Chronic graft-versus-host disease (cGVHD) currently represents the leading cause of nonrelapse mortality and morbidity after allogeneic hematopoietic stem cell transplantation (SCT). In parallel with an increased use of granulocyte colony-stimulating factor (G-CSF)-mobilized stem cell products as a graft source, the incidence of cGVHD has dramatically increased. Currently, up to 50% of SCT recipients develop this multisystem inflammatory disease that occurs late after bone marrow transplantation. Although cGVHD can affect almost any target tissue, the predominant and diagnostic organ pathologies that develop are usually cutaneous and/or pulmonary fibrosis (scleroderma and bronchiolitis obliterans, respectively) [1, 2]. Unfortunately, as for most diseases with fibrotic manifestations, there is currently no satisfactory therapy for cGVHD. Standard primary treatment is glucocorticoids with or without other immunosuppressive agents; however, nearly 50% of patients continue to have inadequate control of their cGVHD and require second-line systemic treatment [3, 4]. Moreover, systemic glucocorticoids are wrought with long term-complications, thereby increasing morbidity and mortality in this patient population that are otherwise cured of their original malignancy.
A much-needed recent surge of preclinical and clinical studies have significantly advanced our understanding of the pathophysiology of cGVHD, which we now recognize as a complex immunologic process incorporating multiple facets of adaptive and innate immunity, including B cells, T cells, and macrophages and their interactions with target tissue. Importantly, these studies have led to the identification of targetable cellular and molecular mediators of cGVHD and have begun to broaden our choice of potential new therapeutics to manage these patients. This review focuses on 3 recently identified therapeutic targets for cGVHD control, IL-17, CSF-1, and Janus kinases (JAKs), and provides an overview of new pharmacologic and cellular approaches currently being implemented in the clinic.
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