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factor is ROR-γt, which has been shown to be sufficient for Th17 cell dif-
ferentiation and whose function is modified by interactions with Runx1,
which can act in concert with ROR-γt to activate IL-17 gene expression [95] .
The role of ROR-γt in GVHD pathogenesis has been examined using geneti-
cally modified animals that lack either T-bet or ROR-γt or both transcrip-
tion factors [96] . In these studies, ROR-γt −/− T cells and wild-type T cells
had comparable abilities to cause GVHD, whereas T-bet −/− T cells were less
pathogenic, and mice transplanted with these cells had attenuated GVHD
and improved survival. The results in this model system suggested a pre-
dominant role for Th1 versus Th17 cells in GVHD induction. Importantly, T
cells deficient for both ROR-γt and T-bet induced minimal GVHD, with all
recipient mice surviving long term with only moderate weight loss. Con-
sistent with these observations, pathologic examination of GVHD target
organs revealed significantly reduced pathology scores in recipients trans-
planted with ROR-γt −/− /T-bet −/− T cells compared to recipients of wild-
type and ROR-γt −/− T cells, suggesting that T-bet and ROR-γt are required
for GVHD induction in vivo. Furthermore, the absence of T-bet and ROR-
γt was associated with a significant reduction in absolute numbers of Th1
and Th17 cells in GVHD target tissues, whereas there was a corresponding
increase in Treg reconstitution. However, even with combined deficiency of
T-bet and ROR-γt in donor T cells, recipient mice were not completely free
of GVHD. This is similar to prior studies using IFN-γ −/− IL-17 −/− animals, in
which GVHD could still be mediated through Th2 pathways [62] . A major
caveat from these studies, however, is that there are other immune popula-
tions that are regulated by the expression of ROR-γt. In particular, innate
lymphoid cells and natural killer (NK)-like cells have been shown to be
ROR-γt + [97] . Thus, one cannot strictly equate ROR-γt + cells with Th17 cells.
The interpretation of these studies therefore needs to be qualified with the
understanding that other ROR-γt + cells, in addition to Th17 cells, may play a
role in mediating GVHD pathophysiology.
284
Role of IL-17 and Th17 cells in clinical GVHD
A strong association of IL-17 and Th17 cells with human inflammatory
diseases has been well documented. For example, in psoriasis, it has been
shown that skin biopsies from patients express high levels of IL-17, IL-23,
and IL-22. In fact, the beneficial effect of TNF inhibition in patients with this
disease was associated with reduced Th17 responses [98] . In human rheu-
matoid arthritis (RA) patients, expression of IL-17 in RA synovium biopsies
was associated with increased severity of the disease and joint damage [99] .
When biopsy samples from patients with Crohn's disease were analyzed,
IL-17 and IL-23 were found to be overexpressed in disease lesions [100] .
These data demonstrate that Th17 cells are present in situ in human inflam-
matory diseases.
The role of Th17 cells in patients with GVHD has not been as well studied
and still remains unclear. Ratajczak and colleagues have performed the
most extensive analysis to date, with approximately 100 patients in three
separate cohorts [101] . In the first cohort, they found an increased percent-
age of CD4 + FOXP3 + Tregs, but a decreased percentage of CD4 + IL-17 + Th17
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