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PATHOGENESIS
The current model for aGVHD pathogenesis can be summarized in a three-step process. First, HSCT conditioning and consequent damage to host tissues leads to activation of host antigen-presenting cells (APCs). Second, donor T cells proliferate in response to contact with activated APCs. Finally, destruction of target tissues (skin, liver, gastrointestinal tract) occurs via cytotoxic T lymphocytes, natural killer cells, and soluble factors (TNF, IFN-ฮณ, IL-1, nitric oxide). Recently, humanized mouse models have demonstrated that donor APC activation of host resident T cells can also elicit a graft-versus-host response. These two proposed mechanisms may not contradict, but rather complement, one another and suggests multiple pathways of disease pathogenesis.
A clear understanding of cGVHD is still lacking and available murine models recapitulate only select features of human disease (e.g. sclerotic skin involvement, autoantibodies). Alloreactive T cells are again thought to play a central role, but a number of other immune mediators have been increasingly implicated. Many cGVHD manifestations resemble autoimmune disease, suggesting a role for B cells in the disease process. Indeed, rituximab (anti-CD20 antibody) is a beneficial salvage therapy in some patients. B cells appear to prime T cells to minor histocompatibility antigens, and serum levels of B cell activating factor of the TNF family (BAFF), a marker of B cell activation, correlate with cGVHD. Multiple autoantibodies are often present in patients with cGVHD, including anti-nuclear, anti-dsDNA, and anti-smooth muscle antibodies, although, to date, they have not been shown to correlate with specific disease manifestations. Activating antibodies against the platelet-derived growth factor receptor (PDGFR) were observed in patients with cGVHD, suggesting that targeting this receptor and its profibrotic pathway with agents such as imatinib mesylate could improve cGVHD. However, the functional significance of these antibodies remains uncertain.
HSCT recipients have also been shown to have a deficiency of regulatory T cells (Tregs) due to decreased thymic differentiation. Tregs are integral to the development and maintenance of self-tolerance, and impairment of Treg function is associated with autoimmunity. In mouse models of allogeneic HSCT, adoptive transfer of Tregs has been shown to ameliorate signs and symptoms of cGVHD. A possible role for Th17 cells was suggested by elevated levels of IL-17 and -22 in tissue and plasma in patients and mouse models of cutaneous cGVHD and IL-17 inhibitors have been investigated as treatment for cGVHD. Of note, different mechanisms may underlie cGVHD based on duration and phenotype of disease.