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2. Author Correction: 5-aminolevulinic acid-mediated photodynamic therapy can target aggressive adult T cell leukemia/lymphoma resistant to conventional chemotherapy

Author

Sando, Yasuhisa, Matsuoka, Ken-ichi, Sumii, Yuichi, Kondo, Takumi, Ikegawa, Shuntaro, Sugiura, Hiroyuki, Nakamura, Makoto, Iwamoto, Miki, Meguri, Yusuke, Asada, Noboru, Ennishi, Daisuke, Nishimori, Hisakazu, Fujii, Keiko, Fujii, Nobuharu, Utsunomiya, Atae, Oka, Takashi, and Maeda, Yoshinobu

Published
2021
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8. Hematopoietic stem cell–derived Tregs are essential for maintaining favorable B cell lymphopoiesis following posttransplant cyclophosphamide

Author

Sumii, Yuichi, primary, Kondo, Takumi, additional, Ikegawa, Shuntaro, additional, Fukumi, Takuya, additional, Iwamoto, Miki, additional, Nishimura, Midori Filiz, additional, Sugiura, Hiroyuki, additional, Sando, Yasuhisa, additional, Nakamura, Makoto, additional, Meguri, Yusuke, additional, Matsushita, Takashi, additional, Tanimine, Naoki, additional, Kimura, Maiko, additional, Asada, Noboru, additional, Ennishi, Daisuke, additional, Maeda, Yoshinobu, additional, and Matsuoka, Ken-ichi, additional

Published
2023
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9. Hematopoietic stem cell-derived Tregs are essential for maintaining favorable B cell lymphopoiesis following posttransplant cyclophosphamide

Author

Sumii, Yuichi, Kondo, Takumi, Ikegawa, Shuntaro, Fukumi, Takuya, Iwamoto, Miki, Nishimura, Midori Filiz, Sugiura, Hiroyuki, Sando, Yasuhisa, Nakamura, Makoto, Meguri, Yusuke, Matsushita, Takashi, Tanimine, Naoki, Kimura, Maiko, Asada, Noboru, Ennishi, Daisuke, Maeda, Yoshinobu, Matsuoka, Ken-Ichi, Sumii, Yuichi, Kondo, Takumi, Ikegawa, Shuntaro, Fukumi, Takuya, Iwamoto, Miki, Nishimura, Midori Filiz, Sugiura, Hiroyuki, Sando, Yasuhisa, Nakamura, Makoto, Meguri, Yusuke, Matsushita, Takashi, Tanimine, Naoki, Kimura, Maiko, Asada, Noboru, Ennishi, Daisuke, Maeda, Yoshinobu, and Matsuoka, Ken-Ichi

Abstract

Posttransplant cyclophosphamide (PTCy) is associated with a low incidence of chronic graft -versus-host disease (cGVHD) following hematopoietic stem cell (HSC) transplantation. Previous studies have shown the important roles of B cell immunity in cGVHD development. Here, we investigated the long-term reconstitution of B lymphopoiesis after PTCy using murine models. We first demonstrated that the immune homeostatic abnormality leading to cGVHD is characterized by an initial increase in effector T cells in the bone marrow and subsequent B and Treg cytopenia. PTCy, but not cyclosporine A or rapamycin, inhibits the initial alloreactive T cell response, which restores intra-bone marrow B lymphogenesis with a concomitant vigorous increase in Tregs. This leads to profound changes in posttransplant B cell homeostasis, including decreased B cell activating factors, increased transitional and regulatory B cells, and decreased germinal center B cells. To identify the cells responsible for PTCy-induced B cell tolerance, we selectively depleted Treg populations that were graft or HSC derived using DEREG mice. Deletion of either Treg population without PTCy resulted in critical B cytopenia. PTCy rescued B lymphopoiesis from graft-derived Treg deletion. In contrast, the negative effect of HSC-derived Treg deletion could not be overcome by PTCy, indicating that HSC-derived Tregs are essential for maintaining favorable B lymphopoiesis following PTCy. These findings define the mechanisms by which PTCy restores homeostasis of the B cell lineage and reestablishes immune tolerance.

Published
2023

10. Responses of regulatory and effector T-cells to low-dose interleukin-2 differ depending on the immune environment after allogeneic stem cell transplantation

Author

Meguri, Yusuke, primary, Asano, Takeru, additional, Yoshioka, Takanori, additional, Iwamoto, Miki, additional, Ikegawa, Shuntaro, additional, Sugiura, Hiroyuki, additional, Kishi, Yuriko, additional, Nakamura, Makoto, additional, Sando, Yasuhisa, additional, Kondo, Takumi, additional, Sumii, Yuichi, additional, Maeda, Yoshinobu, additional, and Matsuoka, Ken-ichi, additional

Published
2022
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11. Successful Treatment of Acute Promyelocytic Leukemia Complicated with Endometrial Cancer by Arsenic Trioxide

