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2. Anti-drug Antibodies Against a Novel Humanized Anti-CD20 Antibody Impair Its Therapeutic Effect on Primary Biliary Cholangitis in Human CD20- and FcγR-Expressing Mice

Author

Moritoki, Yuki, Tsuneyama, Koichi, Nakamura, Yuka, Kikuchi, Kentaro, Shiota, Akira, Ohsugi, Yoshiyuki, Lian, Zhe-Xiong, Zhang, Weici, Yang, Guo-Xiang, Ueki, Shigeharu, Takeda, Masahide, Omokawa, Ayumi, Saga, Tomoo, Saga, Akiko, Watanabe, Daisuke, Miura, Masahito, Ueno, Yoshiyuki, Leung, Patrick SC, Tanaka, Atsushi, Gershwin, M Eric, and Hirokawa, Makoto

Subjects
Digestive Diseases, Rare Diseases, Liver Disease, Biotechnology, Chronic Liver Disease and Cirrhosis, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Inflammatory and immune system, Oral and gastrointestinal, Animals, Antibodies, Monoclonal, Humanized, Antigens, CD20, B-Lymphocytes, CD8-Positive T-Lymphocytes, Cells, Cultured, Disease Models, Animal, Female, Humans, Immunoglobulin G, Immunotherapy, Inflammation, Interleukin-10, Liver, Liver Cirrhosis, Biliary, Mice, Mice, Inbred C57BL, Mice, Transgenic, Receptor, Transforming Growth Factor-beta Type II, Receptors, IgG, anti-drug antibodies, anti-mitochondrial antibodies, B cell depletion therapy, human anti-chimeric antibodies, humanized anti-human CD20 antibody, mouse anti-human antibodies, primary biliary cholangitis, Immunology, Medical Microbiology
Abstract

There is considerable interest in expanding B cell-targeted therapies in human autoimmune diseases. However, clinical trials in human primary biliary cholangitis (PBC) using a chimeric antibody against human CD20 (hCD20) have showed limited efficacy. Two potential explanations for these disappointing results are the appearance of anti-drug antibodies (ADAs) and the high frequency of patients with moderate PBC or patients who had failed ursodeoxycholic acid treatment. Here, we studied a novel humanized IgG1 antibody against hCD20 and explored its efficacy in early stage PBC using a well-defined murine model. We developed a unique murine model consisting of dnTGF-βRII mice expressing hCD20 and human Fcγ receptors (hFcγRs). Beginning at 4-6 weeks of age, equivalent to stage I/II human PBC, female mice were given weekly injections of an anti-hCD20 antibody (TKM-011) or vehicle control, and monitored for liver histology as well as a broad panel of immunological readouts. After 16 weeks' treatment, we observed a significant reduction in portal inflammation, a decrease in liver-infiltrating mononuclear cells as well as a reduction in liver CD8+ T cells. Importantly, direct correlations between numbers of liver non-B cells and B cells (r = 0.7426, p = 0.0006) and between numbers of liver memory CD8+ T cells and B cells (r = 0.6423, p = 0.0054) were apparent. Accompanying these changes was a dramatic reduction in anti-mitochondrial antibodies (AMAs), interleukin (IL)-12p40 and IL-5, and elevated levels of the anti-inflammatory chemokine CXCL1/KC. In mice that developed ADAs, clinical improvements were less pronounced. Sustained treatment with B cell-targeted therapies may broadly inhibit effector pathways in PBC, but may need to be administered early in the natural history of PBC.

