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Tomohiro Morio

Publications and source records attributed to Tomohiro Morio.

34 records · Page 2Linked to original sources
PubMed2004

Allogeneic hematopoietic stem cell transplantation for seven children with X-linked hyper-IgM syndrome: a single center experience.

X-linked hyper-IgM syndrome (XHIM), or hyper-IgM syndrome type 1 (HIGM1), is a rare primary immunodeficiency disorder susceptible to recurrent bacterial infection and opportunistic infection such as Pneumocystis carinii and Cryptosporidium parvum. The long-term outcome is quite poor, and allogeneic hematopoietic stem cell transplantation (HSCT) offers the only cure. Seven patients with XHIM, from age 3 to 19 years (mean 11.3 years), underwent allogeneic HSCT in our institution. Details of pre- and post-transplantation data and transplantation procedure were analyzed retrospectively. The donors were HLA-identical siblings for three patients and HLA-identical unrelated donors for four patients. All but one received conventional conditioning regimen consisting of busulfan and cyclophosphamide and prophylaxis for graft-versus-host disease (GVHD) consisting of cyclosporine and methotrexate. Five out of seven patients are alive and well with normal CD40L expression, and four of these five are free of intravenous immunoglobulin supplementation. The two patients who died had prolonged episodes of severe and recurrent infections and organ damage. We conclude that conventional allogeneic HSCT from HLA matched related or unrelated donors is curative and feasible for XHIM patients, if performed before significant infections and organ damage occur. For the high-risk patients, an alternative approach including nonmyeloablative HSCT may be more feasible.

Adolescent↗
PubMed2004

Pancytopenia presenting with monosomy 7 which disappeared after immunosuppressive therapy.

Monosomy 7 syndrome in infant is considered as pre-leukemic condition of poor prognosis. However, it seems controversial recently, because some cases of monosomy 7 syndrome showed spontaneous remission. We report 2-year-old girl with severe pancytopenia, who presented with monosomy 7. Morphologically, there was little dysplasia in the trilineage hematopoiesis. Monosomy 7 clone of CD34 positive cells, bone marrow mononuclear cells (BMMNC), and peripheral nuclear cells was 4.0, 40, and 3.8%, respectively. Immunosuppressive therapy was effective along with the disappearance of monosomy 7 clone. WT1 mRNA expression was not increased in monosomy 7 clone. Pathogenesis of monosomy 7 and its relation to aplastic anemia is discussed.

Anemia, Aplastic↗
PubMed2004

Epstein-Barr virus-associated posttransplant lymphoproliferative disorder after a cord blood stem cell transplantation presenting with pulmonary nodules.

Sixteen months after a cord blood stem cell transplantation, a 6-year-old girl was diagnosed with Epstein-Barr virus-associated posttransplant lymphoproliferative disorder (EBV-PTLD). A CT scan revealed nodules in both lungs, but the patient had neither lymphadenopathy nor other lesions. The diagnosis was confirmed by histopathologic evaluation and the increased level of EBV DNA in the peripheral blood. The patient was successfully treated with rituximab, and a complete regression of the tumors was achieved. This case reveals the need to include EBV-PTLD in the differential diagnosis of pulmonary nodules, as well as demonstrating that rituximab may be effective treatment of EBV-PTLD after cord blood stem cell transplantation.

Antibodies, Monoclonal↗
PubMed2003

Clinical course of patients with WASP gene mutations.

Mutations of the Wiskott-Aldrich syndrome protein (WASP) gene result either in the classic Wiskott-Aldrich syndrome (WAS) or in a less severe form, X-linked thrombocytopenia (XLT). A phenotype-genotype correlation has been reported by some but not by other investigators. In this study, we characterized WASP gene mutations in 50 Japanese patients and analyzed the clinical phenotype and course of each. All patients with missense mutations were WASP-positive. In contrast, patients with nonsense mutations, large deletions, small deletions, and small insertions were WASP-negative. Patients with splice anomalies were either WASP-positive or WASP-negative. The clinical phenotype of each patient was correlated with the presence or absence of WASP. Lack of WASP expression was associated with susceptibility to bacterial, viral, fungal, and Pneumocystis carinii infections and with severe eczema, intestinal hemorrhage, death from intracranial bleeding, and malignancies. Rates for overall survival and survival without intracranial hemorrhage or other serious complications were significantly lower in WASP-negative patients. This analysis provides evidence for a strong phenotype-genotype correlation and demonstrates that WAS protein expression is a useful tool for predicting long-term prognosis for patients with WAS/XLT. Based on data presented here, hematopoietic stem cell transplantation should be considered, especially for WASP-negative patients, while the patients are young to improve prognosis.