Author

Sugiura, Hiroyuki, Nishimori, Hisakazu, Matsuoka, Hirofumi, Nakamura, Keiichiro, Fujii, Keiko, Fujii, Nobuharu, Matsuoka, Ken-ichi, and Maeda, Yoshinobu

Subjects
arsenic trioxide, immune system diseases, endometrial cancer, synchronous multiple primary malignant tumor, acute promyelocytic leukemia, chemotherapy, neoplasms
Abstract

Acute promyelocytic leukemia (APL) is a hematological emergency that requires urgent intervention because of the high incidence of early hemorrhagic death. When patients with APL experience a synchronous solid organ tumor, the tumor’s treatment must also be done properly. Differentiation-inducing therapy using arsenic trioxide (ATO) has less hematological toxicity compared to cytotoxic chemotherapy and might be preferable for untreated APL patients with a synchronous solid organ tumor. Here we describe the first successful case of untreated APL and synchronous endometrial cancer (in an adult Japanese woman) treated with ATO consolidation therapy and the subsequent surgery and chemotherapy for endometrial cancer.

Published
2021

12. Responses of regulatory and effector T-cells to low-dose interleukin-2 differ depending on the immune environment after allogeneic stem cell transplantation

Author

Meguri, Yusuke, Asano, Takeru, Yoshioka, Takanori, Iwamoto, Miki, Ikegawa, Shuntaro, Sugiura, Hiroyuki, Kishi, Yuriko, Nakamura, Makoto, Sando, Yasuhisa, Kondo, Takumi, Sumii, Yuichi, Maeda, Yoshinobu, Matsuoka, Ken-Ichi, Meguri, Yusuke, Asano, Takeru, Yoshioka, Takanori, Iwamoto, Miki, Ikegawa, Shuntaro, Sugiura, Hiroyuki, Kishi, Yuriko, Nakamura, Makoto, Sando, Yasuhisa, Kondo, Takumi, Sumii, Yuichi, Maeda, Yoshinobu, and Matsuoka, Ken-Ichi

Abstract

CD4(+)Foxp3(+) regulatory T cells (Tregs) play a central role in the maintenance of immune tolerance after allogeneic hematopoietic stem cell transplantation (HSCT). Tregs promptly respond to low concentrations of IL-2 through the constitutive expression of high-affinity IL-2 receptors. It has been reported that low-dose IL-2 therapy increased circulating Tregs and improved clinical symptoms of chronic GVHD. Clinical studies of IL-2 therapy so far have mainly targeted patients in the chronic phase of transplantation when acute immune responses has subsided. However, the biological and clinical effects of exogenous IL-2 in an acute immune environment have not been well investigated. In the current study, we investigated the impact of exogenous IL-2 therapy on the post-transplant homeostasis of T cell subsets which influence the balance between GVHD and GVL in the acute phase, by setting the various immune environments early after HSCT in murine model. We initially found that 5,000 IU of IL-2 was enough to induce the active proliferation of Treg without influencing other conventional T cells (Tcons) when administered to normal mice. However, activated Tcons showed the response to the same dose of IL-2 in recipients after allogeneic HSCT. In a mild inflammatory environment within a threshold, exogenous IL-2 could effectively modulate Treg homeostasis with just limited influence to activated T cells, which resulted in an efficient GVHD suppression. In contrast, in a severely inflammatory environment, exogenous IL-2 enhanced activated T cells rather than Tregs, which resulted in the exacerbation of GVHD. Of interest, in an immune-tolerant state after transplant, exogenous IL-2 triggered effector T-cells to exert an anti-tumor effect with maintaining GVHD suppression. These data suggested that the responses of Tregs and effector T cells to exogenous IL-2 differ depending on the immune environment in the host, and the mutual balance of the response to IL-2 between T-cell s

Published
2022

15. Concurrent Onset of Chronic Lymphocytic Leukemia and Atypical Phenotype Acute Myeloid Leukemia Revealed by Autopsy

Author

Kiso, Sayaka, primary, Sugiura, Hiroyuki, additional, Kuroi, Taiga, additional, Omote, Rika, additional, Toji, Tomohiro, additional, Ishikawa, Tatsunori, additional, Okamoto, Sachiyo, additional, Nomura, Naho, additional, Masunari, Taro, additional, Sezaki, Nobuo, additional, Kiguchi, Toru, additional, and Tanimoto, Mitsune, additional

Published
2021
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17. Pretransplant Short-Term Exposure of Donor Graft Cells to ITK Selective Inhibitor Ameliorates Acute Graft-versus-Host Disease by Inhibiting Effector T Cell Differentiation while Sparing Regulatory T Cells

Author

Kondo, Takumi, primary, Ikegawa, Shuntaro, additional, Fukumi, Takuya, additional, Sumii, Yuichi, additional, Sugiura, Hiroyuki, additional, Sando, Yasuhisa, additional, Nakamura, Makoto, additional, Meguri, Yusuke, additional, Iwamoto, Miki, additional, Maeda, Yoshinobu, additional, and Matsuoka, Ken-ichi, additional

