T Kishimoto

Tokyo Institute of Technology, Edo, Tōkyō, Japan

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Publications (611)2859.18 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: To examine the effects of soluble factors secreted by human papillomavirus (HPV)-associated cells on human immunodeficiency virus (HIV) expression. Supernatants collected from cultured cervical biopsies and cervical cancer cell lines, and HPV-immortalized and normal keratinocytes were tested for the ability to induce HIV p24 production in two cell lines that contained latent HIV (the U1 monocytic line and the ACH-2 T cell line). Levels of HIV p24 were measured by enzyme-linked immunosorbent assay (ELISA). Culture supernatants were also assayed for the inflammatory cytokines interleukin 6, tumor necrosis factor, and interleukin 1 beta by ELISA. Supernatants from all epithelial cells tested upregulated HIV p24 expression in the U1 line but not in the ACH-2 cells. Only differentiated normal keratinocytes induced p24 production by ACH-2 cells. Neutralization of the cytokines, particularly interleukin 6, partially reduced the level of HIV-inducing activity in the culture supernatants. Additionally, cervical biopsies from HIV-infected women cultured in vitro also were able to induce HIV in U1 cells but not ACH-2 cells. Our results suggest that HPV infection of the cervix might influence HIV pathogenesis by inducing the production of immune and inflammatory factors that enhance HIV expression.
    Obstetrics and Gynecology 01/2001; 96(6):879-85. DOI:10.1016/S0029-7844(00)01057-7 · 5.18 Impact Factor
  • J Chargui · A Oyama · R Yoshimura · S Wada · T Hase · T Kishimoto
    Transplantation Proceedings 12/2000; 32(7):2462-3. DOI:10.1016/S0041-1345(00)01744-9 · 0.98 Impact Factor
  • T Hase · R Yoshimura · S Wada · Y Wantanabe · A Izawa · M Isobe · T Kishimoto · J Chargui
    Transplantation Proceedings 12/2000; 32(7):2080-1. DOI:10.1016/S0041-1345(00)01577-3 · 0.98 Impact Factor
  • Y Watanabe · R Yoshimura · S Wada · J Chargui · J Suzuki · K Kimura · M Isobe · T Kishimoto
    Transplantation Proceedings 12/2000; 32(7):1997-8. DOI:10.1016/S0041-1345(00)01528-1 · 0.98 Impact Factor
  • Transplantation Proceedings 12/2000; 32(7):2073-4. DOI:10.1016/S0041-1345(00)01573-6 · 0.98 Impact Factor
  • J Chargui · H Masao · R Yoshimura · S Wada · Y Watanabe · H Tanaka · T Kishimoto
    Transplantation Proceedings 12/2000; 32(7):2454-5. DOI:10.1016/S0041-1345(00)01740-1 · 0.98 Impact Factor
  • YS Han · M Ueda · S Tanabe · T Nakatani · T Kishimoto · R Nagai
    Transplantation Proceedings 12/2000; 32(7):1786-8. DOI:10.1016/S0041-1345(00)01373-7 · 0.98 Impact Factor
  • Source
    N Nishimoto · T Kishimoto · K Yoshizaki
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    ABSTRACT: Interleukin 6 (IL6) is a pleiotropic cytokine with a wide range of biological activities. IL6 transgene into mice gives rise to the abnormalities such as hypergammaglobulinaemia, thrombocytosis, infiltration of inflammatory cells into the tissues, mesangial cell proliferation of the kidney as well as splenomegaly and lymphadenopathy, which are predictable by the biological functions of IL6 shown in vitro. Continuous overproduction of IL6 is observed in patients with some immune-inflammatory diseases such as Castleman's disease and rheumatoid arthritis that are frequently associated with similar abnormalities to those of IL6 transgenic mice, strongly suggesting the involvement of IL6 in the human diseases. Successful treatment of the model animals for immune-inflammatory diseases with anti-IL6 receptor (IL6R) antibody thus indicates the possible application of IL6 blocking agents to treat the IL6 related immune-inflammatory diseases of humans. In this review, the new therapeutic strategy for Castleman's disease and RA using humanized antibody to human IL6 receptor, MRA, is discussed.