Adolescent↗
PubMed2003

Oxidative stress induces nuclear loss of DNA repair proteins Ku70 and Ku80 and apoptosis in pancreatic acinar AR42J cells.

Cell death linked to oxidative DNA damage has been implicated in acute pancreatitis. The severe DNA damage, which is beyond the capacity of the DNA repair proteins, triggers apoptosis. It has been hypothesized that oxidative stress may induce a decrease in the Ku70 and Ku80 levels and apoptosis in pancreatic acinar cells. In this study, it was found that oxidative stress caused by glucose oxidase (GO) acting on beta-d-glucose, glucose/glucose oxidase (G/GO), induced slight changes in cytoplasmic Ku70 and Ku80 but drastically induced a decrease in nuclear Ku70 and Ku80 both time- and concentration-dependently in AR42J cells. G/GO induced apoptosis determined by poly(ADP-ribose) polymerase cleavage, an increase in expression of p53 and Bax, and a decrease in Bcl-2 expression. G/GO-induced apoptosis was in parallel with the loss of nuclear Ku proteins in AR42J cells. Caspase-3 inhibitor prevented G/GO-induced nuclear Ku loss and cell death. G/GO did not induce apoptosis in the cells transfected with either the Ku70 or Ku80 expression gene but increased apoptosis in those transfected with the Ku dominant negative mutant. Pulse and pulse-chase results show that G/GO induced Ku70 and Ku80 syntheses, even though Ku70 and Ku80 were degraded both in cytoplasm and nucleus. G/GO-induced decrease in Ku binding to importin alpha and importin beta reflects possible modification of nuclear import of Ku proteins. The importin beta level was not changed by G/GO. These results demonstrate that nuclear decrease in Ku70 and Ku80 may result from the decrease in Ku binding to nuclear transporter importins and the degradation of Ku proteins. The nuclear loss of Ku proteins may underlie the mechanism of apoptosis in pancreatic acinar cells after oxidative stress.

Antigens, Nuclear↗
PubMed2003

Prognostic factors for chronic active Epstein-Barr virus infection.

Chronic active Epstein-Barr virus infection (CAEBV) is a high-mortality and high-morbidity disease. To clarify the prognostic factors, a national survey was performed in Japan, and data for 82 patients who met the criteria for CAEBV were analyzed. Of these 82 patients, 47 were alive and 35 had already died. Multivariate analysis revealed that thromobocytopenia and age at disease onset were correlated with mortality. The probability of 5-year survival was 0.45 for older patients (onset age, > or = 8 years), 0.94 for younger patients (P<.001), 0.38 for patients with thrombocytopenia (platelet count < 12 x 10(4) platelets/microL at diagnosis), and 0.76 for patients without thrombocytopenia (P=.01). Furthermore, patients with T cell infection by EBV had shorter survival times than patients with natural killer cell infection (probability of 5-year survival, 0.59 vs. 0.87; P<.009). Patients with CAEBV with late onset of disease, thrombocytopenia, and T cell infection had significantly poorer outcomes.

Adolescent↗
PubMed2003

Preferential expansion of Vgamma9-JgammaP/Vdelta2-Jdelta3 gammadelta T cells in nasal T-cell lymphoma and chronic active Epstein-Barr virus infection.

