
GVHD, providing evidence that selective targeting of CD28 may be a better
therapeutic strategy for inducing immunological tolerance than blocking
the ligands for both CD28 and CTLA4
[17,19,20]
. In this scenario, preferen-
tial blocking or selective targeting of CD28 has been proposed and evalu-
ated. Belatacept, a second-generation CTLA4-Ig, binds CD80 2-fold better
and CD86 4-fold better than the parent CTLA4-Ig and shows a 10-fold more
potent inhibition of T-cell activation
in vitro
versus the parent CTLA4-Ig
[21]
. In clinical trials, Belatacept has shown considerable promise in renal
transplantation as part of a maintenance immunosuppression regimen
[22]
. Thus, the efficacy of Belatacept in the prevention of GVHD waits to be
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