The MEK inhibitor trametinib separates murine graft-versus-host disease from graft-versus-tumor effects

Itamura, Hidekazu; Shindo, Takero; Tawara, Isao; Kubota, Yasushi; Kariya, Ryusho; Okada, Seiji; Komanduri, Krishna V.; Kimura, Shinya

doi:10.1172/jci.insight.86331

Cited by 22 publications

(28 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Microarray analysis of microRNAs in BM‐MSC‐derived EVs versus NHDF‐derived EVs revealed the differential expression of multiple microRNAs, suggesting the involvement of multiple biological processes. Previous studies have demonstrated that BM‐MSCs inhibit the proliferation of activated T cells via cell cycle arrest and modulate the expression of various cytokines, including proinflammatory (e.g., IL‐2, IFN‐γ, TNF‐α) and anti‐inflammatory cytokines (e.g., IL‐4, IL‐10), which play important roles in the pathogenesis of acute GVHD . The GO enrichment analysis identified the down‐regulation of multiple cell proliferation‐related processes but not altered production of these cytokines.…”

Section: Discussionmentioning

confidence: 93%

Graft-Versus-Host Disease Amelioration by Human Bone Marrow Mesenchymal Stromal/Stem Cell-Derived Extracellular Vesicles Is Associated with Peripheral Preservation of Naive T Cell Populations

et al. 2017

Self Cite

View full text Add to dashboard Cite

A substantial proportion of patients with acute graft-versus-host disease (aGVHD) respond to cell therapy with culture-expanded human bone marrow mesenchymal stromal/stem cells (BM-MSCs). However, the mechanisms by which these cells can ameliorate aGVHD-associated complications remain to be clarified. We show here that BM-MSC-derived extracellular vesicles (EVs) recapitulated the therapeutic effects of BM-MSCs against aGVHD. Systemic infusion of human BM-MSCderived EVs prolonged the survival of mice with aGVHD and reduced the pathologic damage in multiple GVHD-targeted organs. In EV-treated GVHD mice, CD41 and CD81 T cells were suppressed. Importantly, the ratio of CD62L-CD441 to CD62L 1 CD44-T cells was decreased, suggesting that BM-MSC-derived EVs suppressed the functional differentiation of T cells from a naive to an effector phenotype. BM-MSC-derived EVs also preserved CD4 1 CD25 1 Foxp31 regulatory T cell populations. In a culture of CD3/CD28-stimulated human peripheral blood mononuclear cells with BM-MSC-derived EVs, CD31 T cell activation was suppressed. However, these cells were not suppressed in cultures with EVs derived from normal human dermal fibroblasts (NHDFs). NHDF-derived EVs did not ameliorate the clinical or pathological characteristics of aGVHD in mice, suggesting an immunoregulatory function unique to BM-MSC-derived EVs. Microarray analysis of microRNAs in BM-MSCderived EVs versus NHDF-derived EVs showed upregulation of miR-125a-3p and downregulation of cell proliferative processes, as identified by Gene Ontology enrichment analysis. Collectively, our findings provide the first evidence that amelioration of aGVHD by therapeutic infusion of BM-MSCderived EVs is associated with the preservation of circulating naive T cells, possibly due to the unique microRNA profiles of BM-MSC-derived EVs. STEM CELLS 2018;36:434-445 SIGNIFICANCE STATEMENTCell therapy with human bone marrow mesenchymal stromal/stem cells (BM-MSCs) is clinically effective for patients with intractable acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation. This study revealed that BM-MSC-derived extracellular vesicles (EVs) recapitulated the therapeutic effects of BM-MSCs against aGVHD by inhibiting effector T cell induction and preserving peripheral naive T cells. Gene Ontology analysis of microRNAs differentially expressed in BM-MSC-derived EVs suggested that these microRNAs may downregulate cell proliferative processes. These findings suggest that BM-MSC-derived EVs mediate the anti-aGVHD effects of BM-MSCs, thereby raising the possibility of using EVs as a cell-free therapy for the treatment of aGVHD.

show abstract

Section: Discussionmentioning

confidence: 93%

Graft-Versus-Host Disease Amelioration by Human Bone Marrow Mesenchymal Stromal/Stem Cell-Derived Extracellular Vesicles Is Associated with Peripheral Preservation of Naive T Cell Populations