    Annals of the Rheumatic Diseases 12/2000; 59 Suppl 1:i21-7. · 10.38 Impact Factor
  • K Yamauchi-Takihara · T Kishimoto
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    ABSTRACT: The binding of ligands to gp130 activates the JAK/STAT signal transduction pathway, where STAT3 plays a central role in transmitting signals from the membrane to the nucleus. STAT3 is essential for gp130-mediated cardiac myocyte hypertrophy. Cardiac-specific disruption of gp130 was shown to present heart failure in response to mechanical stress accompanied by an increase in apoptosis. Thus, the inactivation of STAT3 resulting from the loss of gp130 may be a key event in the transition from cardiac hypertrophy to heart failure. Proper vascular growth is essential for normal cardiac development and remodeling process. Recently, bcl-xL and VEGF have identified as target genes of STAT and together can promote cardiac myocyte survival by prevention of apoptosis and restoration of energy deprivation. In this review, STAT3 is highlighted as a regulator of angiogenic factors, and activation of STAT-mediated signaling in the cardiac myocyte is proposed as a novel therapeutic strategy for the prevention of heart failure.
    Trends in Cardiovascular Medicine 11/2000; 10(7):298-303. DOI:10.1016/S1050-1738(01)00066-4 · 2.91 Impact Factor
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    M Kawano · R Yasumoto · T Tanaka · N Nishisaka · T Naganuma · T Kishimoto
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    ABSTRACT: Between May 1997 and February 1998, 40 cases of renal stones and 40 cases of ureteral stones in 60 males and 20 females were treated with the Dornier Lithotripter Compact. The size of the stones ranged from 5 mm to 80 mm. Three patients required epidural anesthesia and 4 patients required a ureteral stent. Fragmentation of the stones was observed in all patients. After 1 month, the efficacy and stone free rates were 91% and 54%, respectively. After 3 months, they were 91% and 68%, respectively. There were no serious side effects such as pyelonephritis, perirenal hematomas, and massive hematuria. In conclusion, the Dornier Lithotripter Compact proved to be a safe and highly effective lithotripter for the treatment of renal and ureteral stones.
    Hinyokika kiyo. Acta urologica Japonica 11/2000; 46(10):701-4.
  • T Nakatani · T Kishimoto · T Tsujino · T Sugimura · A Oyama · T Kato · E Higashihara
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    ABSTRACT: Urological procedures for progressive renal dysfunction due to polycystic kidney disease (PKD) such as percutaneous puncture of renal cysts are merely symptomatic treatments and have little effect on renal function. At present, the two most effective methods of preventing renal dysfunction are blood pressure management and dietetic therapy, which are more effective with early initiation. Moreover, as PKD is an autosomal dominant disease, there is a high risk that family members of the patient may have asymptomatic PKD. It is essential to identify and treat such potential patients at an early stage in order to prevent progressive renal dysfunction. In place of the traditional nephrectomy, we attempted transcutaneous renal arterial embolization (TRAE) for hemorrhage into renal cysts, hematuria and obstruction of intestine due to proliferation of cysts after the introduction of hemodialysis. When TRAE was carried out on one kidney, the cysts in the other kidney proliferated and even though the renal arteries were completely embolized, it required 5 to 6 weeks for the kidney to contract. Our conclusions are TRAE is effective with no adverse reactions for PKD. These results suggest that in the future TRAE may become the preferred treatment for PKD in place of nephrectomy.
    Hinyokika kiyo. Acta urologica Japonica 10/2000; 46(9):645-50.
