title: Reversal of CD8 T-cell-mediated mucocutaneous graft-versus-host-like disease by the JAK inhibitor tofacitinib.
abstract: The utility of allogeneic hematopoietic stem cell transplantation is limited by graft-versus-host disease (GVHD), a significant cause of morbidity and mortality. Patients with GVHD exhibit cutaneous manifestations with histological features of interface dermatitis followed by scleroderma-like changes. JAK inhibitors represent a class of immunomodulatory drugs that inhibit signaling by multiple cytokines. Herein we report the effects of tofacitinib in a murine model of GVHD. Oral administration of tofacitinib prevented GVHD-like disease manifested by weight loss and mucocutaneous lesions. More importantly, tofacitinib was also effective in reversing established disease. Tofacitinib diminished the expansion and activation of murine CD8 T cells in this model, and had similar effects on IL-2-stimulated human CD8 T cells. Tofacitinib also inhibited the expression of IFN-γ-inducible chemoattractants by keratinocytes, and IFN-γ-inducible cell death of keratinocytes. Tofacitinib may be an effective drug for treatment against CD8 T-cell-mediated mucocutaneous diseases in patients with GVHD.
authors.affiliation: Dermatology Branch, National Cancer Institute, Bethesda, Maryland, USA.
authors.forename: Naoko
authors.initials: N
authors.lastname: Okiyama
authors.affiliation: Translational Immunology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Furumoto
authors.affiliation: Dermatology Branch, National Cancer Institute, Bethesda, Maryland, USA.
authors.forename: Vadim A
authors.initials: VA
authors.lastname: Villarroel
authors.affiliation: Dermatology Branch, National Cancer Institute, Bethesda, Maryland, USA.
authors.forename: Jay T
authors.initials: JT
authors.lastname: Linton
authors.affiliation: Translational Immunology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Wanxia L
authors.initials: WL
authors.lastname: Tsai
authors.affiliation: Dermatology Branch, National Cancer Institute, Bethesda, Maryland, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Gutermuth
authors.affiliation: Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Kamran
authors.initials: K
authors.lastname: Ghoreschi
authors.affiliation: Translational Immunology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Massimo
authors.initials: M
authors.lastname: Gadina
authors.affiliation: Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: O'Shea
authors.affiliation: Dermatology Branch, National Cancer Institute, Bethesda, Maryland, USA. Electronic address: katzs@od.niams.nih.gov.
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Katz
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003872:Dermatitis / Q000188:drug therapy* / Q000378:metabolism; D005786:Gene Expression Regulation; D006086:Graft vs Host Disease / Q000188:drug therapy*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D015603:Keratinocytes / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D010880:Piperidines / Q000008:administration & dosage*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage*; D011758:Pyrroles / Q000008:administration & dosage*
chemical_list: D018925:Chemokines; D016207:Cytokines; D007376:Interleukin-2; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; C479163:tofacitinib