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…We extend these findings to T cells and show that inhibition of PRMT5 with a selective small-molecule PRMT5 inhibitor results in decreased ERK1/2 phosphorylation. Targeting the RAS/MEK/ERK pathway (46) using an MEK inhibitor, such as trametinib, has been shown to inhibit alloreactivity and suppress aGVHD by decreasing ERK1/2 phosphorylation and expansion of donor T cells and sparing Tregs (47). Therefore, downregulation of the ERK pathway could be a major mechanism by which inhibition of PRMT5 exerts its protective effects in aGVHD.…”

Section: Discussionmentioning

confidence: 99%

PRMT5 regulates T cell interferon response and is a target for acute graft-versus-host disease

Snyder¹,

Zitzer²,

Gao³

et al. 2020

JCI Insight

View full text Add to dashboard Cite

“…Mice were fed an adenine-rich diet for 2 months and trametinib, at a dose (0.3 mg/kg) that inhibits 75% of ERK1/2 signaling, was concurrently administered. 56 Adenine is metabolized into 2,8-dihydroxyadenine, which precipitates in the tubules and causes obstruction, resulting in progressive tubular necrosis, macrophage infiltration, tubulointerstitial fibrosis, and diminished renal function. 32 Trametinib treatment significantly decreased collagen deposition and myofibroblast expansion, as exemplified by aSMA or vimentin expression ( Figure 6).…”

Section: Discussionmentioning

confidence: 99%

The MEK Inhibitor Trametinib Ameliorates Kidney Fibrosis by Suppressing ERK1/2 and mTORC1 Signaling

Andrikopoulos

Kieswich

Pacheco

et al. 2018

JASN

View full text Add to dashboard Cite

Background During kidney fibrosis, a hallmark and promoter of CKD (regardless of the underlying renal disorder leading to CKD), the extracellular-regulated kinase 1/2 (ERK1/2) pathway, is activated and has been implicated in the detrimental differentiation and expansion of kidney fibroblasts. An ERK1/2 pathway inhibitor, trametinib, is currently used in the treatment of melanoma, but its efficacy in the setting of CKD and renal fibrosis has not been explored.Methods We investigated whether trametinib has antifibrotic effects in two mouse models of renal fibrosis -mice subjected to unilateral ureteral obstruction (UUO) or fed an adenine-rich diet-as well as in cultured primary human fibroblasts. We also used immunoblot analysis, immunohistochemical staining, and other tools to study underlying molecular mechanisms for antifibrotic effects.Results Trametinib significantly attenuated collagen deposition and myofibroblast differentiation and expansion in UUO and adenine-fed mice. We also discovered that in injured kidneys, inhibition of the ERK1/2 pathway by trametinib ameliorated mammalian target of rapamycin complex 1 (mTORC1) activation, another key profibrotic signaling pathway. Trametinib also inhibited the ERK1/2 pathway in cultured primary human renal fibroblasts stimulated by application of TGF-b1, the major profibrotic cytokine, thereby suppressing downstream mTORC1 pathway activation. Additionally, trametinib reduced the expression of myofibroblast marker a-smooth muscle actin and the proliferation of renal fibroblasts, corroborating our in vivo data. Crucially, trametinib also significantly ameliorated renal fibrosis progression when administered to animals subsequent to myofibroblast activation.Conclusions Further study of trametinib as a potential candidate for the treatment of chronic renal fibrotic diseases of diverse etiologies is warranted.

show abstract

The MEK inhibitor trametinib separates murine graft-versus-host disease from graft-versus-tumor effects

Cited by 22 publications

References 50 publications

Graft-Versus-Host Disease Amelioration by Human Bone Marrow Mesenchymal Stromal/Stem Cell-Derived Extracellular Vesicles Is Associated with Peripheral Preservation of Naive T Cell Populations

Graft-Versus-Host Disease Amelioration by Human Bone Marrow Mesenchymal Stromal/Stem Cell-Derived Extracellular Vesicles Is Associated with Peripheral Preservation of Naive T Cell Populations

PRMT5 regulates T cell interferon response and is a target for acute graft-versus-host disease

The MEK Inhibitor Trametinib Ameliorates Kidney Fibrosis by Suppressing ERK1/2 and mTORC1 Signaling

Contact Info

Product

Resources

About