Harutaka Katano

National Institute of Infectious Diseases, Tokyo, Edo, Tōkyō, Japan

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Publications (139)442.95 Total impact

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    ABSTRACT: Severe immunodeficient mice have become invaluable tools in human stem cell and tumor research. In this study, we compared the phagocytic activity of peritoneal macrophages against primary effusion lymphoma (PEL) among Rag-2/Jak3 double-deficient (Rag-2−/−Jak3−/−) mice with NOD and non-NOD (Balb/c and C57/BL6). We also evaluated lymphomatous effusion and infiltration in a PEL xenograft mouse model using these severe immunodeficient mice. In the phagocytic assay, peritoneal macrophages in the NOD background phagocytosed CFSE-labeled BCBL-1, a PEL cell line, less efficiently than those in the non-NOD background. BCBL-1 cells were successfully engrafted into both the NOD background and non-NOD background; however, the volume of ascites of the NOD background was significantly higher than that of the non-NOD background. Moreover, the organ invasion of PEL cells was suppressed in non-NOD background mice. Thus, the NOD genetic background is considered to contribute to more lymphomatous effusion and the infiltration of PEL cells than a non-NOD background. Our results showed that the NOD background allowed more lymphomatous effusion and infiltration than other backgrounds and peritoneal macrophages played a critical role in preventing the growth and infiltration of PEL cells.
    No preview · Article · Jan 2016
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    ABSTRACT: Introduction: Kawasaki disease (KD) is the most common multisystem vasculitis in childhood. Pathogens can be associated with onset of KD. However, a lack of consistency prevails among reports about the disease. Case Presentation: For this case of a one year-old boy with four recurrent episodes of KD within a year, we analyzed profiles of pathogen reads in his serum and pharynx specimens using next-generation sequencing. Comparative analysis of the identified bacterial reads from serum samples found significant correlation of bacteria such as Streptococcus and Haemophilus spp. with the first and fourth episodes (R2 = .9506) before treatment. In the first convalescent phase, the genus Streptococcus was reduced remarkably (p< .0001). From sequencing of the pharynx specimen from the fourth episode similar correlation was found with serum from the fourth episode (R2 = .6633). Conclusion: In this case, the genus Streptococcus might be associated with onset of KD. Further studies must be undertaken to evaluate the putative association of microorganism infection with KD pathogenesis.
    Preview · Article · Dec 2015
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    ABSTRACT: Biological robustness is exposed to stochastic perturbations, which should be controlled by intrinsic mechanisms; the promiscuous signaling network without appropriate alleviation is the true nature of cancer cells. B cell receptor (BCR) signaling is a major source of gene expression signature important for B cell. It is still unclear the mechanism by which the expression of functionally important genes is continuously deregulated in malignant lymphomas. Using RISC-capture assay, we reveal that multiple BCR signaling factors are persistently regulated by microRNA (miRNA) in human B cells. Clinical samples from patients with diffuse large B-cell lymphoma (DLBCL, n = 83) show loss of an essential miRNA set (miR-200c, miR-203, miR-31). Conventional screening and RISC profiling identify multiple targets (CD79B, SYK, PKC beta II, PLC gamma 1, IKK beta, NIK, MYD88, PI3K class I (alpha/beta/delta/gamma), RasGRP3); signaling network habitually faces interference composed by miRNA group in normal B cells. We demonstrate that simultaneous depletion of the key miRNAs enhances translation of the multiple targets and causes chronic activation of NF-kappa B, PI3K-Akt, and Ras-Erk cascades, leading to B cell transformation. This study suggests that compensatory actions by multiple miRNAs rather than by a single miRNA ensure robustness of biological processes.
    Preview · Article · Dec 2015 · Scientific Reports
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    ABSTRACT: Congenital infection with human cytomegalovirus (CMV) through the placenta is one of the major causes of birth and developmental abnormalities. Guinea pig CMV (GPCMV) causes in utero infection, which makes its animal models useful for studies on congenital diseases. Here, we established an ex vivo culture method for tissue slices prepared from guinea pig placentas and demonstrated that viral spread in the model resembles those in the placenta of GPCMV-infected animals and that the infection is independent of the pentameric glycoprotein complex for endothelial/epithelial cell tropism. Thus, this model affords a useful tool for pathobiological studies on CMV placental infection.
