tofacitinib and Graft-vs-Host-Disease

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.

Topics: Administration, Oral; Animals; Bone Marrow; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Cell Proliferation; Chemokines; Cytokines; Dermatitis; Gene Expression Regulation; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Interleukin-2; Keratinocytes; Mice; Mice, Inbred C57BL; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles

Acute graft-versus-host disease (GVHD) is a critical obstacle to bone marrow transplantation. Although numerous studies have described immunosuppression protocols to mitigate acute GVHD, the need still exists for a more efficient immunosuppressant with fewer side effects. Here, we evaluated the protective effect of CP-690550, a newly developed Janus kinase inhibitor, in an acute GVHD model.. CP-690550 was chemically synthesized. Acute GVHD was induced through the transfer of parent B6 (H-2) bone marrow and CD4 T cells into lethally irradiated (B6×bm12)F1 (H-2) mice. RESULTS.: CP-690550 treatments confined to days -3 to 11 of GVHD induction provided full protection against allogeneic, acute GVHD-related lethality and histopathology. An analysis of the initial donor-derived CD4 T-cell responses revealed that the inhibitory effects of CP-690550 were largely related to the suppression of donor CD4 T-cell-mediated interferon (IFN)-γ production. Enhanced inhibition of T helper 1 cell differentiation, rather than the inhibition of allogeneic CD4 T-cell proliferation or T helper 17 cell differentiation, was also confirmed in allogeneic mixed lymphocyte reactions. Because lethality was considerably delayed by the systemic blockade of IFN-γ, the principal protective effect of CP-690550 occurred through the modulation of IFN-γ production.. The targeting of Janus kinase with a sensitive and specific inhibitor, CP-690550, conferred effective protection from acute GVHD induced by a semiallogeneic major histocompatibility complex class II-disparate combination. Protection from acute GVHD was largely mediated by the inhibition of IFN-γ production.

Topics: Animals; Bone Marrow Cells; CD4-Positive T-Lymphocytes; Cell Differentiation; Cytokines; Dendritic Cells; Graft vs Host Disease; Interferon-gamma; Interleukin-2; Janus Kinase 3; Lymphocyte Activation; Lymphocyte Depletion; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Phosphorylation; Piperidines; Pyrimidines; Pyrroles; STAT3 Transcription Factor