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Dual inhibition of the MEK/ERK and PI3K/AKT pathways prevents pulmonary GVHD suppressing perivenulitis and bronchiolitis.
Muranushi, Hiroyuki; Shindo, Takero; Chen-Yoshikawa, Toyofumi F; Yoshizawa, Akihiko; Thi Ngo, Huong; Gochi, Fumiaki; Date, Hiroshi; Takaori-Kondo, Akifumi.
Afiliação
  • Muranushi H; Department of Hematology/Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
  • Shindo T; Department of Hematology/Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
  • Chen-Yoshikawa TF; Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
  • Yoshizawa A; Department of Diagnostic Pathology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
  • Thi Ngo H; Department of Hematology/Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
  • Gochi F; Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
  • Date H; Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
  • Takaori-Kondo A; Department of Hematology/Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Blood Adv ; 7(1): 106-121, 2023 01 10.
Article em En | MEDLINE | ID: mdl-35468620
Patients with pulmonary graft-versus-host disease (pGVHD) have a poor prognosis after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Furthermore, pGVHD pathogenesis is not fully elucidated in humans, and currently available immunosuppressants are inadequately effective. We performed pathologic evaluation of lung specimens from 45 allo-HSCT recipients with pGVHD who underwent lung transplantation. Patient pathology was characterized by bronchiolitis and subpleural perivascular inflammation, with B-cell, monocyte, and T-cell accumulation around bronchioles. Bronchiolitis, perivascular inflammation, and peribronchial macrophage aggregation were also identified in a murine pGVHD model after transplant of bone marrow cells and splenocytes from C57BL/6 to B10.BR mice. Among mitogen-activated protein kinase kinase (MEK) inhibitors, cobimetinib, but not trametinib, improved survival rates. Cobimetinib attenuated bronchiolitis, improved airway resistance and lung compliance in the mice, and suppressed activation of B cells and tumor necrosis factor α production by monocytes in vitro; these features were not suppressed by trametinib or tacrolimus. Furthermore, cobimetinib suppressed activation of phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling, resulting in B-cell and monocyte suppression. Dual inhibition of the MEK/extracellular signal-regulated kinase (ERK) and PI3K/AKT pathways using a combination of trametinib and the PI3K inhibitor taselisib strongly suppressed B-cell activation in vitro and improved mouse survival rates compared with vehicle or monotherapy with trametinib or taselisib. Imaging mass cytometry of human pGVHD revealed that T cells around bronchioles were positive for phosphorylated ERK, whereas B cells were positive for phosphorylated AKT. Thus, perivascular inflammation and bronchiolitis mediated by activation of the MEK/ERK and PI3K/AKT pathways are essential for pGVHD and represent a potential novel therapeutic target in humans.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Bronquiolite / Doença Enxerto-Hospedeiro Idioma: En Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Bronquiolite / Doença Enxerto-Hospedeiro Idioma: En Ano de publicação: 2023 Tipo de documento: Article