Published
2018

3. Clonal hematopoiesis in adult pure red cell aplasia

Author

Fujishima, Naohito, Kohmaru, Junki, Koyota, Souichi, Kuba, Keiji, Saga, Tomoo, Omokawa, Ayumi, Moritoki, Yuki, Ueki, Shigeharu, Ishida, Fumihiro, Nakao, Shinji, Matsuda, Akira, Ohta, Akiko, Tohyama, Kaoru, Yamasaki, Hiroshi, Usuki, Kensuke, Nakashima, Yasuhiro, Sato, Shinya, Miyazaki, Yasushi, Nannya, Yasuhito, Ogawa, Seishi, Sawada, Kenichi, Mitani, Kinuko, and Hirokawa, Makoto

Published
2021
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7. Prognostic Impact of Donor Source on Allogeneic Hematopoietic Stem Cell Transplantation Outcomes in Adults with Chronic Myelomonocytic Leukemia: A Nationwide Retrospective Analysis in Japan

Author

Itonaga, Hidehiro, Aoki, Kazunari, Aoki, Jun, Ishikawa, Takayuki, Ishiyama, Ken, Uchida, Naoyuki, Sakura, Toru, Ohashi, Kazuteru, Kurokawa, Mineo, Ozawa, Yukiyasu, Matsuoka, Ken-ichi, Nakamura, Yukinori, Kimura, Fumihiko, Iwato, Koji, Nawa, Yuichiro, Hirokawa, Makoto, Kato, Koji, Ichinohe, Tatsuo, Atsuta, Yoshiko, and Miyazaki, Yasushi

Published
2018
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12. Impacts of graft-versus-host disease on outcomes after allogeneic hematopoietic stem cell transplantation for chronic myelomonocytic leukemia: A nationwide retrospective study

Author

Itonaga, Hidehiro, Iwanaga, Masako, Aoki, Kazunari, Aoki, Jun, Ishiyama, Ken, Ishikawa, Takayuki, Sakura, Toru, Fukuda, Takahiro, Najima, Yuho, Yujiri, Toshiaki, Mori, Takehiko, Kurokawa, Mineo, Nawa, Yuichiro, Uchida, Naoyuki, Morishita, Yoshihisa, Hashimoto, Hisako, Eto, Tetsuya, Hirokawa, Makoto, Morishima, Yasuo, Nagamura-Inoue, Tokiko, Atsuta, Yoshiko, and Miyazaki, Yasushi

Published
2016
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17. Diagnosis and treatment of macrocytic anemias in adults

Author

Nagao, Takayo, Hirokawa, Makoto, Nagao, Takayo, and Hirokawa, Makoto

Abstract

Anemia is one of the most common health problems in the primary care setting. Macrocytosis in adults is defined as a red blood cell (RBC) mean corpuscular volume (MCV) >100 femtoliter (fL). Macrocytic anemias are generally classified into megaloblastic or nonmegaloblastic anemia. Megaloblastic anemia is caused by deficiency or impaired utilization of vitamin B12 and/or folate, whereas nonmegaloblastic macrocytic anemia is caused by various diseases such as myelodysplastic syndrome (MDS), liver dysfunction, alcoholism, hypothyroidism, certain drugs, and by less commonly inherited disorders of DNA synthesis. Macrocytic anemias are treated with cause-specific therapies, and it is crucial to differentiate nonmegaloblastic from megaloblastic anemia. Because MDS and myeloid neoplasms commonly affect the elderly, primary care physicians may encounter more cases of macrocytic anemias in the near future, as the older population increases. When MDS is suspected along with leukocytopenia and/or thrombocytopenia with anemia, a hematology consultation may be appropriate.

Published
2023

18. Clonal hematopoiesis in adult pure red cell aplasia

Author

Fujishima, Naohito, Kohmaru, Junki, Koyota, Souichi, Kuba, Keiji, Saga, Tomoo, Omokawa, Ayumi, Moritoki, Yuki, Ueki, Shigeharu, Ishida, Fumihiro, Nakao, Shinji, Matsuda, Akira, Ohta, Akiko, Tohyama, Kaoru, Yamasaki, Hiroshi, Usuki, Kensuke, Nakashima, Yasuhiro, Sato, Shinya, Miyazaki, Yasushi, Nannya, Yasuhito, Ogawa, Seishi, Sawada, Kenichi, Mitani, Kinuko, Hirokawa, Makoto, Fujishima, Naohito, Kohmaru, Junki, Koyota, Souichi, Kuba, Keiji, Saga, Tomoo, Omokawa, Ayumi, Moritoki, Yuki, Ueki, Shigeharu, Ishida, Fumihiro, Nakao, Shinji, Matsuda, Akira, Ohta, Akiko, Tohyama, Kaoru, Yamasaki, Hiroshi, Usuki, Kensuke, Nakashima, Yasuhiro, Sato, Shinya, Miyazaki, Yasushi, Nannya, Yasuhito, Ogawa, Seishi, Sawada, Kenichi, Mitani, Kinuko, and Hirokawa, Makoto