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    ABSTRACT: We reported that the activation of gp130 transduced hypertrophic and cytoprotective signals via Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway in cardiac myocytes. Recent in vivo experiments have demonstrated that the JAK/STAT pathway is activated in acute pressure overload hearts. The present study was designed to examine whether the JAK/STAT pathway is also activated in acute myocardial infarction (AMI) and to determine its pathophysiological roles in ischemic heart disease. AMI model was generated by the ligation of proximal left anterior descending coronary artery of male Wistar rat. They were sacrificed at various time points ranging from 1 to 24 h after coronary ligation and their hearts were examined. Tyrosine phosphorylation of STAT3 was observed in the myocardium obtained from both the ischemic area and the healthy border area adjacent to the infarcted area. The AMI rats were next randomly assigned to two groups, one with coronary ligation only (group M), and the other with coronary ligation with AG-490 treatment (1 mg/kg i.v., every 4 h), a specific JAK2 inhibitor (group A). In group A, phosphorylation of STAT3 was significantly suppressed and caspase-3 activity and Bax expression were significantly increased in the myocardium after AMI. In group M, few apoptotic myocytes were identified in the border area by means of TUNEL assay. However, a significant increase in apoptotic cells was observed in group A. Administration of JAK2 inhibitor resulted in deterioration of myocardial viability in AMI hearts. The JAK/STAT pathway is activated in AMI myocardium and plays a pivotal role in cytoprotective signaling.
    Cardiovascular Research 10/2000; 47(4):797-805. · 5.94 Impact Factor
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    M Iwabuchi · K Ohsumi · T M Yamamoto · W Sawada · T Kishimoto
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    ABSTRACT: To investigate the regulatory mechanisms of the cell cycle transition from M phase to M phase in meiotic cycles, a Xenopus oocyte extract that performs the M-M transition has been developed. Using the meiotic extract, we found that a low level of Cdc2 activity remained at the exit of meiosis I (MI), due to incomplete degradation of cyclin B. The inactivation of the residual Cdc2 activity induced both entry into S phase and tyrosine phosphorylation on Cdc2 after MI. Quantitative analysis demonstrated that a considerable amount of Wee1 was present at the MI exit and Cdc2 inhibitory phosphorylation during this period was suppressed by the dominance of Cdc2 over Wee1. Consistently, the addition of more than a critical amount of Wee1 to the extract induced Cdc2 inhibitory phosphorylation, changing the M-M transition into an M-S-M transition. Thus, the Cdc2 activity remaining at MI exit is required for suppressing entry into S phase during the meiotic M-M transition period.
    The EMBO Journal 10/2000; 19(17):4513-23. DOI:10.1093/emboj/19.17.4513 · 10.43 Impact Factor
  • S Wada · R Yoshimura · M Kyo · T Hase · C Masuda · Y Watanabe · S Ikemoto · H Kawashima · T Kishimoto
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    ABSTRACT: Transurethral resection of the prostate (TURP) is the gold standard treatment for benign prostatic hyperplasia (BPH). Recently, less invasive transurethral laser prostatectomy, such as visual laser ablation (VLAP) or interstitial laser coagulation (ILCP), have been developed. Herein, we investigated the efficacy of VLAP and ILCP compared to TURP. A total of 80 patients with BPH were treated: 20 patients by VLAP, 30 patients by ILCP and 30 patients by TURP. All patients were followed up for 12 months after their operations. Treatment outcomes were evaluated by four different criteria: (i) the International Prostatic Symptom Score (I-PSS), (ii) the maximum flow rate (Qmax), (iii) postvoided residual urine volume before treatment and one, three, six and 12 months after treatment, and (iv) prostatic volume before operation and three and six months postoperatively. The I-PSS, Qmax and residual urine volume were significantly improved compared to baseline levels and the improvement continued for 12 months in the three groups: for I-PSS (P<0.001 in the VLAP group and P<0.0001 in the ILCP and TURP groups), Qmax (P<0.001 in the VLAP and ILCP groups, and P<0.0001 in the TURP group), residual urine volume (P<0.01 in the VLAP group and P<0.0001 in the ILCP and TURP groups). Significant reduction of the prostatic volume was recorded only in the ILCP and TURP groups (P<0.001). Visual laser ablation and ILCP can be good alternative treatments for BPH. Visual laser ablation provides good outcomes in patients with small-sized BPH and with risk factors such as heart disease or anticoagulation therapy.
    International Journal of Urology 10/2000; 7(10):373-7. · 2.41 Impact Factor
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    ABSTRACT: We report two cases of female urethral diverticula. A 49-year-old woman (case 1) complained of perineal pain when she voided urine. A 36-year-old woman (case 2) complained of perineal pain. In both cases, intravenous pyerography and urethrography revealed diverticula around their urethra, and we diagnosed them with urethral diverticula which surrounded their urethra by magnetic resonance imaging. We treated them by transvaginal diverticulectomy. Case 2 was successfully treated, but the diverticulum recurred after one year in case 1. There are over 200 reported cases of female diverticula in the Japanese literature, but a urethral diverticulum surrounding the urethra is rare.