Published
2021
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18. Donor Treg expansion by liposomal α‐galactosylceramide modulates Tfh cells and prevents sclerodermatous chronic graft‐versus‐host disease

Author

Sugiura, Hiroyuki, primary, Matsuoka, Ken‐ichi, additional, Fukumi, Takuya, additional, Sumii, Yuichi, additional, Kondo, Takumi, additional, Ikegawa, Shuntaro, additional, Meguri, Yusuke, additional, Iwamoto, Miki, additional, Sando, Yasuhisa, additional, Nakamura, Makoto, additional, Toji, Tomohiro, additional, Ishii, Yasuyuki, additional, and Maeda, Yoshinobu, additional

Published
2021
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19. Donor Treg expansion by liposomal alpha-galactosylceramide modulates Tfh cells and prevents sclerodermatous chronic graft-versus-host disease

Author

Sugiura, Hiroyuki, Matsuoka, Ken-Ichi, Fukumi, Takuya, Sumii, Yuichi, Kondo, Takumi, Ikegawa, Shuntaro, Meguri, Yusuke, Iwamoto, Miki, Sando, Yasuhisa, Nakamura, Makoto, Toji, Tomohiro, Ishii, Yasuyuki, Maeda, Yoshinobu, Sugiura, Hiroyuki, Matsuoka, Ken-Ichi, Fukumi, Takuya, Sumii, Yuichi, Kondo, Takumi, Ikegawa, Shuntaro, Meguri, Yusuke, Iwamoto, Miki, Sando, Yasuhisa, Nakamura, Makoto, Toji, Tomohiro, Ishii, Yasuyuki, and Maeda, Yoshinobu

Abstract

Background and Aim: Chronic graft-versus-host disease (cGVHD) is a major cause of nonrelapse morbidity and mortality following hematopoietic stem cell transplantation (HSCT). alpha-Galactosylceramide (alpha-GC) is a synthetic glycolipid that is recognized by the invariant T-cell receptor of invariant natural killer T (iNKT) cells in a CD1d-restricted manner. Stimulation of iNKT cells by alpha-GC leads to the production of not only immune-stimulatory cytokines but also immune-regulatory cytokines followed by regulatory T-cell (Treg) expansion in vivo. Methods: We investigated the effect of iNKT stimulation by liposomal alpha-GC just after transplant on the subsequent immune reconstitution and the development of sclerodermatous cGVHD. Results: Our study showed that multiple administrations of liposomal alpha-GC modulated both host- and donor-derived iNKT cell homeostasis and induced an early expansion of donor Tregs. We also demonstrated that the immune modulation of the acute phase was followed by the decreased levels of CXCL13 in plasma and follicular helper T cells in lymph nodes, which inhibited germinal center formation, resulting in the efficient prevention of sclerodermatous cGVHD. Conclusions: These data demonstrated an important coordination of T- and B-cell immunity in the pathogenesis of cGVHD and may provide a novel clinical strategy for the induction of immune tolerance after allogeneic HSCT.

Published
2021

20. Reduced dose of PTCy followed by adjuvant alpha-galactosylceramide enhances GVL effect without sacrificing GVHD suppression

Author

Nakamura, Makoto, Meguri, Yusuke, Ikegawa, Shuntaro, Kondo, Takumi, Sumii, Yuichi, Fukumi, Takuya, Iwamoto, Miki, Sando, Yasuhisa, Sugiura, Hiroyuki, Asada, Noboru, Ennishi, Daisuke, Tomida, Shuta, Fukuda-Kawaguchi, Emi, Ishii, Yasuyuki, Maeda, Yoshinobu, Matsuoka, Ken-Ichi, Nakamura, Makoto, Meguri, Yusuke, Ikegawa, Shuntaro, Kondo, Takumi, Sumii, Yuichi, Fukumi, Takuya, Iwamoto, Miki, Sando, Yasuhisa, Sugiura, Hiroyuki, Asada, Noboru, Ennishi, Daisuke, Tomida, Shuta, Fukuda-Kawaguchi, Emi, Ishii, Yasuyuki, Maeda, Yoshinobu, and Matsuoka, Ken-Ichi

Abstract

Posttransplantation cyclophosphamide (PTCy) has become a popular option for haploidentical hematopoietic stem cell transplantation (HSCT). However, personalized methods to adjust immune intensity after PTCy for each patient's condition have not been well studied. Here, we investigated the effects of reducing the dose of PTCy followed by alpha -galactosylceramide (alpha -GC), a ligand of iNKT cells, on the reciprocal balance between graft-versus-host disease (GVHD) and the graft-versus-leukemia (GVL) effect. In a murine haploidentical HSCT model, insufficient GVHD prevention after reduced-dose PTCy was efficiently compensated for by multiple administrations of alpha -GC. The ligand treatment maintained the enhanced GVL effect after reduced-dose PTCy. Phenotypic analyses revealed that donor-derived B cells presented the ligand and induced preferential skewing to the NKT2 phenotype rather than the NKT1 phenotype, which was followed by the early recovery of all T cell subsets, especially CD4(+)Foxp3(+) regulatory T cells. These studies indicate that alpha -GC administration soon after reduced-dose PTCy restores GVHD-preventing activity and maintains the GVL effect, which is enhanced by reducing the dose of PTCy. Our results provide important information for the development of a novel strategy to optimize PTCy-based transplantation, particularly in patients with a potential relapse risk.

