Chronic graft-versus-host disease (cGVHD) is characterized as autoimmune-like fibrosis and antibody production mediated by pathogenic T cells and B cells. MicroRNA-17-92 (miR-17-92) influences the survival, differentiation, and function of lymphocytes in cancer, infections, and autoimmunity. To determine whether miR-17-92 regulates T- and B-cell responses in cGVHD, we generated mice conditionally deficient for miR-17-92 in T cells, B cells, or both. Using murine models of allogeneic bone marrow transplantation, we demonstrate that expression of miR-17-92 in donor T and B cells is essential for the induction of both scleroderma and bronchiolitis obliterans in cGVHD. Mechanistically, miR-17-92 expressed in T cells not only enhances the differentiation of pathogenic T helper 1 (Th1) and Th17 cells, but also promotes the generation of follicular Th cells, germinal center (GC) B cells, and plasma cells. In B cells, miR-17-92 expression is required for autoantibody production and immunoglobulin G deposition in the skin. Furthermore, we evaluated a translational approach using antagomirs specific for either miR-17 or miR-19, key members in miR-17-92 cluster. In a lupus-like cGVHD model, systemic administration of anti–miR-17, but not anti–miR-19, alleviates clinical manifestations and proteinuria incidence in recipients through inhibiting donor lymphocyte expansion, B-cell activation, and GC responses. Blockade of miR-17 also ameliorates skin damage by reducing Th17 differentiation in a scleroderma-cGVHD model. Taken together, our work reveals that miR-17-92 is required for T-cell and B-cell differentiation and function, and thus for the development of cGVHD. Furthermore, pharmacological inhibition of miR-17 represents a potential therapeutic strategy for the prevention of cGVHD.
Bibliographical noteFunding Information:
This work was supported, in part, by the National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases (NIAID; grant R01 AI118305) and NIH/National Cancer Institute (NCI; grants CA118116 and CA169116) (X.-Z.Y.); and NIH/NCI (grant P01 CA142106) and NIH/ NIAID (grant (AI056299) (B.R.B.).
The authors appreciate the technical support provided by the Department of Laboratory Animal Research, Flow Cytometry Core, and Cell and Molecular Imaging Core at MUSC. The authors appreciate the assistance provided by Shikhar Mehrotra and Pravin Kesarwani in confirming the miR-17-92 deficiency in T and B cells from miR-17-92 conditional KO mice with quantitative polymerase chain reaction. This work was supported, in part, by the National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases (NIAID; grant R01 AI118305) and NIH/National Cancer Institute (NCI; grants CA118116 and CA169116) (X.-Z.Y.); and NIH/NCI (grant P01 CA142106) and NIH/ NIAID (grant (AI056299) (B.R.B.).
© 2018 by The American Society of Hematology
- MiR-17-92 mediates the progression of scleroderma and bronchiolitis obliterans in cGVHD by enhancing T- and B-cell responses.
- Pharmacologically blocking the activity of miR-17-92 with an anti–miR-17 antagomir effectively alleviates cGVHD.