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.
In Brief
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.
References
Competing Interests
Dr. Socié indicated no relevant conflicts of interest.