    No preview · Article · Nov 2015 · Placenta
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    ABSTRACT: Kaposi sarcoma and primary effusion lymphoma cells are infected with Kaposi sarcoma-associated herpesvirus (KSHV), predominantly in the latent form, and KSHV replication is observed rarely. Angiogenesis plays a crucial role in the pathogenesis of both Kaposi sarcoma and primary effusion lymphoma. In this study, we found that fumagillin, a potent angiogenesis inhibitor, induced replication of KSHV in primary effusion lymphoma cell lines. The transcript and protein product of replication transcriptional activator (RTA) were induced by 1-10 μM fumagillin at 24 and 48 hours, respectively. Western blot analysis demonstrated that 10 μM fumagillin induced not only RTA expression but also other KSHV-encoded lytic proteins. A real-time PCR array detecting KSHV gene expression demonstrated that the expression profiles of KSHV induced by fumagillin were similar to those induced by 12-O-tetradecanoylphorbol-13-acetate (TPA), but the amounts of each transcript were lower than those induced by TPA. Finally, real-time PCR demonstrated an increase in that viral DNA copy number per cell in fumagillin-stimulated primary effusion lymphoma cell lines, indicating replication of KSHV. In addition to TPA, 10 μM fumagillin resulted in growth inhibition of primary effusion lymphoma cell lines. These observations suggest that an angiogenesis inhibitor is an agent with potent effects on cell growth and KSHV reactivation in primary effusion lymphoma cells. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Jun 2015 · Biochemical and Biophysical Research Communications
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    ABSTRACT: Trichodysplasia spinulosa-associated polyomavirus (TSV) was identified in, and shown to be the probable cause of, trichodysplasia spinulosa, a rare skin disease. To date, serological analyses have revealed that TSV infection is common among adults in the general population of Europe and Australia. However, there have been no reports of TSV in Asia. To study the prevalence of TSV infection in Japan. TSV-VP1 expressed in a recombinant baculovirus expression system in an insect cell line, Tn5, self-assembled into virus-like particles. Overall, 1000 serum samples were examined by enzyme-linked immunosorbent assays using virus-like particles of TSV as antigen. Participants ranged in age from 0 to 94 years. Overall, 629 of 1000 serum samples (62.9%) were positive for anti-TSV antibodies. The seropositive rate increased with age and the seroprevalence of TSV significantly increased from 17.1% (25/146) in children aged from 0 to 4 years to 78.7% (472/600) in adults aged over 20 years (odds ratio=0.056, 95% confidence interval=0.035-0.900, P=0.000, Chi-squared test). TSV seropositivity was not different between sera obtained in 1980 and 2012, and was not associated with sex. Competitive assay demonstrated that TSV antibodies did not cross-react with BK virus or Merkel cell polyomavirus. These results provide evidence that TSV circulates widely in the Japanese population, with primary exposure occurring mainly at early childhood, similar to that previously reported in other countries. Copyright © 2015 Elsevier B.V. All rights reserved.
    Full-text · Article · Apr 2015 · Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology
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    ABSTRACT: In our recombinant baculovirus system, VP1 protein of merkel cell polyomavirus (MCPyV), which is implicated as a causative agent in Merkel cell carcinoma, was self-assembled into MCPyV-like particles (MCPyV-LP) with two different sizes in insect cells, followed by being released into the culture medium. DNA molecules of 1.5- to 5-kb, which were derived from host insect cells, were packaged in large, ~50-nm spherical particles but not in small, ~25-nm particles. Structure reconstruction using cryo-electron microscopy showed that large MCPyV-LPs are composed of 72 pentameric capsomeres arranged in a T = 7 icosahedral surface lattice and are 48 nm in diameter. The MCPyV-LPs did not share antigenic determinants with BK- and JC viruses (BKPyV and JCPyV). The VLP-based enzyme immunoassay was applied to investigate age-specific prevalence of MCPyV infection in the general Japanese population aged 1-70 years. While seroprevalence of MCPyV increased with age in children and young individuals, its seropositivity in each age group was lower compared with BKPyV and JCPyV.