Abstract

Idiopathic pure red cell aplasia (PRCA) and secondary PRCA associated with thymoma and large granular lymphocyte leukemia are generally considered to be immune-mediated. The PRCA2004/2006 study showed that poor responses to immunosuppression and anemia relapse were associated with death. PRCA may represent the prodrome to MDS. Thus, clonal hematopoiesis may be responsible for treatment failure. We investigated gene mutations in myeloid neoplasm-associated genes in acquired PRCA. We identified 21 mutations affecting amino acid sequences in 11 of the 38 adult PRCA patients (28.9%) using stringent filtering of the error-prone sequences and SNPs. Four PRCA patients showed 7 driver mutations in TET2, DNMT3A and KDM6A, and 2 PRCA patients carried multiple mutations in TET2. Five PRCA patients had mutations with high VAFs exceeding 0.3. These results suggest that clonal hematopoiesis by stem/progenitor cells might be related to the pathophysiology of chronic PRCA in certain adult patients.

Published
2023

19. High-throughput sequencing of IgG B-cell receptors reveals frequent usage of the rearranged IGHV4-28/IGHJ4 gene in primary immune thrombocytopenia

Author

Hirokawa, Makoto, Fujishima, Naohito, Togashi, Masaru, Saga, Akiko, Omokawa, Ayumi, Saga, Tomoo, Moritoki, Yuki, Ueki, Shigeharu, Takahashi, Naoto, Kitaura, Kazutaka, Suzuki, Ryuji, Hirokawa, Makoto, Fujishima, Naohito, Togashi, Masaru, Saga, Akiko, Omokawa, Ayumi, Saga, Tomoo, Moritoki, Yuki, Ueki, Shigeharu, Takahashi, Naoto, Kitaura, Kazutaka, and Suzuki, Ryuji

Abstract

Primary immune thrombocytopenia (ITP) is an acquired form of thrombocytopenia caused by IgG anti-platelet autoantibodies and represents an organ-specific autoimmune disorder. Although the glycoprotein (GP) IIb/IIIa and GPIb/IX have been shown to be targets for autoantibodies, the antigen specificity of autoantibodies is not fully elucidated. To identify the characteristics of IgG B-cell receptor (BCR) repertoires in ITP, we took advantage of adaptor-ligation PCR and high-throughput DNA sequencing methods for analyzing the clone-based repertoires of IgG-expressing peripheral blood B cells. A total of 2,009,943 in-frame and 315,469 unique reads for IGH (immunoglobulin heavy) were obtained from twenty blood samples. Comparison of the IGHV repertoires between patients and controls revealed an increased usage of IGHV4-28 in ITP patients. One hundred eighty-six distinct IGHV4-28-carrying sequences were identified in ITP patients and the majority of these clones used an IGHJ4 segment. The IGHV4-28/IGHJ4-carrying B-cell clones were found in all ITP patients. Oligoclonal expansions of IGHV4-28/IGHJ4-carrying B cells were accompanied by multiple related clones with single amino substitution in the CDR3 region suggesting somatic hypermutation. Taken together, the expansion of IGHV4-28/IGHJ4-carrying IgG-expressing B cells in ITP may be the result of certain antigenic pressure and may provide a clue for the immune pathophysiology of ITP.