    Hinyokika kiyo. Acta urologica Japonica 10/2000; 46(9):639-42.
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    ABSTRACT: Inactivation of cyclin B-Cdc2 kinase at the exit from M phase depends on the specific proteolysis of the cyclin B subunit, whereas the Cdc2 subunit remains present at nearly constant levels throughout the cell cycle. It is unknown how Cdc2 escapes degradation when cyclin B is destroyed. In Xenopus egg extracts that reproduce the exit from M phase in vitro, we have found that dissociation of the cyclin B-Cdc2 complex occurred under conditions where cyclin B was tethered to the 26S proteasome but not yet degraded. The dephosphorylation of Thr 161 on Cdc2 was unlikely to be necessary for the dissociation of the two subunits. However, the dissociation was dependent on the presence of a functional destruction box in cyclin B. Cyclin B ubiquitination was also, by itself, not sufficient for separation of Cdc2 and cyclin B. The 26S proteasome, but not the 20S proteasome, was capable of dissociating the two subunits. These results indicate that the cyclin B and Cdc2 subunits are separated by the proteasome through a mechanism that precedes proteolysis of cyclin B and is independent of proteolysis. As a result, cyclin B levels decrease on exit from M phase but Cdc2 levels remain constant.
    Genes & Development 10/2000; 14(18):2344-57. · 10.80 Impact Factor
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    ABSTRACT: Previous experiments have shown that STAT-induced STAT inhibitor-1 (SSI-1; also named suppressors of cytokine signaling-1 (SOCS-1) or Janus kinase binding protein) is predominantly expressed in lymphoid organs and functions in vitro as a negative regulator of cytokine signaling. To determine the function of SOCS-1 in vivo, we generated SSI-1 transgenic mice using the lck proximal promoter that drives transgene expression in T cell lineage. In thymocytes expressing SSI-1 transgene, tyrosine phosphorylation of STATs in response to cytokines such as IFN-gamma, IL-6, and IL-7 was inhibited, suggesting that SSI-1 suppresses cytokine signaling in primary lymphocytes. In addition, lck-SSI-1 transgenic mice showed a reduction in the number of thymocytes as a result of the developmental blocking during triple-negative stage. They also exhibited a relative increase in the percentage of CD4+ T cells, a reduction in the number of gammadelta T cells, as well as the spontaneous activation and increased apoptosis of peripheral T cells. Thus, enforced expression of SSI-1 disturbs the development of thymocytes and the homeostasis of peripheral T cells. All these features of lck-SSI-1 transgenic mice strikingly resemble the phenotype of mice lacking common gamma-chain or Janus kinase-3, suggesting that transgene-derived SSI-1 inhibits the functions of common gamma-chain-using cytokines. Taken together, these results suggest that SSI-1 can also inhibit a wide variety of cytokines in vivo.