    Full-text · Article · Feb 2015 · PLoS ONE
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    ABSTRACT: Background: Human herpesvirus-6 (HHV-6) is the etiological agent of exanthema subitum-associated encephalopathy, which usually occurs in children younger than 3years. Brain imaging shows various abnormalities. Patient: A previously healthy 4-year-old girl developed acute encephalopathy with clinical features consisting of fever, repetitive seizures, and a disturbance of consciousness. The patient did not show skin rash suggestive of exanthema subitum during the course of her illness. The primary HHV-6 infection was diagnosed based on the absence of IgG against HHV-6 and identification of the virus DNA in the acute phase serum and a significant increase of the anti-HHV-6 IgG titers in the convalescent phase sera. Diffusion-weighted images showed transient high signal intensity in the bilateral periventricular white matter and splenium of the corpus callosum and in the gray matter structures such as the bilateral basal ganglia and thalami. Upon therapy with steroid and γ-globulin, the patient recovered without any neurological deficits. Conclusion: Primary HHV-6 infection can cause acute encephalopathy without exanthema subitum. The etiological diagnosis is possible only by examining the blood and cerebrospinal fluid, when the patient shows no skin rash. This condition should be included in the differential diagnosis of acute encephalopathy even in patients older than 3years.
    No preview · Article · Jan 2015 · Brain and Development
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    ABSTRACT: We report a case of Merkel cell carcinoma (MCC) on the dorsal aspect of the right middle finger associated with multiple squamous cell carcinomas (SCC) possibly arising in chronic radiation dermatitis of the hand of an 80-year-old surgeon. In spite of resection of the primary lesion and right axillary lymph nodes, he died of the tumor 5 months after the first visit. Cutaneous and lymph node lesions of MCC were negative for Merkel cell polyoma virus (MCPyV) by immunostaining using monoclonal antibody (CM2B4) and anti-large T antigen of MCPyV polyclonal antibody, and real-time polymerase chain reaction. Several differences in clinicopathological findings have been found between MCPyV-positive cases and negative ones. Several authors have reported that MCPyV-negative cases have a worse prognosis than MCPyV-positive ones. Furthermore, in cases of MCC associated with SCC, most tumors have been reported to be MCPyV-negative. We should pay more attention to the relationship between the carcinogenesis of MCC and ionizing irradiation.
    No preview · Article · Dec 2014 · The Journal of Dermatology
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    ABSTRACT: Background: Human herpesvirus 8 (HHV8)-positive plasmablastic lymphoma is a disease which correlates with acquired immunodeficiency syndrome (AIDS). Little is known about the pathogenesis of the disease due to its rarity. We report an autopsy case about AIDS related HHV-8-positive plasmablastic lymphoma and presents an examination about HHV8 related proteins for the disease by using immunohistochemical techniques. Case presentation: Two kinds of tumors complicated the male AIDS patient: one was HHV-8-positive plasmablastic lymphoma and the other was Kaposi's sarcoma (KS). Immunohistochemically, the lymphoma cells were positive for HHV8-associated lytic early proteins as well as HHV8 latency-associated nuclear antigen 1 (LANA-1), and, on the other hand, the lymphoma cells were negative for lytic immediately early proteins. KS was positive for only LANA-1. Conclusion: These findings indicate that the lymphoma cells acquired an ability to proliferate without de novo HHV8 replication. Moreover, the onset mechanisms of HHV-8-positive plasmablastic lymphoma may be different from those of KS.
