Browsing by Author "Seike, Keisuke"

Now showing 1 - 3 of 3
  • Thumbnail Image
    Item
    Mitochondrial Complex II In Intestinal Epithelial Cells Regulates T-cell Mediated Immunopathology
    (Springer Nature, 2021) Fujiwara, Hideaki; Seike, Keisuke; Brooks, Michael D.; Mathew, Anna V.; Kovalenko, Ilya; Pal, Anupama; Lee, Ho-Joon; Peltier, Daniel; Kim, Stephanie; Liu, Chen; Oravecz-Wilson, Katherine; Li, Lu; Sun, Yaping; Byun, Jaeman; Maeda, Yoshinobu; Wicha, Max S.; Saunders, Tom; Rehemtulla, Alnawaz; Lyssiotis, Costas A.; Pennathur, Subramaniam; Reddy, Pavan; Microbiology and Immunology, School of Medicine
    Intestinal epithelial cell (IEC) damage by T cells contributes to graft-versus-host disease (GVHD), inflammatory bowel disease (IBD) and immune checkpoint blockade (ICB) mediated colitis. But little is known about the target cell intrinsic features that influence disease severity. Herein we identified disruption of oxidative phosphorylation and an increase in succinate levels in the IECs from several distinct in vivo models of T cell mediated colitis. Metabolic flux studies, complemented by imaging and protein analyses identified disruption of IEC intrinsic succinate dehydrogenase A (SDHA), a component of mitochondrial complex II, in causing these metabolic alterations. The relevance of IEC intrinsic SDHA in mediating disease severity was confirmed by complementary chemical and genetic experimental approaches and validated in human clinical samples. These data identify a critical role for the alteration of the IEC specific mitochondrial complex II component SDHA in the regulation of the severity of T cell mediated intestinal diseases.
  • Thumbnail Image
    Item
    Oral inflammation and microbiome dysbiosis exacerbate chronic graft-versus-host disease
    (American Society of Hematology, 2025) Kambara, Yui; Fujiwara, Hideaki; Yamamoto, Akira; Gotoh, Kazuyoshi; Tsuji, Shuma; Kunihiro, Mari; Oyama, Tadashi; Terao, Toshiki; Sato, Ayame; Tanaka, Takehiro; Peltier, Daniel; Seike, Keisuke; Nishimori, Hisakazu; Asada, Noboru; Ennishi, Daisuke; Fujii, Keiko; Fujii, Nobuharu; Matsuoka, Ken-Ichi; Soga, Yoshihiko; Reddy, Pavan; Maeda, Yoshinobu; Pediatrics, School of Medicine
    The oral microbiota, second in abundance to the gut, is implicated in chronic systemic diseases, but its specific role in graft-versus-host disease (GVHD) pathogenesis has been unclear. Our study finds that mucositis-induced oral dysbiosis in patients after hematopoietic cell transplantation (HCT) associated with increased chronic GVHD (cGVHD), even in patients receiving posttransplant cyclophosphamide. In murine HCT models, oral dysbiosis caused by bilateral molar ligatures exacerbated cGVHD and increased bacterial load in the oral cavity and gut, with Enterococcaceae significantly increasing in both organs. In this model, the migration of Enterococcaceae to cervical lymph nodes both before and after transplantation activated antigen-presenting cells, thereby promoting the expansion of donor-derived inflammatory T cells. Based on these results, we hypothesize that pathogenic bacteria increase in the oral cavity might not only exacerbate local inflammation but also enhance systemic inflammation throughout the HCT course. Additionally, these bacteria translocated to the gut and formed ectopic colonies, further amplifying systemic inflammation. Furthermore, interventions targeting the oral microbiome mitigated murine cGVHD. Collectively, our findings highlight the importance of oral dysbiosis in cGVHD and suggest that modulation of the oral microbiome during transplantation may be an effective approach for preventing or treating cGVHD.
  • Thumbnail Image
    Item
    Rearrangement of T Cell genome architecture regulates GVHD
    (Elsevier, 2022-08-06) Sun, Yaping; Dotson, Gabrielle A.; Muir, Lindsey A.; Ronquist, Scott; Oravecz-Wilson, Katherine; Peltier, Daniel; Seike, Keisuke; Li, Lu; Meixner, Walter; Rajapakse, Indika; Reddy, Pavan; Pediatrics, School of Medicine
    WAPL, cohesin's DNA release factor, regulates three-dimensional (3D) chromatin architecture. The 3D chromatin structure and its relevance to mature T cell functions is not well understood. We show that in vivo lymphopenic expansion, and alloantigen-driven proliferation, alters the 3D structure and function of the genome in mature T cells. Conditional deletion of WAPL, cohesin's DNA release factor, in T cells reduced long-range genomic interactions and altered chromatin A/B compartments and interactions within topologically associating domains (TADs) of the chromatin in T cells at baseline. WAPL deficiency in T cells reduced loop extensions, changed expression of cell cycling genes and reduced proliferation following in vitro and in vivo stimulation, and reduced severity of graft-versus-host disease (GVHD) following experimental allogeneic hematopoietic stem cell transplantation. These data collectively characterize 3D genomic architecture of T cells in vivo and demonstrate biological and clinical implications for its disruption by cohesin release factor WAPL.