We recently established an Epstein-Barr virus (EBV)-positive gammadelta T-cell line from a nasal T/natural killer (NK)-cell lymphoma (Nagata H, Konno A, Kimura N, Zhang Y, Kimura M, Demachi A, Sekine T, Yamamoto K, Shimizu N: Characterization of novel natural killer (NK)-cell and gammadelta T-cell lines established from primary lesions of nasal T/NK-cell lymphomas associated with the Epstein-Barr virus. Blood 2001, 97:708-713). Subsequently, we established two novel EBV-positive gammadelta T-cell lines from the peripheral blood of patients with chronic active EBV infection. Analysis of the terminal repeat of EBV showed that the three cell lines consisted of monoclonal populations, and flow cytometry showed that they had a common phenotype of gammadelta T cells: CD3(+) CD4(-) CD8(-) CD16(-) CD19(-) CD56(+) CD57(-) HLA-DR(+) T-cell receptor (TCR) alphabeta(-) TCR gammadelta(+). Analysis for the expression of TCR by flow cytometry showed that all three cell lines were Vgamma9(+)/Vdelta2(+), but negative for VgammaI, Vdelta1, or Vdelta3 TCR. Southern blot analysis for TCR genes showed that the three cell lines had a common rearrangement of Vgamma9-JgammaP and Jdelta3 genes. Polymerase chain reaction and sequence analysis of the junction between Vdelta and Jdelta genes revealed that the Jdelta3 genes were rearranged with the Vdelta2 genes. In contrast, none of the EBV-negative gammadelta T-cell lines, Molt-14, Peer, or Loucy, which were analyzed for controls, had Vgamma9 or Vdelta2 TCR, or a rearrangement of Jdelta3 genes. These results indicated that Vgamma9-JgammaP/Vdelta2-Jdelta3(+) gammadelta T cells were preferentially affected by EBV and expanded in patients with nasal gammadelta T-cell lymphoma and chronic active EBV infection. Jdelta3(+) gammadelta T cells are known to be a very minor population in gammadelta T cells of peripheral blood, whereas Vgamma9-JgammaP/Vdelta2-Jdelta1(+) cells are the major population. The close association of EBV with this particular gammadelta T-cell population may provide a key to the etiology of EBV-positive lymphoproliferative diseases.

Antigens, CD↗
PubMed2003

Common cytological and cytogenetic features of Epstein-Barr virus (EBV)-positive natural killer (NK) cells and cell lines derived from patients with nasal T/NK-cell lymphomas, chronic active EBV infection and hydroa vacciniforme-like eruptions.

In this study, we describe the cytological and cytogenetic features of six Epstein-Barr virus (EBV)-infected natural killer (NK) cell clones. Three cell clones, SNK-1, -3 and -6, were derived from patients with nasal T/NK-cell lymphomas; two cell clones, SNK-5 and -10, were isolated from patients with chronic active EBV infection (CAEBV); and the other cell clone, SNK-11, was from a patient with hydroa vacciniforme (HV)-like eruptions. An analysis of the number of EBV-terminal repeats showed that the SNK cell clones had monoclonal EBV genomes identical to the original EBV-infected cells of the respective patients, and SNK cells had the type II latency of EBV infection, suggesting that not only the cell clones isolated from nasal T/NK-cell lymphomas but also those isolated from CAEBV and HV-like eruptions had been transformed by EBV to a certain degree. Cytogenetic analysis detected deletions in chromosome 6q in five out of the six SNK cell clones, while 6q was not deleted in four control cell lines of T-cell lineage. This suggested that a 6q deletion is a characteristic feature of EBV-positive NK cells, which proliferated in the diseased individuals. The results showed that EBV-positive NK cells in malignant and non-malignant lymphoproliferative diseases shared common cytological and cytogenetic features.

Adolescent↗
PubMed2003

Characterization of Epstein-Barr virus (EBV)-positive NK cells isolated from hydroa vacciniforme-like eruptions.