    No preview · Article · Oct 2014 · International journal of clinical and experimental pathology
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    ABSTRACT: Purpose: Primary effusion lymphoma (PEL) is an aggressive subtype of non-Hodgkin lymphoma that shows malignant effusion most commonly seen in advanced AIDS patients. In this study, we clarified the potential role of VEGF and IL-6 in PEL fluid retention and evaluated the efficacy of humanized anti-VEGF monoclonal antibody (mAb), bevacizumab, and humanized anti-IL-6 receptor mAb, tocilizumab, against PEL. Methods: The production of VEGF and IL-6, and the expression of IL-6Rα in PEL cell lines were examined. The antiproliferative effect of bevacizumab and tocilizumab on PEL cells was evaluated in vitro. The effect of tocilizumab on VEGF was also examined. An intraperitoneal xenograft mouse model was used for in vivo efficacy. Results: Although we found the production of VEGF and IL-6, and the expression of IL-6Rα in PEL cell lines, bevacizumab and tocilizumab did not inhibit the proliferation of PEL cells in vitro. Tocilizumab decreased VEGF mRNA and VEGF production by inhibiting Stat3 phosphorylation and Stat3 binding to VEGF promoter. In a PEL xenograft mouse model that showed profuse ascites, bevacizumab suppressed ascites formation completely, indicating the critical role of VEGF for PEL fluid retention. Tocilizumab also significantly inhibited ascites formation in vivo. Moreover, these mAbs improved the overall survival of treated mice. Conclusions: IL-6-VEGF axis contributed to fluid retention, and bevacizumab and tocilizumab could be effective molecular targeting therapies for PEL.
    No preview · Article · Oct 2014 · Journal of Cancer Research and Clinical Oncology
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    ABSTRACT: We describe a fatal case of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome with human herpesvirus-6B (HHV-6B)-associated lymphadenitis and virus-associated hemophagocytic syndrome triggered by an over-the-counter medication to treat respiratory and influenza-like symptoms. Histologically, the structure of the lymph node was disrupted with infiltration of large lymphocytes carrying intranuclear acidophilic inclusion bodies. Immunohistochemistry and real-time PCR analysis revealed that these large lymphocytes were positive for HHV-6B. Numerous HHV-6 particles were detected in the inclusion body of the lymphocytes by electron microscopy. Interestingly, immunohistochemistry revealed that HHV-6B-infected cells in the lymph node were CD3(+), CD4(+), CD25(+), and FoxP3(+) T cells, indicating a phenotypic resemblance to regulatory T-cells. This case provides direct evidence of HHV-6 infection in CD25(+)/FoxP3(+) T cells in a case of acute lymphadenitis of DRESS syndrome, suggesting a significant role of HHV-6 infection of regulatory T-cells in the pathogenesis of DRESS syndrome.
    Full-text · Article · Sep 2014 · Journal of Clinical Virology
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    ABSTRACT: Trichodysplasia spinulosa-associated polyomavirus (TSV) was identified in a seven-month-old girl with myocarditis. The number of TSV genomes detected was higher in the heart than in the other organs. The full-length TSV genome was cloned from the heart. This suggests a possible role of TSV infection in the pathogenesis of myocarditis in infants.
    No preview · Article · Sep 2014 · International journal of clinical and experimental pathology
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    ABSTRACT: Balamuthia mandrillaris is an amoeba found in fresh water and soil that causes granulomatous amoebic encephalitis. We report herein an autopsy case of B. mandrillaris amoebic encephalitis, which was definitely diagnosed by PCR. An 81-year-old man, who had Sjögren's syndrome, manifested drowsiness 2 months before his death with progressive deterioration. Neuroimaging demonstrated foci of T2- and fluid-attenuated inversion recovery high and T1 low-intensity with irregular post-contrast ring enhancement in the cerebral hemisphere, thalamus and midbrain. Pathologically, multiple hemorrhagic and necrotic lesions were found in the cerebrum, thalamus, midbrain, pons, medulla and cerebellum, which were characterized by liquefactive necrosis, marked edema, hemorrhage and necrotizing vasculitis associated with the perivascular accumulation of amoebic trophozoites, a few cysts, and the infiltration of numerous neutrophils and microglia/macrophages. The trophozoites were ovoid or round, 10–60 μm in diameter, and they showed foamy cytoplasm and a round nucleus with small karyosome in the center. The PCR and immunohistochemistry from paraffin-embedded brain specimens revealed angioinvasive encephalitis due to B. mandrillaris. Human cases of B. mandrillaris brain infection are rare in Japan, with only a few brief reports in the literature.
