Role of Th17 cells and interleukin 17 in graft-versushost disease and graft-versusleukemia reactivity - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 275

different homing molecules was increased in the respective target organs.
Again, the major caveat with these studies is that the forced expression of T
cells along select differentiation pathways may not necessarily be an accu-
rate reflection of what occurs when CD4 + T cells have unrestricted options
available to them.

Role of IL-17 and Th17 cells in chronic GVHD

Clinically, GVHD has been divided into acute and chronic phases that have
historically been distinguished primarily by their temporal onset. In con-
trast to acute GVHD, in which pathology is generally restricted to the skin,
liver, and intestinal tract, chronic GVHD has unique clinical features in that
organ involvement tends to be more extensive and more frequently involves
the lung, eyes, and mucous membranes, tissue sites that are less involved
than in acute GVHD [63] . Moreover, chronic GVHD often presents with
clinical manifestations that resemble those seen in autoimmune diseases
such as systemic lupus erythematosus, Sjogren's syndrome, scleroderma,
and rheumatoid arthritis [64-66] . These distinguishing clinical features of
chronic GVHD have been the impetus for the reclassification of this disease
with diagnostic criteria that, in part, highlight the similarities that this syn-
drome has with other autoimmune disorders [67] . These new criteria are
meant to emphasize that chronic GVHD is not merely an extension of ante-
cedent acute GVHD, but is a distinct clinical and pathophysiological entity.
Whereas the pathophysiology of acute GVHD has been extensively exam-
ined using a variety of murine BMT models, the pathogenesis of chronic
GVHD is much less well understood. That being said, a number of studies
have recently been conducted in an effort not only to uncover the patho-
physiology of chronic GVHD, but also to delineate the role that IL-17 and
Th17 cells may play in this disorder. It should be emphasized, however, that
since there is no animal model that recapitulates all of the varied manifesta-
tions of chronic GVHD, the studies that have been conducted have gener-
ally examined select, yet important, features of this protean disorder.

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A potential pathogenic role for IL-17-secreting CD4 + T cells was initially sup-
ported by studies conducted in an effort to understand how acute GVHD,
which is a proinflammatory syndrome, transitions into chronic GVHD,
which is characterized by features of autoimmunity [68,69] . Using an adop-
tive transfer model, we observed that spleen cells from mice undergoing
acute GVHD could induce pathological damage in secondary immuno-
deficient animals of the same donor MHC type. This was determined to be
mediated by CD4 + T cells, which were responsible for inducing pathological
damage in the colon and liver. The fact that T cells in both primary GVHD
animals and secondary immunodeficient mice were of the same MHC type
was evidence that these T cells were reactive against self-antigens [68] .
Subsequent studies demonstrated that GVHD-associated autoimmunity
and, by extension, chronic GVHD were attributable to the progressive loss
of CD4 + CD25 + FOXP3 + regulatory T cells during the course of acute GVHD
[69] . This led to the expansion of donor-derived CD4 + T cells with both Th1
and Th17 cytokine phenotypes along with the overproduction of proinflam-
matory cytokines, including IFN-γ and IL-17. Intracellular cytokine staining
confirmed the presence of Th1 and Th17 cells in spleen and target organs of