Role of Th17 cells and interleukin 17 in graft-versushost disease and graft-versusleukemia reactivity - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 273

able to blunt the severity of GVHD was evidence that there was to some
extent a reciprocal regulation between IFN-γ and IL-17 and, by extension,
Th1 and Th17 cells. The concept that these two cytokines may serve to regu-
late each other was bolstered by data showing that pulmonary inflamma-
tion induced in the absence of IFN-γ results in the emergence of pathogenic
IL-17-producing CD4 + T cells [57] .

In a subsequent paper, Kappel and colleagues [58] confirmed that donor-
derived IL-17-secreting CD4 + T cells were generated early post-transplanta-
tion and that a significant percentage of them secreted both IL-17 and IFN-γ.
A new finding of this paper was that other Th17-cell-derived cytokines such
as IL-22 and IL-17F were also increased in secondary lymphoid tissue of
GVHD recipients. Notably, this was observed only early post-transplantation,
within the first 7-14 days, and was not seen in all tissue sites. Unlike the
study by Yi et al. [56] , however, there was no difference in GVHD mortal-
ity between recipients that received whole T cells from wild-type animals
and those that received cells from IL-17 −/− animals. When purified CD4 + T
cells were examined as a donor T-cell source, there was a delay noted in the
onset of mortality in recipients of IL-17-deficient grafts, but overall GVHD
mortality was unaffected. Thus, one would conclude from this work that
the absence of donor-derived IL-17 had no appreciable effect on GVHD
severity and, in particular, did not lead to an exacerbation of disease. Also,
these investigators observed that there was a significant reduction in IFN-
γ-producing CD4 + T cells, which differed from the earlier results [56] . The
reason for these disparate results is not entirely clear since a similar murine
model was employed for at least some of the studies in both of the reports.

276

An alternative approach to investigating the role of IL-17 was employed by
Carlson and colleagues, who used an in vitro culture system to generate
highly purified Th17 cells for subsequent transplantation into recipient ani-
mals [59] . By using a combination of Th17-polarizing cytokines including
TGF-β, IL-6, TNF-α, IL-1β, and anti-IL-2 and anti-IFN-γ antibodies, they
were able to generate IL-17-producing CD4 + T cells with more than 90%
purity. Notably, the majority of these cells also expressed IL-17F as seen
by intracellular cytokine staining, indicating that at least two IL-17 family
members were induced under these conditions. When these highly puri-
fied cells from B6 mice were adoptively transferred into lethally irradiated
MHC-incompatible recipients, they were sufficient to induce lethal GVHD
and also acted synergistically with naïve T cells to mediate GVHD. The most
significant finding was that GVHD induced by these in vitro -generated
cells was characterized by preferential pathological damage in the skin and
lung of recipient mice compared to either whole T cells or purified CD4 +
T cells, despite there being no overall difference in survival. Interestingly,
upon transfer, some in vitro -polarized Th17 cells acquired the ability to
produce the Th1 cytokine IFN-γ and nearly all lost expression of IL-17F,
suggesting phenotypic instability of these in vitro -generated cells. Subse-
quent studies, however, determined that skin lesions, in particular, were not
dependent upon IFN-γ, indicating that pathological damage was not due
to the conversion of Th17 cells into IFN-γ-producing Th1 cells. In fact, only
blockade of IL-17A resulted in decreased skin pathology induced by Th17
cells, although this treatment did not affect any of the systemic manifesta-
tions of acute GVHD. It is noteworthy that in vitro -differentiated Th17 cells