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significant reduction of GVHD symptoms and improvement in survival
(compared to the addition of IL-2 or RAPA individually).
BLI evaluation of strategies to reduce GVHD and retain or
enhance GVL
As entry into secondary structures is crucial for the activation and prolifera-
tion of alloreactive T cells, studies have suggested that other populations
of T cells might have variable access to these sites, and as a result, differ in
their ability to induce GVHD
[23,69,70]
. For instance, unlike naïve T cells
which readily induce GVHD, CD4
+
CD44
hi
CD62L
low
memory T cells can
improve immune reconstitution and GVL activity without causing much
GVHD
[69,70]
. We have shown via BLI that this is due to a lack of memory
cell infiltration and proliferation in secondary lymph nodes
[23]
. Similarly,
memory CD8
+
CD44
hi
cells were found to cause less GVHD than CD8
+
CD44
lo
naïve cells
[71]
. In both memory and naïve CD8 populations, luc
+
CD8
+
T
cells migrated to lymph nodes and spleen by day 3, followed by migration
to the gut and skin by day 5. The signals generated from CD8
+
CD44
hi
cells,
however, were significantly lower (~7-fold) than their naïve counterparts.
In this model, CD8
+
CD44
hi
cells were just as effective at eradicating a luc
+
B-cell lymphoma (BCL-1) as CD8
+
CD44
lo
T cells.
67
Another T-cell population, know as cytokine-induced killer (CIK) cells, can
be generated from either peripheral blood mononuclear cells in humans
or splenocytes in mice by culturing cells in the presence of anti-CD3 mAb,
IL-2, and IFN-γ
[72]
. The result is a population in which most of the cells
express both NK and T-cell markers that can exert a graft-versus-tumor
(GVT) effect after HCT in rodent models
[73]
. CIKs have a limited capac-
ity to induce GVHD, which is (at least partially) due to their production of
IFN-γ
[74]
. BLI studies of CIK cells in two different murine models of murine
allogeneic HCT have shown that CIK expand and proliferate in GVHD target
organs, although at a rate far less than an equivalent number of
luc
+
sple-
nocytes from the same donor strain
[75]
. This was possible even without
the addition of exogenous IL-2, an essential cytokine for CIK grown
in vitro
.
Additionally, we could visualize with BLI both a tissue-specific homing of
CIK cells to tumor sites and NKG2D-mediated killing of the tumors
[75]
.
NK cells have been shown to not have the capacity to induce GVHD, but
can have GVL effects
[76-78]
. Using NK cells isolated from
luc
+
C57BL/6
mice, it was demonstrated that NK cells display a similar migration pattern
to that of CD4
+
and CD8
+
T cells, although they did not persist as long
[79]
.
Specifically, BLI from NK cells first appeared in lymph nodes and spleen
in the first 3 days after allogeneic transplantation, followed by migration
to the abdomen by day 6. NK cells also upregulate the gut-homing recep-
tor, α4β7, and the skin-homing receptor, P-selectin. Also similar to T cells,
NK cell homing to lymph nodes could by reduced by treatment with anti-
CD62L Ab, and CD62L is downregulated on the NK cells following activa-
tion. As IL-2 is important for the activation and function of NK cells
[80]
,
IL-2 was administered to facilitate expansion of NK cells. Not only was IL-2
effective in increasing the expansion of NK cells
in vivo
, it also enhanced the
GVL activity of the transplanted NK cells against a
luc
+
A20 B cell lymphoma
[79]
. In a subsequent study
[81]
, it was determined that NK cells could also
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