Published
2023

20. G-Protein-Coupled Estrogen Receptor Agonist Suppresses Airway Inflammation in a Mouse Model of Asthma through IL-10

Author

Itoga, Masamichi, Konno, Yasunori, Moritoki, Yuki, Saito, Yukiko, Ito, Wataru, Tamaki, Mami, Kobayashi, Yoshiki, Kayaba, Hiroyuki, Kikuchi, Yuta, Chihara, Junichi, Takeda, Masahide, Ueki, Shigeharu, Hirokawa, Makoto, Itoga, Masamichi, Konno, Yasunori, Moritoki, Yuki, Saito, Yukiko, Ito, Wataru, Tamaki, Mami, Kobayashi, Yoshiki, Kayaba, Hiroyuki, Kikuchi, Yuta, Chihara, Junichi, Takeda, Masahide, Ueki, Shigeharu, and Hirokawa, Makoto

Abstract

Estrogen influences the disease severity and sexual dimorphism in asthma, which is caused by complex mechanisms. Besides classical nuclear estrogen receptors (ER alpha beta), G-protein-coupled estrogen receptor (GPER) was recently established as an estrogen receptor on the cell membrane. Although GPER is associated with immunoregulatory functions of estrogen, the pathophysiological role of GPER in allergic inflammatory lung disease has not been examined. We investigated the effect of GPER-specific agonist G-1 in asthmatic mice. GPER expression in asthmatic lung was confirmed by immunofluorescent staining. OVA-sensitized BALB/c and C57BL/6 mice were treated with G-1 by daily subcutaneous injections during an airway challenge phase, followed by histological and biochemical examination. Strikingly, administration of G-1 attenuated airway hyperresponsiveness, accumulation of inflammatory cells, and levels of Th2 cytokines (IL-5 and IL-13) in BAL fluid. G-1 treatment also decreased serum levels of anti-OVA IgE antibodies. The frequency of splenic Foxp3(+) CD4(+) regulatory T cells and IL-10-producing GPER(+) CD4(+) T cells was significantly increased in G-1-treated mice. Additionally, splenocytes isolated from G-1-treated mice showed greater IL-10 production. G-1-induced amelioration of airway inflammation and IgE production were abolished in IL-10-deficient mice. Taken together, these results indicate that extended GPER activation negatively regulates the acute asthmatic condition by altering the IL-10-producing lymphocyte population. The current results have potential importance for understanding the mechanistic aspects of function of estrogen in allergic inflammatory response.

Published
2023

21. Functional Analysis of Free Fatty Acid Receptor GPR120 in Human Eosinophils: Implications in Metabolic Homeostasis

Author

Konno, Yasunori, Ueki, Shigeharu, Takeda, Masahide, Kobayashi, Yoshiki, Tamaki, Mami, Moritoki, Yuki, Oyamada, Hajime, Itoga, Masamichi, Kayaba, Hiroyuki, Omokawa, Ayumi, Hirokawa, Makoto, Konno, Yasunori, Ueki, Shigeharu, Takeda, Masahide, Kobayashi, Yoshiki, Tamaki, Mami, Moritoki, Yuki, Oyamada, Hajime, Itoga, Masamichi, Kayaba, Hiroyuki, Omokawa, Ayumi, and Hirokawa, Makoto

Abstract

Recent evidence has shown that eosinophils play an important role in metabolic homeostasis through Th2 cytokine production. GPR120 (FFA4) is a G protein-coupled receptor (GPCR) for long-chain fatty acids that functions as a regulator of physiological energy metabolism. In the present study, we aimed to investigate whether human eosinophils express GPR120 and, if present, whether it possesses a functional capacity on eosinophils. Eosinophils isolated from peripheral venous blood expressed GPR120 at both the mRNA and protein levels. Stimulation with a synthetic GPR120 agonist, GW9508, induced rapid down-regulation of cell surface expression of GPR120, suggesting ligand-dependent receptor internalization. Although GPR120 activation did not induce eosinophil chemotactic response and degranulation, we found that GW9508 inhibited eosinophil spontaneous apoptosis and Fas receptor expression. The anti-apoptotic effect was attenuated by phosphoinositide 3-kinase (PI3K) inhibitors and was associated with inhibition of caspase-3 activity. Eosinophil response investigated using ELISpot assay indicated that stimulation with a GPR120 agonist induced IL-4 secretion. These findings demonstrate the novel functional properties of fatty acid sensor GPR120 on human eosinophils and indicate the previously unrecognized link between nutrient metabolism and the immune system.