    The Journal of Immunology 09/2000; 165(4):1799-806. DOI:10.4049/jimmunol.165.4.1799 · 4.92 Impact Factor
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    ABSTRACT: Surrogate light chains (lambda 5/VpreB) are selectively expressed in early precursors of B cells. B-cell defects in X-linked agammaglobulinemia (XLA) are caused by mutations in the gene for Bruton's tyrosine kinase. To elucidate the nature of early B-lineage cells in bone marrow (BM), samples from 13 XLA patients and 24 healthy controls of different ages were comparatively analyzed using an antihuman VpreB monoclonal antibody. Expression of surrogate light (SL) and mu-heavy chains were examined after cell membrane permeabilization because they are mainly expressed in the cytoplasm of early B-lineage cells. A flow cytometric analysis of normal BM identified 5 discrete cell types of B cells: mu(-)SL(++) (pro-B [B-cell progenitor]), mu(low)SL(++) (pre-B1a), mu(low)SL(+) (pre-B1b), mu(low)SL(- )(pre-B2), and mu(high)SL(- )(B). The large cells, presumably in cycling states, were enriched in pre-B1a cells. The frequencies of B-lineage cells in BM were higher in young children, and declined with advancing age. In contrast, XLA showed a profound reduction in BM B-lineage cells. In XLA BM, an expansion of pro-B cells with some small pre-B1a cells was marked, but other cells were negligible. These observations illustrate a B-cell maturation defect in XLA as well as a normal human B-cell differentiation pathway. The results suggest that the genetic defect in XLA may impede the evolution of pro-B cells beyond the earlier pre-B stage into the later stage of pre-B cells in B-cell development. (Blood. 2000;96:610-617)
    Blood 08/2000; 96(2):610-7. · 10.45 Impact Factor
  • GI Kusakawa · T Saito · R Onuki · K Ishiguro · T Kishimoto · SI Hisanaga
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    ABSTRACT: Cyclin-dependent kinase 5 (CDK5) is a unique CDK, the activity of which can be detected in postmitotic neurons. To date, CDK5 purified from mammalian brains has always been associated with a truncated form of the 35-kDa major brain specific activator (p35, also known as nck5a) of CDK5, known as p25. In this study, we report that p35 can be cleaved to p25 both in vitro and in vivo by calpain. In a rat brain extract, p35 was cleaved to p25 by incubation with Ca(2+). This cleavage was inhibited by a calpain inhibitor peptide derived from calpastatin and was ablated by separating the p35.CDK5 from calpain by centrifugation. The p35 recovered in the pellet after centrifugation could then be cleaved to p25 by purified calpain. Cleavage of p35 was also induced in primary cultured neurons by treatment with a Ca(2+) ionophore and Ca(2+) and inhibited by calpain inhibitor I. The cleavage changed the solubility of the CDK5 active complex from the particulate fraction to the soluble fraction but did not affect the histone H1 kinase activity. Increased cleavage was detected in cultured neurons undergoing cell death, suggesting a role of the cleavage in neuronal cell death.
    Journal of Biological Chemistry 07/2000; 275(22):17166-72. DOI:10.1074/jbc.M907757199 · 4.57 Impact Factor
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    H Saito · Y Morita · M Fujimoto · M Narazaki · T. and Naka · T Kishimoto
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    ABSTRACT: STAT-induced STAT inhibitor-1 (SSI-1), also referred to as suppressor of cytokine signaling-1 and JAK-binding protein, is a member of a new family, the members of which are negative regulators of cytokine signals. SSI-1 is induced by various cytokines; however, the transcriptional mechanism of the SSI-1 gene is not fully understood. Here, we showed that transcription of the mouse SSI-1 gene was initiated from six adjoining sites accompanying three GC boxes and a single GC box-like element near them, but not from the TATA box or an initiator sequence. We also showed that IFN-gamma induced SSI-1 mRNA more strongly than IL-6 in NIH-3T3 fibroblasts and that this IFN-gamma effect was mediated by Stat1. To determine the signal pathway downstream of Stat1, transcriptional activities of several mutant promoters were examined. The region mediating stimulatory effect of IFN-gamma to the gene transcription was localized to the -88/-60 region containing three tandem GAAA units, named variant IFN-gamma-responsive element (VIRE), while four IFN-gamma activation site (GAS)-like elements located far upstream were not related to the IFN-gamma response. Gel-shift assays revealed that IFN-gamma induced IFN regulatory factor-1 (IRF-1) binding to VIRE, but not that of IRF-2 or three components of ISGF3. Furthermore, forced expression of IRF-1 mimicked and that of IRF-2 inhibited the stimulatory effect of IFN-gamma on SSI-1 gene transcription. Finally, mouse embryonal fibroblasts lacking IRF-1 showed impaired SSI-1 mRNA induction by IFN-gamma. These results demonstrated that IRF-1, which is induced by activation of Stat1, mediated transcriptional activation of the SSI-1 gene by IFN-gamma via VIRE.