Recently, the involvement of Epstein-Barr virus (EBV) in hydroa vacciniforme (HV)-like eruptions has been suggested. To elucidate the role of EBV in this disease, we isolated EBV-infected cell clones from peripheral blood mononuclear cells (PBMC) and the skin lesions of a patient with HV-like eruptions; cells isolated from PBMC were designated SNK-12, and those from the eruption SNK-11. Both cells expressed CD16, CD56, and HLA-DR and had germline configurations of the T-cell receptor and the immunoglobulin genes, indicating that the cell clones were of NK cell lineage. The analysis of EBV terminal repeats indicated that the cells were monoclonal, had identical clonality, and originated from EBV-positive cells in the PBMC and eruption. Both clones expressed EBNA-1, but not EBNA-2. Although LMP-1 was weakly detected in SNK-11, no LMP-1 was detected in SNK-12. Interestingly, EBV-infected cells required less IL-2 for in vitro growth in the later phase of this disease and this appeared to correlate with the expression of LMP-1, suggesting that the proliferative capacity of the EBV-positive NK cells increased during the time course of the disease, and LMP-1 expression might be responsible for that. This is the first report of the isolation of EBV-infected cells from the skin lesions of HV-like eruptions and strongly suggests that the HV-like eruption in the patient was caused by clonal NK cells with latent EBV infection.

Cell Culture Techniques↗
PubMed2003

Type two hyper-IgM syndrome caused by mutation in activation-induced cytidine deaminase.

Thirteen Japanese patients with hyper-IgM syndrome but normal CD40 ligand were characterized. All patients had mutations in AID (activation-induced cytidine deaminase) gene. Five of them had a missense mutation of Arg112His. In all patients, serum IgG, IgA and IgE levels were undetectable, B cells failed to produce detectable amounts of IgE even if cultured them with anti-CD40 and IL-4. Somatic hypermutation (SHM) was also impaired in their peripheral blood B cells. These results suggest that Arg112 is the hot spot of AID mutation and demonstrate that AID plays indispensable roles in class switch recombination (CSR) and somatic hypermutation (SHM) in human B cells. In addition, serum IgM levels in the patients have been continuously high even after proper intravenous immunogloburin infusion (IVIG) and without infection, indicate that AID has the function to induce spontaneous IgM production in B cells.

Adult↗
PubMed2003

Coordinated regulation of the promoter and enhancer regions of human CD23 gene by signal through IL-4R and CD40, and the role of Ku70/80 in the enhancer activity.

CD23 has roles in proliferation, antigen uptake and presentation, and the generation of IgE. Signals through IL-4R and CD40 stimulate transcription of CD23 in B cells and are necessary for immunoglobulin class switch (IgCS). The same signals induce nuclear translocation of Ku, which is also required for IgCS, in human resting B cells, suggesting that these signaling pathways are connected. We examined the regulation of CD23 gene, and located the minimal promoter at -132+80 region. A pair of 188bp inverted repeats inhibited its activity. The intronic region including EBV responsive element (EBVRE) and the surrounding sequence, required the gene specific promoter to enhance the reporter gene activity. Western blotting and FACS analysis using subclones of DND39 B cells infected with recombinant EBV, revealed that CD23 upregulation did not necessarily correlate with EBNA 2 and LMP 1 expression. Although the specific binding of Ku to EBVRE was not demonstrated, dominant negative Ku80 suppressed IL-4 + anti-CD40-driven CD23 expression. These results suggest that Ku is involved in gene regulation as a signal transducer and gene enhance. Detailed analysis of CD23 gene regulation would lead to a better understanding of disorders such as allergy and lymphoproliferation.

Antigens, Nuclear↗
PubMed2002

Immunosuppressive effects of tautomycetin in vivo and in vitro via T cell-specific apoptosis induction.

Tautomycetin (TMC) was identified as an immunosuppressor of activated T cells. Inhibition of T cell proliferation with TMC was observed at concentrations 100-fold lower than those needed to achieve maximal inhibition with cyclosporin A (CsA). TMC specifically blocked tyrosine phosphorylation of intracellular signal mediators downstream of Src tyrosine kinases in a T cell-specific manner, leading to apoptosis due to cleavage of Bcl-2, caspase-9, caspase-3, and poly(ADP-ribose) polymerase, but not caspase-1. In TMC-treated rats that received a heterotopic cardiac allograft, the graft survived more than 160 days, comparable to graft survival in allografted rats treated with CsA. Thus, TMC, whose mechanism of action is different from that of CsA or FK506, can be used as a potent T cell-specific immunosuppressor.

Animals↗