Published
2023

32. Impact of age on outcomes of allogeneic hematopoietic stem cell transplantation with reduced intensity conditioning in elderly patients with acute myeloid leukemia

Author

Aoki, Jun, Kanamori, Heiwa, Tanaka, Masatsugu, Yamasaki, Satoshi, Fukuda, Takahiro, Ogawa, Hiroyasu, Iwato, Koji, Ohashi, Kazuteru, Okumura, Hirokazu, Onizuka, Makoto, Maesako, Yoshitomo, Teshima, Takanori, Kobayashi, Naoki, Morishima, Yasuo, Hirokawa, Makoto, Atsuta, Yoshiko, Yano, Shingo, and Takami, Akiyoshi

Published
2016
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34. Long-term outcome of patients with acquired chronic pure red cell aplasia (PRCA) following immunosuppressive therapy: a final report of the nationwide cohort study in 2004/2006 by the Japan PRCA collaborative study group

Author

Hirokawa, Makoto, Sawada, Kenichi, Fujishima, Naohito, Teramura, Masanao, Bessho, Masami, Dan, Kazuo, Tsurumi, Hisashi, Nakao, Shinji, Urabe, Akio, Fujisawa, Shin, Yonemura, Yuji, Kawano, Fumio, Oshimi, Kazuo, Sugimoto, Koichi, Matsuda, Akira, Karasawa, Masamitsu, Arai, Ayako, Komatsu, Norio, Harigae, Hideo, Omine, Mitsuhiro, Ozawa, Keiya, and Kurokawa, Mineo

Published
2015
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37. Safety and feasibility of high-dose ranimustine (MCNU), carboplatin, etoposide, and cyclophosphamide (MCVC) therapy followed by autologous stem cell transplantation for malignant lymphoma: Verlag Dr. Kovac, ISBN: 978-3-8300-6328-5, 98,80 €

Author

Kameoka, Yoshihiro, Takahashi, Naoto, Ishizawa, Kenichi, Kato, Yuichi, Ito, Jugo, Sasaki, Osamu, Murai, Kazunori, Noji, Hideyoshi, Hirokawa, Makoto, Tajima, Katsusi, Shichishima, Tsutomu, Ishida, Yoji, Harigae, Hideo, and Sawada, Kenichi

Published
2012
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42. Dynamics of human erythroblast enucleation

Author

Hebiguchi, Miwa, Hirokawa, Makoto, Guo, Yong-Mei, Saito, Kunie, Wakui, Hideki, Komatsuda, Atsushi, Fujishima, Naohito, Takahashi, Naoto, Takahashi, Tsutomu, Sasaki, Takehiko, Nunomura, Wataru, Takakuwa, Yuichi, and Sawada, Kenichi

Published
2008
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43. Eosinophil ETosis–Mediated Release of Galectin‐10 in Eosinophilic Granulomatosis With Polyangiitis

Author

Fukuchi, Mineyo, primary, Kamide, Yosuke, additional, Ueki, Shigeharu, additional, Miyabe, Yui, additional, Konno, Yasunori, additional, Oka, Nobuyuki, additional, Takeuchi, Hiroki, additional, Koyota, Souichi, additional, Hirokawa, Makoto, additional, Yamada, Takechiyo, additional, Melo, Rossana C. N., additional, Weller, Peter F., additional, and Taniguchi, Masami, additional

Published
2021
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46. Fluorescence In Situ Hybridization Monitoring of BCR-ABL-Positive Neutrophils in Chronic-Phase Chronic Myeloid Leukemia Patients during the Primary Stage of Imatinib Mesylate Therapy

Author

Takahashi, Naoto, Miura, Ikuo, Kobayashi, Yoshimi, Kume, Masaaki, Yoshioka, Tomoko, Otane, Wataru, Ohtsubo, Kaori, Takahashi, Kaoru, Kitabayashi, Atsushi, Kawabata, Yoshinari, Hirokawa, Makoto, Nishijima, Hirokazu, Ichinohasama, Ryo, DeCoteau, John, Miura, Akira B., and Sawada, Ken-ichi

Published
2005
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