In vivo imaging of graftversus-host disease and graftversus-leukemia - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 69

An additional imaging study provided further evidence of the importance
of cell adhesion and rolling in the intestines during GVHD [89] . In this
study, intravital fluorescence microscopy of colonic microcirculation was
conducted on adoptively transferred rhodamine-labeled CD8 + T cells in
a murine GVHD model. By using antibodies against P-selectin, E-selectin
and P-selectin glycoprotein ligand 1 (PSGL-1), it was observed that block-
ing P-selectin and PSGL-1 reduced rolling and adhesion in inflamed colonic
venules by more than 71%, while inhibition of E-selectin had no effect.
Therefore, inhibition of the P-selectin/PSGL-1 interaction could be another
potential therapy for GVHD.

Fluorescence imaging evaluation of strategies to reduce
GVHD and retain GVT

As discussed above, leukocyte adhesion and rolling plays an important role
in GVHD pathogenesis in the intestine (see section “Fluorescence imaging
of GVHD” above). Castor et al. have demonstrated a novel way to reduce
leukocyte adhesion and improve survival after GVHD induction [90] . A
chemokine, CCL3 (MIP-1α), recruits T cells to GVHD target organs in the
final phase of GVHD (i.e. target tissue infiltration and damage) [91] . Che-
mokine-binding proteins (CBPs) derived from ticks, termed evasins, have
very specific chemokine-binding affinities. Because evasin-1 had been
shown to inactivate CCL3 [92] and it can decrease the adhesion, rolling and
transmigration of leukocytes [93] , Castor et al. administered evasin-1 in a
mouse model of GVHD. They found, via intravital immunofluorescence
microscopy of GFP + splenocytes, that 20 days after GVHD induction, there
was a marked increase in the number of leukocytes adhering to intestinal
venules in mice with GVHD over healthy controls. The treatment of GVHD
with evasin-1 thus greatly reduced leukocyte adhesion and decreased mor-
tality from the disease. The improvement in survival with evasin-1 treat-
ment also correlated with histological findings which indicated a significant
preservation of the serous and muscular layers of the intestine. Fortunately,
the GVL activity of infused splenocytes of a GFP + tumor line was unaffected
by evasin-1 treatment. Together this study demonstrated the importance of
CCL3 in GVHD and the therapeutic potential of evasin-1 in neutralizing this
cytokine and reducing GVHD.

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Inducible costimulator (ICOS) belongs to the CD28 superfamily and reacts
to its ligand, ICOSL (a.k.a. B7h), which is present on macrophages, dendritic
cells and B cells, and can be upregulated in response to TNF-α, which is
usually produced during GVHD [94] . Since it is thought that ICOS may have
involvement in T-cell priming and early activation [95] , Taylor et al. evalu-
ated the effects of an ICOS blockade on GVHD induction [96] . By imaging
GFP + effector T cells at 1 and 2 weeks after GVHD induction, they found
anti-ICOS Ab treatment to profoundly reduce the infiltration of T cells in
the small intestine (ileum) and skin, but little differences in lymph nodes,
spleen or other GVHD target tissues. The anti-ICOS treatment also signifi-
cantly increased mean survival times in multiple strain combinations, even
when it was administered 5 days after transplantation. These data suggest
that ICOS stimulation may have differential effects on T-cell homing, in
addition to its effects on T-cell activation and expansion, and that interrup-
tion of ICOS/ICOSL interactions may be another strategy to reduce GVHD.