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医学部 医学科 発達泌尿生殖医学講座小児科学分野 |
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助教 |
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Uchiyama T., Kawai T., Nakabayashi K., Nakazawa Y., Goto F., Okamura K., Nishimura T., Kato K., Watanabe N., Miura A., Yasuda T., Ando Y., Minegishi T., Edasawa K., Shimura M., Akiba Y., Sato-Otsubo A., Mizukami T., Kato M., Akashi K., Nunoi H., Onodera M.
Molecular Therapy 2023年
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Molecular Therapy
Stem cell gene therapy using the MFGS-gp91phox retroviral vector was performed on a 27-year-old patient with X-linked chronic granulomatous disease (X-CGD) in 2014. The patient's refractory infections were resolved, whereas the oxidase-positive neutrophils disappeared within 6 months. Thirty-two months after gene therapy, the patient developed myelodysplastic syndrome (MDS), and vector integration into the MECOM locus was identified in blast cells. The vector integration into MECOM was detectable in most myeloid cells at 12 months after gene therapy. However, the patient exhibited normal hematopoiesis until the onset of MDS, suggesting that MECOM transactivation contributed to clonal hematopoiesis, and the blast transformation likely arose after the acquisition of additional genetic lesions. In whole-genome sequencing, the biallelic loss of the WT1 tumor suppressor gene, which occurred immediately before tumorigenesis, was identified as a potential candidate genetic alteration. The provirus CYBB cDNA in the blasts contained 108 G-to-A mutations exclusively in the coding strand, suggesting the occurrence of APOBEC3-mediated hypermutations during the transduction of CD34-positive cells. A hypermutation-mediated loss of oxidase activity may have facilitated the survival and proliferation of the clone with MECOM transactivation. Our data provide valuable insights into the complex mechanisms underlying the development of leukemia in X-CGD gene therapy.
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Epidemiology conduction of paediatric rheumatic diseases based on the registry database of the Pediatric Rheumatology Association of Japan. 査読あり
Narazaki H, Akioka S, Akutsu Y, Araki M, Fujieda M, Fukuhara D, Hara R, Hashimoto K, Hattori S, Hayashibe R, Imagawa T, Inoue Y, Ishida H, Ito S, Itoh Y, Kawabe T, Kitoh T, Kobayashi I, Matsubayashi T, Miyamae T, Mizuta M, Mori M, Murase A, Nakagishi Y, Nagatani K, Nakano N, Nishimura T, Nozawa T, Okamoto N, Okura Y, Sawada H, Sawanobori E, Sugita Y, Tanabe Y, Tomiita M, Yamaguchi KI, Yasuoka R, Yokoyama K
Modern rheumatology 2022年9月
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Nunoi H., Xie P., Nakamura H., Aratani Y., Fang J., Nishimura T., Kataoka H., Maeda H., Matsukura M.
Inflammation 45 ( 4 ) 1668 - 1679 2022年8月
記述言語：日本語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Inflammation
Chronic granulomatous disease (CGD) is a primary immunodeficiency wherein phagocytes are unable to produce reactive oxygen species (ROS) owing to a defect in the nicotinamide adenine dinucleotide phosphate oxidase (NADPH) complex. Patients with CGD experience bacterial and fungal infections and excessive inflammatory disorders. Bone marrow transplantation and gene therapy are theoretically curative; however, residual pathogenic components cause inflammation and/or organic damage in patients. Moreover, antibiotic treatments may not help in preventing excessive inflammation due to the residual presence of fungal cell wall β-glucan. Thus, better treatment strategies against CGD are urgently required. Polyethylene glycol–conjugated recombinant porcine d-amino acid oxidase (PEG-pDAO) supplies ROS to defective NADPH oxidase in neutrophils of patients with CGD, following which the neutrophils regain bactericidal activity in vitro. In this study, we employed an in vivo nonviable Candida albicans (nCA)–induced lung inflammation model of gp91-phox knockout CGD mice and supplied novel PEG conjugates of Fusarium spp. d-amino acid oxidase (PEG-fDAO), as it exhibits higher enzyme activity than PEG-pDAO. The body weight, lung weight, and lung pathology were evaluated using three experimental strategies with the in vivo lung inflammation model to test the efficacy of the ROS-generating enzyme replacement therapy with PEG-fDAO. The lung weight and pathological findings suggest the condition was ameliorated by administration PEG-fDAO, followed by intraperitoneal injection of d-phenylalanine or d-proline. Although a more precise protocol is essential, these data reveal the targeted delivery of PEG-fDAO to the nCA-induced inflammation site and show that PEG-fDAO can be used to treat inflammation in CGD in vivo.