Published
2021

21. Secondary Pulmonary Alveolar Proteinosis Associated with Primary Myelofibrosis and Ruxolitinib Treatment: An Autopsy Case

Author

Sugiura, Hiroyuki, Nishimori, Hisakazu, Nishii, Kazuya, Toji, Tomohiro, Fujii, Keiko, Fujii, Nobuharu, Matsuoka, Ken-ichi, Nakata, Koh, Kiura, Katsuyuki, Maeda, Yoshinobu, Sugiura, Hiroyuki, Nishimori, Hisakazu, Nishii, Kazuya, Toji, Tomohiro, Fujii, Keiko, Fujii, Nobuharu, Matsuoka, Ken-ichi, Nakata, Koh, Kiura, Katsuyuki, and Maeda, Yoshinobu

Abstract

Pulmonary alveolar proteinosis (PAP) is an uncommon lung disorder characterized by the excessive accumulation of surfactant-derived lipoproteins in the pulmonary alveoli and terminal bronchiole. Secondary PAP associated with primary myelofibrosis (PMF) is extremely rare, and to our knowledge, no autopsy case has been reported. We herein report an autopsy case of secondary PAP occurring in a patient with PMF who was treated with the Janus kinase 1/2 inhibitor ruxolitinib. We confirmed a diagnosis of PAP with complications based on the pathological findings at the autopsy. Notably, this case might suggest an association between ruxolitinib treatment and PAP occurrence.

Published
2020

24. Mechanistic Analysis of Prolonged Negative Impacts of Anti-CCR4 Antibody Mogamulizumab on Regulatory T Cell Homeostasis after Allogeneic Hematopoietic Stem Cell Transplantation

Author

Sando, Yasuhisa, primary, Matsuoka, Ken-Ichi, additional, Meguri, Yusuke, additional, Kondo, Takumi, additional, Ikegawa, Shuntaro, additional, Sugiura, Hiroyuki, additional, Nakamura, Makoto, additional, Iwamoto, Miki, additional, Asano, Takeru, additional, Yoshioka, Takanori, additional, and Maeda, Yoshinobu, additional

Published
2018
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27. Enhancement of Growth and Yield of Barley by the Soil Conditioner FFC-ace

Author

Fujita, Keiko, Suzuki, Tomoko, Hasegawa, Sachiko, Meguro, Akane, Sugiura, Hiroyuki, Toyoda, Kazuhiro, Shiraishi, Tomonori, Sakaguchi, Ei, Nishimura, Tomio, and Kunoh, Hitoshi

Subjects
FFC-ace (soil conditioner), enhanced growth and yield, chemical analysis of grains, food and beverages, barley (Hordeum vulgare L.), enhanced photosynthesis and transpiration
Abstract

The effects of a unique soil conditioner, FFC-ace, on photosynthesis, transpiration, growth and yield of barley were examined in a field experiment. FFC-ace well-mixed with sandy soil greatly enhanced root and shoot growth, tillering and the number of grains per stock. The total yield in the treated plot increased by about 172%. The plants grown in the FFC-ace plot were greener and contained a higher level of chlorophyll, compared with the control. Photosynthesis and transpiration, which are tightly linked to productivity were also significantly enhanced at the broad range of photon flux observed in our study. The quality of grain harvested from the FFC-ace plot was similar to the control plot in terms of nutritional and inorganic components. The increased photosynthesis in the FFC-ace treated barley reflects a higher absorption of CO(2) from the atmosphere. It was also noted that the efficiency of water utilization for photosynthesis was significantly greater under the high light intensity in the treated plot. The relationship between application of FFC-ace and absorption of atmospheric CO(2) is discussed. Our investigation provides data showing that application of FFC-ace to soil significantly reduces water requirements for plant growth and yield., 本報は，㈱エフエフシー・ジャパンから販売されている土壌改質材FFCエースTMの作物の生長促進効果について，2006年11月から翌年６月，本学農学部内の実験圃場で実施された，オオムギの生育ならびに収量調査に関する試験結果をとりまとめたものである．実施圃場の砂土壌にFFCエースを所定量混和した区画を設け，オオムギの種子を播種した．なお，対照区は非導入土壌とした．定期的に行った生育調査の結果，FFCエースを導入した土壌では非導入の区画と比べて，生育初期における根の生育が良好となり，地上部における分けつ数の増加とともに穂の生長も旺盛となって，１穂当たりの収穫量（粒数）の著しい増加をもたらした．結果，FFCエース導入区における全収量は非導入区と比べて約1.7倍となった．また，それぞれから収穫したオオムギ粒に含まれる栄養価ならびに無機元素類の量には，FFCエースの導入，非導入によって大きな違いは認められず，導入の効果は収量に大きく反映された．事実，調査期間中に行った測定から，FFCエースを投入した土壌で生育するオオムギ葉は高いクロロフィル量を示しており，光合成が促進されているものと考えられた．実際，播種後４ヶ月目以降，光合成ならびに蒸散速度値を測定した結果，FFCエース導入区で生育したオオムギでは常に高い値を示した．また，FFCエースの導入によって強光条件下における水利用効率が促進された．本報告では，FFCエースの投与と空気中からの二酸化炭素の吸収量との関連について考察するとともに，併せて，FFCエースの土壌への導入によって作物の生育に必要な灌水量を大きく減らすことができる可能性についても言及したい．

