Cobimetinib suppresses murine pulmonary GVHD, whereas trametinib does not. (A-D) B10.BR mice were treated with CY/TBI and transplanted with bone marrow cells (BM) only or BM plus T cells (BM + T) from C57BL/6 mice. (A) Survival curves of mice (n = 10 per group) transplanted with BM or BM + T and treated with trametinib or cobimetinib. Transplantations were performed twice, independently. (B) H&E–stained specimens of bronchioles from mice transplanted with BM or BM + T and treated with trametinib or cobimetinib. Proportions of bronchiolitis among all bronchioles (C) and clinical GVHD scores (D) of the mice. (E-Q) B10.BR mice were treated with CY/TBI and transplanted with BM only or BM plus splenocytes from C57BL/6 mice. (E) Survival curves of mice transplanted with BM or BM + S and treated with trametinib, cobimetinib, or tacrolimus. Tacrolimus-treated group, n = 10 mice; other groups, n = 20 mice. Transplantations were performed 4 times independently. (F-H) Pathologic images of H&E–stained specimens from mice transplanted with BM + S: bronchiolitis (F), perivascular inflammation (G), and macrophage aggregation (H). (I) Proportions of mice with bronchiolitis, perivascular inflammation (PI), and macrophage aggregation (MA) among 10 mice given BM + S. (J) Representative pathologic images of H&E–stained tissues around bronchioles. (K) Proportions of bronchiolitis in all mouse bronchioles (n = 5 mice per group). Bars, mean values; error ranges, standard error of the mean (SEM). (L) Airway resistance of the mice is shown. Bars, mean values; error range, SEM. (M) Bar graphs of lung compliance data are shown. Bars, mean; error range, SEM. (N-Q) Immunohistochemically stained murine lung specimens. Representative images of CD4 staining (N) and numbers of CD4⁺ cells in peribronchial areas (O) (n = 5 per group). Representative images of B220 staining (P) and numbers of B220⁺ cells in peribronchial areas (Q) (n = 5 per group). (R) B10.BR mice were treated with CY/TBI and transplanted with BM only, or BM with B and T cells from C57BL/6 mice. Survival curves of mice (n = 10 per group) transplanted with BM or BM + B/T cells and treated with trametinib or cobimetinib. Transplantations were performed twice independently. The log-rank test was used to compare survival rates between the 2 groups, and the two-tailed unpaired t test was used for comparisons between 2 groups of continuous variables. ∗P < .05, ∗∗P < .01. Cobi, cobimetinib; N.S., not significant; Tra, trametinib.