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Recent topics and advanced therapies in chronic granulomatous disease 査読あり
Nunoi H., Nakamura H., Nishimura T., Matsukura M.
Human Cell 36 ( 2 ) 515 - 527 2022年
記述言語：日本語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Human Cell
Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by the inability of phagocytes to produce reactive oxygen species (ROS) owing to a defect in any of the five components (CYBB/gp91phox, CYBA/p22phox, NCF1/p47phox, NCF2/p67phox, and NCF4/p40phox) and a concomitant regulatory component of Rac1/2 and CYBC1/Eros of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. Patients with CGD are at an increased risk of life-threatening infections caused by catalase-positive bacteria and fungi and of inflammatory complications such as CGD colitis. Antimicrobial and azole antifungal prophylaxes have considerably reduced the incidence and severity of bacterial and improved fungal infections and overall survival. CGD studies have revealed the precise epidemiology and role of NADPH oxidase in innate immunity which has led to a new understanding of the importance of phagocyte oxygen metabolism in various host-defense systems and the fields leading to cell death processes. Moreover, ROS plays central roles in the determination of cell fate as secondary messengers and by modifying of various signaling molecules. According to this increasing knowledge about the effects of ROS on the inflammasomal system, immunomodulatory treatments, such as IFN-γ and anti-IL-1 antibodies, have been established. This review covers the current topics in CGD and the relationship between ROS and ROS-mediated pathophysiological phenomena. In addition to the shirt summary of hematopoietic stem cell transplantation and gene therapy, we introduce a novel ROS-producing enzyme replacement therapy using PEG-fDAO to compensate for NADPH oxidase deficiency.
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Functional analysis of novel A20 variants in patients with atypical inflammatory diseases 査読あり
Kadowaki S., Hashimoto K., Nishimura T., Kashimada K., Kadowaki T., Kawamoto N., Imai K., Okada S., Kanegane H., Ohnishi H.
Arthritis Research and Therapy 23 ( 1 ) 52 2021年12月
記述言語：日本語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Arthritis Research and Therapy
Background: A20 haploinsufficiency (HA20) is an early-onset autoinflammatory disease caused by mutations in the TNFAIP3 gene, which encodes the protein A20. Numerous truncating mutations in the TNFAIP3 gene have been reported in HA20 patients, whereas fewer missense variants have had their pathogenicity confirmed. Here, we evaluated the pathogenic significance of three previously unreported missense variants of the TNFAIP3 gene in suspected cases of HA20. Methods: We obtained the clinical features and immunological data of three patients with missense variants (Glu192Lys, Ile310Thr, and Gln709Arg) of unknown significance of TNFAIP3. We then performed in vitro functional assays including analysis of nuclear factor (NF)-κB reporter gene activity, detection of A20 expression and phosphorylation of A20 by IκB kinase β (IKKβ), and K63-deubiquitination assay using TNFAIP3-deficient HEK293 cells. Three known pathogenic missense mutations reported previously were also investigated. Results: The inhibitory effect on NF-κB reporter gene activity was significantly disrupted by A20 Glu192Lys and the three known mutations. The variants Ile310Thr and Gln709Arg did not show a difference from the wild type in any of the assays performed in this study. Conclusions: Among the three variants in the TNFAIP3 gene, Glu192Lys was interpreted as being likely pathogenic, but Ile310Thr and Gln709Arg as being not pathogenic (uncertain significance and likely benign, respectively), based on the American College of Medical Genetics and Genomics standards and guidelines. Our study highlights the necessity of performing in vitro functional assays, notably, NF-κB reporter gene assay, to evaluate the pathogenicity of TNFAIP3 missense variants for the accurate diagnosis of HA20.