Published
2010

28. Impact of Incomplete Blood Count Recovery Prior to Allogeneic Hematopoietic Stem Cell Transplantation on Engraftment and Early Infection in Patients with Acute Myeloid Leukemia

Author

Asano, Takeru, primary, Ikegawa, Shuntaro, additional, Inomata, Tomoko, additional, Ikeda, Naoto, additional, Sugiura, Hiroyuki, additional, Kuroi, Taiga, additional, Yoshida, Shohei, additional, Nishimori, Hisakazu, additional, Matsuoka, Ken-ichi, additional, Fujii, Nobuharu, additional, Kondo, Eisei, additional, Maeda, Yoshinobu, additional, and Tanimoto, Mitsune, additional

Published
2016
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29. Successful Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Mild Renal Dysfunction Calculated By Creatinin Clearance

Author

Ikegawa, Shuntaro, primary, Inomata, Tomoko, additional, Ikeda, Naoto, additional, Sugiura, Hiroyuki, additional, Kuroi, Taiga, additional, Asano, Takeru, additional, Yoshida, Shohei, additional, Nishimori, Hisakazu, additional, Matsuoka, Ken-ichi, additional, Fujii, Nobuharu, additional, Kondo, Eisei, additional, Maeda, Yoshinobu, additional, and Tanimoto, Mitsune, additional

Published
2016
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30. Peripheral Eosinophilia May Prevent Progression to Severe Acute GVHD after Allogeneic Hematopoietic Stem Cell Transplantation

Author

Sakai, Kazuya, primary, Ueda, Atushi, additional, Takaya, Ryosuke, additional, Ochi, Shinichi, additional, Nabe, Shogo, additional, Nagayama, Takashi, additional, Muranushi, Hiroyuki, additional, Sugiura, Hiroyuki, additional, Okada, Kazuya, additional, Sato, Aki, additional, Sato, Takayuki, additional, Maeda, Takeshi, additional, Onishi, Tatsuhito, additional, and Ueda, Yasunori, additional

Published
2016
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35. Hairy Cell Leukemia with Systemic Lymphadenopathy: Detection of BRAF Mutations in Both Lymph Node and Peripheral Blood Specimens

Author

Okada, Kazuya, primary, Kunitomi, Akane, additional, Sakai, Kazuya, additional, Muranushi, Hiroyuki, additional, Okamoto, Yusuke, additional, Tsukamoto, Taku, additional, Sugiura, Hiroyuki, additional, Matsui, Hiroyuki, additional, Jo, Tomoyasu, additional, Ueda, Tomoaki, additional, Onishi, Tatsuhito, additional, Ide, Masaru, additional, Kimura, Shinya, additional, Notohara, Kenji, additional, and Ueda, Yasunori, additional

Published
2015
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36. Clinical Significance of Risk Stratification Based on Disease Risk Index and Hematopoietic Cell Transplantation-Comorbidity Index

Author

Sato, Takayuki, primary, Ochi, Shinichi, additional, Nagayama, Takashi, additional, Nabe, Shogo, additional, Sakai, Kazuya, additional, Muranushi, Hiroyuki, additional, Okamoto, Yusuke, additional, Sugiura, Hiroyuki, additional, Okada, Kazuya, additional, Sato, Aki, additional, Maeda, Takeshi, additional, Onishi, Tatsuhito, additional, and Ueda, Yasunori, additional

Published
2014
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37. SUV Max Reduction Criteria of Interim Positron Emission Tomography Improves Prognostic Value in Diffuse Large B-Cell Lymphoma: A Single-Center Retrospective Review