    The Journal of Immunology 07/2000; 164(11):5833-43. DOI:10.4049/jimmunol.164.11.5833 · 4.92 Impact Factor

Publication Stats

39k Citations
2,859.18 Total Impact Points


  • 1991–2011
    • Tokyo Institute of Technology
      • • Department of Bioscience
      • • School of Bioscience and Biotechnology
      Edo, Tōkyō, Japan
  • 1985–2009
    • Osaka University
      • • Division of Immune Regulation
      • • Immunology Division
      • • School of Medicine
      • • Department of Internal Medicine
      • • Division of Cellular and Molecular Biology
      Suika, Ōsaka, Japan
  • 1982–2009
    • Osaka City University
      • • Graduate School of Medicine
      • • Department of Urology
      Ōsaka, Ōsaka, Japan
  • 2004
    • Yokohama City University
      • Department of Pediatrics
      Yokohama, Kanagawa, Japan
  • 2001
    • KAKEN Pharmaceutical Co.,Ltd
      New York City, New York, United States
    • American Society of Hematology
      American Fork, Utah, United States
    • St. Elizabeth's Medical Center
      Boston, Massachusetts, United States
  • 2000
    • Howard Hughes Medical Institute
      Ашбърн, Virginia, United States
    • Tokyo Medical and Dental University
      • Department of Molecular Cell Biology
      Edo, Tōkyō, Japan
    • Shinshu University
      Shonai, Nagano, Japan
  • 1993–2000
    • Izumi City Hospital
      Ōsaka, Ōsaka, Japan
    • Tokyo Metropolitan Institute of Gerontology
      Edo, Tōkyō, Japan
    • University of Rostock
      Rostock, Mecklenburg-Vorpommern, Germany
  • 1999
    • Hokkaido University
      • Faculty of Science
      Sapporo, Hokkaidō, Japan
    • Kyoto Prefectural University
      Kioto, Kyōto, Japan
  • 1998
    • Kyoto Prefectural University of Medicine
      Kioto, Kyōto, Japan
  • 1995–1998
    • Osaka City General Hospital
      Ōsaka, Ōsaka, Japan
    • Showa University
      • Department of Biochemistry
      Shinagawa, Tōkyō, Japan
  • 1997
    • Huntington Hospital
      Huntington, New York, United States
  • 1996
    • The University of Tokyo
      • Institute of Medical Science
      Kashiwa, Chiba-ken, Japan
    • University of Zurich
      • Institut für Experimentelle Immunologie
      Zürich, ZH, Switzerland
  • 1995–1996
    • University of California, San Diego
      • Department of Medicine
      San Diego, CA, United States
  • 1994–1995
    • Tottori University
      • Department of Obstetrics and Gynecology
      TTJ, Tottori, Japan
    • Kumamoto Municipal Citizens Hospital
      Kumamoto, Kumamoto Prefecture, Japan
    • University of California, Los Angeles
      • Department of Obstetrics and Gynecology
      Los Ángeles, California, United States
    • University of Tsukuba
      • Institute of Clinical Medicine
      Tsukuba, Ibaraki, Japan
  • 1993–1995
    • Kanazawa University
      • • Department of Obstetrics and Gynecology
      • • Department of Biology
      Kanazawa, Ishikawa, Japan
  • 1991–1993
    • Nara Medical University
      • Department of Internal Medicine
      Kashihara, Nara, Japan
  • 1989–1991
    • Hiroshima University
      • • Department of General Internal Medicine
      • • Institute for Nuclear Medicine and Biology Research
      Hirosima, Hiroshima, Japan
    • University of Alabama at Birmingham
      • Department of Microbiology
      Birmingham, AL, United States
    • Icahn School of Medicine at Mount Sinai
      Borough of Manhattan, New York, United States
  • 1986–1989
    • Institut de Biologie Moléculaire et Cellulaire (IBMC)
      Strasburg, Alsace, France
  • 1988
    • Osaka Minami Medical Center
      Ōsaka, Ōsaka, Japan
    • New York State
      New York City, New York, United States
      Edo, Tōkyō, Japan
    • Kanazawa Medical University
      • Department of Hematology and Immunology
      Kanazawa, Ishikawa, Japan
  • 1977–1980
    • Fukushima Medical University
      Hukusima, Fukushima, Japan
  • 1979
    • Memorial Sloan-Kettering Cancer Center
      New York City, New York, United States