    No preview · Article · Sep 2014 · Neuropathology
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    ABSTRACT: It has been unclear whether chromosomally integrated human herpesvirus 6 (ciHHV-6) can be activated with pathogenic effects on the human body. We present molecular and virological evidence of ciHHV-6A activation in a patient with X-linked severe combined immunodeficiency. These findings have significant implications for the management of patients with ciHHV-6.
    Preview · Article · May 2014 · Clinical Infectious Diseases
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    ABSTRACT: Opportunistic infections and malignancies such as malignant lymphoma and Kaposi sarcoma are significant complications of human immunodeficiency virus (HIV) infection. However, following the introduction of antiretroviral therapy in Japan in 1997, the incidence of clinical complications has decreased. In the present study, autopsy cases of HIV infection in Japan were retrospectively investigated to reveal the prevalence of opportunistic infections and malignancies. A total of 225 autopsy cases of HIV infection identified at 4 Japanese hospitals from 1985-2012 were retrospectively reviewed. Clinical data were collected from patient medical records. Mean CD4 counts of patients were 77.0 cells/muL in patients who received any antiretroviral therapy during their lives (ART (+) patients) and 39.6 cells/muL in naive patients (ART (-) patients). Cytomegalovirus infection (142 cases, 63.1%) and pneumocystis pneumonia (66 cases, 29.3%) were the most frequent opportunistic infections, and their prevalence was significantly lower in ART (+) patients than ART (-) patients. Non-Hodgkin lymphoma and Kaposi sarcoma were observed in 30.1% and 16.2% of ART (-) patients, and 37.9% and 15.2% of ART (+) patients, respectively. Malignant lymphoma was the most frequent cause of death, followed by cytomegalovirus infection regardless of ART. Non-acquired immunodeficiency syndrome (AIDS)-defining cancers such as liver and lung cancer caused death more frequently in ART (+) patients (9.1%) than in ART (-) patients (1.5%; P = 0.026). The prevalence of infectious diseases and malignancies were revealed in autopsy cases of HIV infection in Japan. The prevalence of cytomegalovirus infection and pneumocystis pneumonia at autopsy were lower in ART (+) patients than ART (-) patients. Higher prevalence of non-AIDS defining malignancies among ART (+) patients than ART (-) patients suggests that onsets of various opportunistic infections and malignancies should be carefully monitored regardless of whether the patient is receiving ART.
    Full-text · Article · Apr 2014 · BMC Infectious Diseases
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    ABSTRACT: Recently, the critical role of CD47 on the surface of resistant cancer cells has been proposed in their evasion of immunosurveillance. Primary effusion lymphoma (PEL) is a subtype of aggressive non-Hodgkin lymphoma that shows serous lymphomatous effusion in body cavities, especially in advanced acquired immunodeficiency syndrome (AIDS). PEL is resistant to conventional chemotherapy and has a poor prognosis. In this study, we evaluated the effect of anti-CD47 antibody (Ab) on PEL in vitro and in vivo. Surface CD47 of PEL cell lines was examined by flow cytometry. Efficacy of knocking down CD47 or anti-CD47 Ab-mediated phagocytosis against PEL was evaluated using mouse peritoneal macrophages and human macrophages in vitro. Primary PEL cells were injected intraperitoneally into NOD/Rag-2/Jak3 double-deficient (NRJ) mice to establish a direct xenograft mouse model. Surface CD47 of PEL cell lines was highly expressed. Knocking down CD47 and anti-CD47 Ab promoted phagocytic activities of macrophages in a CD47 expression-dependent manner in vitro. Treatment with anti-CD47 Ab inhibited ascite formation and organ invasion completely in vivo compared with control IgG-treated mice. CD47 plays the pivotal role in the immune evasion of PEL cells in body cavities. Therapeutic antibody targeting of CD47 could be an effective therapy for PEL.
    No preview · Article · Apr 2014 · European journal of cancer (Oxford, England: 1990)
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    ABSTRACT: Abstract is missing (Short Communication).