Author

Okamoto, Yusuke, primary, Ochi, Shinichi, additional, Nagayama, Takashi, additional, Nabe, Shogo, additional, Sakai, Kazuya, additional, Muranushi, Hiroyuki, additional, Sugiura, Hiroyuki, additional, Okada, Kazuya, additional, Sato, Aki, additional, Sato, Takayuki, additional, Maeda, Takeshi, additional, Onishi, Tatsuhito, additional, and Ueda, Yasunori, additional

Published
2014
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38. Absolute Lymphocyte Count As an Independent Prognostic Factor of IPI and NCCN-IPI in DLBCL Patients

Author

Okada, Kazuya, primary, Ochi, Shinichi, additional, Nagayama, Takashi, additional, Nabe, Shogo, additional, Sakai, Kazuya, additional, Muranushi, Hiroyuki, additional, Okamoto, Yusuke, additional, Sugiura, Hiroyuki, additional, Sato, Aki, additional, Sato, Takayuki, additional, Maeda, Takeshi, additional, Onishi, Tatsuhito, additional, and Ueda, Yasunori, additional

Published
2014
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39. Analysis of Tumor Lysis Syndrome Treated in Our Hospital

Author

Okamoto, Yusuke, primary, Tsukamoto, Taku, additional, Sugiura, Hiroyuki, additional, Matsui, Hiroyuki, additional, Ueda, Tomoaki, additional, Okada, Kazuya, additional, Jo, Tomoyasu, additional, Onishi, Tatsuhito, additional, Maeda, Takeshi, additional, and Ueda, Yasunori, additional

Published
2014
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40. The Curative Potential Of Fludarabine125, Melphalan100, and Busulfan4 As a Conditioning Regimen For Myeloid Malignancies Of Elderly Patients

Author

Ueda, Tomoaki, primary, Sato, Aki, additional, Sakai, Kazuya, additional, Muranushi, Hiroyuki, additional, Okamoto, Yusuke, additional, Tsukamoto, Taku, additional, Sugiura, Hiroyuki, additional, Matsui, Hiroyuki, additional, Jo, Tomoyasu, additional, Okada, Kazuya, additional, Maeda, Takeshi, additional, Onishi, Tatsuhito, additional, Kunitomi, Akane, additional, and Ueda, Yasunori, additional

Published
2013
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41. Pre-Treatment WT1 mRNA Expression Level In Peripheral Blood Predicts Response and Overall Survival Of Myelodysplastic Syndrome Patients In The Azacitidine Era

Author

Jo, Tomoyasu, primary, Sakai, Kazuya, additional, Muranushi, Hiroyuki, additional, Okamoto, Yusuke, additional, Tsukamoto, Taku, additional, Sugiura, Hiroyuki, additional, Matsui, Hiroyuki, additional, Ueda, Tomoaki, additional, Okada, Kazuya, additional, Maeda, Takeshi, additional, Onishi, Tatsuhito, additional, Kunitomi, Akane, additional, and Ueda, Yasunori, additional

Published
2013
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42. Risk Factors and Prognosis of Hemorrhagic Cystitis after Allogeneic Stem Cell Transplantation: Retrospective Analysis in a Single Institution

Author

Arai, Yasuyuki, primary, Maeda, Takeshi, additional, Sugiura, Hiroyuki, additional, Matsui, Hiroyuki, additional, Moriwake, Tomoko, additional, Jo, Tomoyasu, additional, Ueda, Tomoaki, additional, Okada, Kazuya, additional, Kawata, Takahito, additional, Oonishi, Tatsuhito, additional, Mizutani, Chisato, additional, Matsuyama, Fumio, additional, and Ueda, Yasunori, additional

Published
2010
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46. Erythema Nodosum Secondary to CD5-Positive Diffuse Large B-Cell Lymphoma as a Paraneoplastic Symptom: A Case Report.

Author

Abe, Masaya, Ohno, Kyotaro, Nakagawa, Yuki, Sato, Yasuharu, and Sugiura, Hiroyuki

Subjects
*ERYTHEMA nodosum, *IDIOPATHIC diseases, *IMMUNE complexes, *SYMPTOMS, *PATHOLOGY
Abstract

Introduction: Erythema nodosum (EN) is the most common form of panniculitis. EN can be idiopathic or secondary to an underlying systemic disease, infection, drug use, or tumor. CD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) is a relapsed and refractory lymphoma, and further understanding of its pathology is required. We report a case of newly diagnosed CD5+ DLBCL with concomitant EN. Within the scope of our search, there were no reports of CD5+ DLBCL complicated with EN. Case Presentation: A 79-year-old woman experienced swelling, warmth, redness, and pain in both legs and a mass lesion on the right side of the back at almost the same time. The respective lesions were diagnosed as EN and CD5+ DLBCL by biopsy. With chemotherapy, the lymphoma and EN improved in parallel courses. The patient has completed scheduled chemotherapy, and there has been no recurrence of swelling in the legs or mass on the right side of the back. Discussion: The lymphoma and EN developed simultaneously and followed a parallel clinical course after chemotherapy, suggesting that EN was a paraneoplastic symptom of CD5+ DLBCL. Recognizing and treating underlying malignancies in patients presenting with EN is crucial. [ABSTRACT FROM AUTHOR]

