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without significant GVHD or toxicities. New techniques of Treg expansion
[78]
now allow the production of sufficient functional Treg for clinical use.
NKT CELLS
A second inhibitory population shown to inhibit acute GVHD lethality is the
NKT subset that co-expresses NK and T-cell surface determinants
[79]
. In
rodents, total lymphoid irradiation combined with anti-thymocyte globulin has
been shown to induce host NKT cells that also promote the generation of Tregs
and the production and release of anti-inflammatory cytokines
[80]
. In HSCT
human recipients, studies indicate that the reduced acute GVHD lethality seen
despite the infusion of high numbers of T cells contained in a G-CSF mobilized
PB stem cell graft is associated with increased donor NKT cells
[81,82]
.
TH17 CELLS
Th17 cells (reviewed in chapter 13 and in reference
[83]
) have recently
emerged as a new player in GVHD. Although the role of this new T-cell sub-
set has been dissected in certain experimental models including inflamma-
tory bowel disease, lung and skin GVHD, experimental GVHD studies have
led to seemingly discordant GVHD lethality results that may be ascribed to
distinct differences in experimental GVHD conditions
[84-86]
. As yet the
role of Th17 cells in humans is uncertain
[87]
.
9
T-cell trafficking
How T cells are recruited into tissues could be pivotal for understanding
the stereotypical involvement of skin, liver and bowel in GVHD. While the
migration of T cells into secondary lymphoid organs during GVHD and other
inflammatory responses has been well characterized, the migration of leu-
kocytes into parenchymal organs is less well understood. This process may
involve changes in vascular permeability and, in certain systems, has been
shown to require specific selectin-ligand, chemokine-receptor and integ-
rin-ligand interactions (reviewed in chapter 16 and in reference
[13]
). Dur-
ing a GVHD reaction, donor T cells initially migrate to spleen and peripheral
lymphoid tissues within hours
[88]
. Naïve donor T cells traffic to lymphoid
tissues, where the subset of alloreactive T cells receive activation signals by
APCs, and then subsequently migrate to specific GVHD target organ sites,
essential for the induction and pathogenesis of acute GVHD
[89]
. Almost all
tissues express transplantation antigens; however, acute GVHD pathology is
primarily limited to only a few locations rich in epithelial cells and express-
ing high levels of MHC antigens - gut, skin, liver, lung, secondary lymphoid
organs and thymus. The ability of alloreactive donor T cells to home to spe-
cific organs is regulated by a unique combination of signals that bind to cor-
responding receptors on host tissues and counter-receptors expressed on
donor T cells, including members of the chemokine family. MIP1a and other
chemokines (such as CCL2-CCL5, CXCL2, CXCL9, CXCL10, CXCL11, CCL17
and CCL27) are over-expressed during GVHD generation and can enhance
the homing of cellular effectors to GVHD target organs.
These results suggest that strategies that influence T-cell migration, particu-
larly to GVHD target organs, may offer promise for reducing GVHD target
organ specific injury, although the redundancy of chemokines and their
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