    Preview · Article · Apr 2014 · Acta Dermato-Venereologica
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    ABSTRACT: The GP129, GP131 and GP133 genes of guinea pig cytomegalovirus (GPCMV) are homologs of human CMV UL128, UL130 and UL131A, respectively, which are essential for infection of endothelial and epithelial cells and for viral transmission to leukocytes. Our previous study demonstrated that a GPCMV strain lacking the 1.6-kb locus that contains the GP129, GP131, and GP133 genes had a growth defect in animals. Here we demonstrated that the wild-type strain but not the 1.6-kb deleted strain formed capsids in macrophages prepared from the peritoneal fluid. To understand the mechanism, we prepared GPCMV strains defective in each of GP129, GP131 and GP133 and found that they were all essential for the infection of peritoneal, splenic and PBMC-derived macrophages/monocytes and expression of immediate-early antigens in the macrophages/monocytes, although they were dispensable for infection of fibroblasts. Monocyte/macrophage-tropism could be one of the important determinants for viral dissemination in vivo.
    Preview · Article · Mar 2014 · Journal of General Virology
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    ABSTRACT: The introduction of combined antiretroviral therapy (ART) has reduced the mortality of patients with human immunodeficiency virus-1 infection worldwide. However, malignant lymphoma is a severe and frequent complication seen in patients with acquired immunodeficiency syndrome (AIDS). The diagnostic criteria for some categories of AIDS-related lymphoma were revised in the World Health Organization International Classification of Lymphoma, fourth edition. The purpose of this study was to assess the clinicopathological characteristics of Japanese patients with AIDS-related lymphoma according to the revised classification. In this retrospective study, 207 AIDS-related lymphoma cases diagnosed between 1987 and 2012 in Japan were subjected to histological subtyping and clinicopathological analyses. Diffuse large B-cell lymphoma (DLBCL) was the predominant histological subtype throughout the study period (n = 104, 50%). Among the DLBCL cases, 24% were of the germinal center (GC) type and 76% were of the non-GC type. Non-GC-type cases showed a significantly lower 1-year survival rate (43%) than the GC-type cases (82%). Cases of Burkitt lymphoma (n = 57, 28%), plasmablastic lymphoma (n = 16, 8%), primary effusion lymphoma (n = 9, 4%), Hodgkin lymphoma (n = 8, 4%), and large B-cell lymphoma arising in Kaposi sarcoma-associated herpesvirus-associated multicentric Castleman disease (n = 2, 1%) were also observed. Hodgkin lymphoma was more common in patients receiving ART (11.1%) than in ART-naïve patients (1.4%). Statistical analyses identified CD10 negativity, BCL-6 negativity, Epstein-Barr virus positivity, and Kaposi sarcoma-associated herpesvirus positivity as risk factors for poor prognosis. This information will help in the early diagnosis of lymphoma in patients with AIDS.
    Full-text · Article · Feb 2014 · Cancer Medicine

Publication Stats

3k Citations
442.95 Total Impact Points

Institutions

  • 1999-2015
    • National Institute of Infectious Diseases, Tokyo
      Edo, Tōkyō, Japan
  • 2013
    • Tokyo University of Agriculture and Technology
      Edo, Tokyo, Japan
  • 2006
    • Kagoshima University
      • Graduate School of Medical and Dental Sciences
      Kagosima, Kagoshima, Japan
  • 2005
    • Toho University
      Edo, Tōkyō, Japan
  • 2004
    • National Institute of Allergy and Infectious Diseases
      • Laboratory of Immunoregulation
      Maryland, United States
  • 2002
    • Kawakita General Hospital
      Edo, Tōkyō, Japan
  • 2001
    • Nippon Medical School
      • Nippon Medical School Hospital
      Edo, Tōkyō, Japan
    • Centers for Disease Control and Prevention
      • Division Of Cancer Prevention and Control
      Атланта, Michigan, United States
  • 1995-2000
    • The University of Tokyo
      • Department of Pathology
      白山, Tōkyō, Japan