Published
2024
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47. Essential Role of Regulatory T Cells on Early B Cell Reconstitution after Haploidentical BMT with Posttransplant Cyclophosphamide

Author

Iwamoto, Miki, Matsuoka, Ken-ichi, Meguri, Yusuke, Ikegawa, Shuntaro, Sugiura, Hiroyuki, Sando, Yasuhisa, Nakamura, Makoto, Asano, Takeru, and Maeda, Yoshinobu

Abstract

Posttransplant cyclophosphamide (PTCy) is an effective prophylaxis for both acute and chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Recent studies reported that PTCy has been associated with low incidence of viral infections or EBV-related posttransplantation lymphoproliferative disease (EB-LPD), suggesting PTCy-based immune modulation leads the favorable immune reconstitution after transplant. Recently, we studied the immune reconstitution dynamics of each lymphocyte subset after transplant using PTCy and reported that PTCy-based immune-modulation strongly promoted Treg-dominant T-cell reconstitution and stem cell-derived mature B-cell generation by using murine model of haploidentical HSCT with PTCy. TCR- and BCR- repertoire analysis demonstrated that PTCy resulted in the broader diversity of both T cell and B cell repertoire than non-PTCy controls. However, the mechanism of coordination of increased Tregs and B cells after PTCy-based HSCT has not well studied. To address this issue, we here investgated the impact and role of PTCy on Tregs and B cell recovery and the mutual influence between the two important subsets by using murine BMT model. Irradiated B6D2F1 mice were transplanted with 5x106spleen cells from the CD45.1 B6 mice together with 5x106TCD-BM from CD45.2 B6 donors. Cyclophosphamide 100mg/kg or control vehicle was administered at day 3 after transplant. Peripheral blood mononuclear cells (PBMCs) and splenic cells were sequentially obtained at day21. The chimeric balances among host-residual H-2kd+ cells, donor graft-derived cells and donor BM-derived cells in Tregs and B cells were monitored separately. To evaluate the homeostatic stability, proliferation marker Ki-67 and anti-apoptotic BCL-2 were also quantitatively examined respectively. To examine the detailed phenotype of Tcells, CD4, CD8, CD25, Foxp3, ICOS, CXCR5 were tested. Also, to examine the detailed phenotype of B cells, the expression of B220, CD21, CD23, CD24 were tested. At day21 after HSCT, the number of Treg cell in spleen was significantly higher on PTCy-treated recipients than that of non-PTCy control (P < 0.05). We also checked the emergence of donor-derived follicular helper T cells (Tfh) in lymph node because recent studies have shown that Tfh could contribute B cell differentiation after HSCT. In our analysis at day21 in this PTCy model, Tfh cells were still few in both PTCy group and non-PTCy group, suggesting the early T cell recovery after PTCy did not promote B cell differentiation into pathological plasmablast. The number of B cell was markedly higher in PTCy-treated recipients than that of non-PTCy control (P < 0.01). The increased B cell population was mainly transitional-1 phenotype suggesting these B cells were recent emigrants from bone marrow. In consistent with low recovery of Tfh cells, plasmablast-like phenotype of B cells were not observed. Next, to evaluate the impact of graft-derived Treg recovery on B cell reconstitution, we depleted Treg from spleen cells of B6 donors by using CD25+ magnetic beads. After the depletion, residual Treg cell in the graft was under 1% of total CD4 T cells. At day21, splenic Treg cells is under 3% of total CD4 T cells in Treg-depleted group, that is much lower than Treg in Treg-repleted group. Interestingly, the number of B cells at day21 in PTCy-treated recipients was equivalent to that of non-PTCy recipients when we depleted Treg from donor graft, suggesting that well-balaced B cell recovery promoted by PTCy was completely abolished by Treg-depletion. Taken together, our data suggested that PTCy could induce the expansion of Treg recovery and naïve B cell recovery without urging early emergence of Tfh cells in lymph node, resulting in well-diversed T and B cell reconstitution. Treg appears to contribute to promote naïve B cell emergence from bone marrow, indicating the T and B cell recovery might be mutually influenced. Moreover, slow recovery of Tfh cells in lymph node could be advantage for preventing B cell from forced differentiation into plasmablast causing GVHD. These data provide the important information for understanding the immunological reconstitution after PTCy-based haploidentical HSCT.

