By Gérard Socié, MD, PhD
2009-07-01
Dr. Socié indicated no relevant conflicts of interest.
Imanguli M, Swaim WD, League SC et al. Increased
T-bet + cytotoxic effectors and type I interferon-mediated processes in
chronic graft-versus-host disease of the oral mucosa. Blood. 2009;113:3620-30.
Chronic graft-versus-host disease (cGVHD) is one, if not the major,
long-term complication of allogeneic hematopoietic stem cell
transplantation. Most of the knowledge of the pathophysiology of cGVHD
has been derived from mouse models. However, experimental models of
cGVHD pathogenesis poorly describe the clinical spectrum of the
disease. T cells are central to the pathophysiology of GVHD. Cytokines
secreted by activated T cells are generally classified as Th1
(secreting IL-2 and IFN-γ) or Th2 (secreting IL-4, IL-5, IL-10, and
IL-13). One of the main accepted paradigms is that acute GVHD is mainly
a Th1 process while chronic is a Th2-mediated disease.
In this article, authors from the NCI studied oral mucosa cGVHD and
correlated cGVHD severity with apoptotic epithelial cells and
infiltrating T cells. Somewhat surprisingly, they found that T-cell
effectors express a Th1-specific transcription factor, T-bet, and a
chemokine receptor CXCR3. Concurrently, in both infiltrating cells and
keratinocytes, they observed increased expression of the CXCR3 ligand
MIG (CXCL9) and IL-15. These are type I interferon-inducible factors
that support migration, Th1 differentiation, and expansion of
alloreactive effectors. These data challenge the current paradigm of
cGVHD as a type II cytokine-driven disorder and support the model that
oral cGVHD results from immigration, proliferation, and differentiation
of Th1 differentiated effectors.
Clinical manifestations of cGVHD closely resemble classic
auto-immune conditions such as scleroderma, lichen planus, and Sjogren
syndrome. Involvement of the oral cavity is second to skin in
frequency, occurring in the majority of patients with cGVHD. Lichen
planus-like oral mucosal lesions are highly specific for cGVHD. Oral
cGVHD presents a significant burden to patients leading to pain, food
intolerance, change in taste, xerostomia, and, ultimately, decreased
quality of life. In addition, the risk of secondary squamous cell
carcinoma is greatly increased in those affected by cGVHD.
This study is one of the very few addressing
cGVHD pathophysiology in humans, and, thus, the authors should be
congratulated for their very well-designed (and analyzed) study. It was
not surprising that the clinical severity of oral cGVHD correlated with
apoptotic epithelial cells found adjacent to infiltrating T cells,
since this represents one of the hallmarks of pathology of GVHD. What
was more surprising was the polarization of these T cells toward a Th1
phenotype. Although well established, the Th2 polarization paradigm of
cGVHD has been challenged in the past few years in a mouse model.1 Future studies will be needed to confirm this group’s results in oral as well as other tissue targets of cGVHD.
One of the most interesting findings in this paper
is the increased expression of the type I interferon-inducible factors
CXCR3 ligand and IL-15. T-cell trafficking and the role of different
chemokine/chemokine receptors have just begun to be explored in human
GVHD, but they likely play a major role. We do not yet know the factors
governing T-cell trafficking to their target organs in GVHD, or if the
plasma (or tissue) levels of these factors are influenced by genetic
regulation. Among the molecules involved in T-cell trafficking, the
chemokine family has been shown to play a predominant role in a murine
model of GVHD. This study is one of the first in humans to provide
evidence on the role of chemokines in cGVHD. This study is thus timely
and clearly warranted.
- Welniak LA, Blazar BR, Murphy WJ. Immunobiology of allogeneic hematopoietic stem cell transplantation. Annu Rev Immunol. 2007;25:139-70.
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