Published
2017
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48. Early Administration of Low-Dose IL-2 Intensify Graft-Versus-Leukemia Effect without Worsening GVHD through Sequential Enhancement of Effector T Cell and CD62L+ Regulatory T Cell Subset

Author

Meguri, Yusuke, Matsuoka, Ken-ichi, Ikegawa, Shuntaro, Sugiura, Hiroyuki, Nakamura, Makoto, Sando, Yasuhisa, Miki, Iwamoto, Yoshioka, Takanori, Asano, Takeru, and Maeda, Yoshinobu

Abstract

Allogeneic hematopoietic stem cell transplantation (HSCT) is the curative treatment of many hematological malignancies, but the relapse is one of the major causes of treatment failure and mortality. Previous clinical studies have shown that low-dose IL-2 was well tolerated and could lower the relapse rate in human T cell depleted allogeneic BMT. On the other hand, we also demonstrated that low-dose IL-2 could preferentially enhance regulatory T cell (Treg) and improve the symptoms of chronic GVHD (NEJM 2011,Sci Trans Med 2013). In murine bone marrow transplantation (BMT) model showed that Treg can protect from lethal GVHD while preserving graft-versus-leukemia (GVL) effect. Especially, CD62L+ Tregs has a higher capacity in suppressing GVHD than their CD62L- counterpart. Our recent study reported that exogenous low-dose IL-2 induced the expression of PD-1 on Treg preferentially and it was most evident in CD44+CD62L+central-memory Treg (Blood 2016). However, the impact of CD62L+ Treg enhanced by low-dose IL-2 on GVHD and GVL has not been well investigated. In this study, we studied the effect of exogenous IL-2 on the lymphocyte phenotypic profiles including naïve- versus memory-type balance and also examined donor-derived immunity, especially GVHD and GVL, by using leukemia-bearing BMT model. Lethally irradiated B6D2F1 recipients were transplanted spleen cells and BM cells from B6 donors and 5000 IU Teceleukin (recombinant IL-2) was injected once a day for 14 days. The number of CD4+CD25+Foxp3+ Treg, CD4+CD25-Foxp3- conventional T cell (Tcon) and CD8+ T cell was compared between IL2- and vehicle-treated groups. The expressions of CD44, CD62L, CCR4, CCR7, Ki-67, PD-1, CTLA-4, LAG3, GITR, ICOS and TIM-3 in each subset were also examined. Lymphocytes profiling analysis showed that IL-2 treatment in the first 7 days resulted in the dominant expansion of effector T cells without Treg increase (Treg 0.10 vs 0.16,p=0.35, Tcon 2.83 vs 4.20, p=0.01, CD8 T cell 5.52 vs 10.4, p=0.01, million). On the contrary, the extended IL-2 treatment in the next 7 days increased CD62L+ Treg (21.5 vs 48.2 % of total Treg, p<0.001, 0.02 vs 0.07 million, p=0.006) without increasing effector T cells. PD-1 on Treg was very high in BMT-recipients even without receiving IL-2, so further enhancement of PD-1 expression by IL-2 was not observed. However, the expression of other inhibitory molecules including CTLA-4 (MFI, 6.61 vs 9.92, p=<0.001), LAG-3 (1.73 vs 2.17, p=0.04) and ICOS (2.41 vs 3.84, P<0.001) was enhanced by the IL-2 treatment. To elucidate the mechanisms of the increase in CD62L+ Treg, the in vivo violet dye dilution assay was performed. We first sorted out CD62L+ T cells by micro-beads from spleen cells, and then adaptively transferred into recipients. Five days treatment of low-dose IL-2 resulted in the enhancement of the division of CD62L+ Treg (% divided cells; 19.5 vs 29.8 % of Treg, p=0.005, 62.3 vs 108 in number, p=0.002). Interestingly, when CD62L- T cells were transferred, IL-2 treatment also induced the division of the cells and, of note, induced the phenotypic change of CD62L- into CD62L+ Treg (7.63 vs 19.8 % of Treg, p=0.009, 91.3 vs 361, p=0.01). These results suggested that IL-2 have the possibility to enhance the proliferative activity of Treg with the up-regulation of CD62L expression. Lastly, we transplanted lucipherase+P815 leukemia cells into this BMT model and evaluated the clinical impact of low-dose IL-2 on GVL by using in vivo bioluminescence system. To assesse the GVL and GVHD independently, we used two different tumor burden models. In the high tumor burden model, IL-2 injection decreased bioluminescence intensity (BLI) of P815 (BLI at week3, 8.3x10E7 vs 8.1x10E6 photon/second, p<0.001) and significantly extends overall survival. On the other hand, in the low tumor burden model, both treatment groups did not die from leukemia but vehicle-treated control group showed a significant higher clinical GVHD score and died from GVHD. These data demonstrated the clinical benefits on anti-tumor effect of IL-2, which could enhance the GVL activity without the detrimental effect on GVHD. In conclusion, our data indicate multiple effects of IL-2 on post-transplant immunity can coordinate to intensify GVL separately from GVHD on the mechanism of sequential enhancement of effector T cell and CD62L+ Treg in the different phases. These data provide the important information for developing Treg-targeted therapy.

Published
2017
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