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Biomedical subjects

Shigeru Fujita

Publications and source records attributed to Shigeru Fujita.

18 recordsLinked to original sources
PubMed2003

Antagonist of secondary lymphoid-tissue chemokine (CCR ligand 21) prevents the development of chronic graft-versus-host disease in mice.

The use of receptor antagonists for chemokines is an alternative approach to blocking chemokine actions and has the potential to provide novel therapeutics. We determined the receptor antagonist properties of murine N-terminally truncated secondary lymphoid tissue chemokine (SLC)/6Ckine/CCR ligand 21 analogs and evaluated the preventive effects of SLC antagonists on chronic graft-vs-host disease (GVHD) in a murine model by blocking the homing of donor CCR7-expressing T cells into the recipient's lymphoid organs. SLC analogs truncated >4 aa residues from the N terminus showed a loss of chemotaxis and Ca2+ influx of CCR7-expressing cells and also inhibited SLC-stimulated chemotaxis and SLC-induced Ca2+ influx completely. To determine whether SLC antagonist inhibits the development of chronic GVHD, chronic GVHD was induced by injecting DBA/2 spleen cells into (C57BL/6 x DBA/2) F1 mice. Total numbers of spleen cells and host B cells, serum levels of IgE, and of total IgG and IgG1 of anti-DNA Abs in SLC antagonist-treated GVHD mice were significantly lower than those in control PBS-treated GVHD mice. This was due to a reduction in the levels of activated donor CD4+ T cells and a decrease in IL-4 production, resulting in a reduction in the numbers of activated host B cells. Therefore, our results suggest that SLC antagonist has beneficial effects for the prevention of chronic GVHD.

Animals↗
PubMed2003

Antagonist of monocyte chemoattractant protein 1 ameliorates the initiation and progression of lupus nephritis and renal vasculitis in MRL/lpr mice.

OBJECTIVE: To examine whether chemokine antagonists inhibit the initiation and progression of lupus nephritis in MRL/lpr mice. METHODS: NH(2)-terminal-truncated monocyte chemoattractant protein 1 (MCP-1)/CCL2 or thymus and activation-regulated chemokine (TARC)/CCL17 analogs were inserted into the pCXN2 expression vector and transfected into a nonmetastatic fibroblastoid cell line, MRL/N-1, established from an MRL/gld mouse. RESULTS: MCP-1 antagonist- or TARC antagonist-transfected MRL/N-1 cells were injected subcutaneously into MRL/lpr mice ages 7 weeks (before the onset of lupus nephritis) and 12 weeks (at the early stage of the disease). After 8 weeks, mice bearing the MCP-1 antagonist showed markedly diminished infiltration of macrophages and T cells, glomerular hypercellularity, glomerulosclerosis, crescent formation, and vasculitis compared with control mice. This seemed to be due to decreased production of interferon-gamma and interleukin-2 in the kidney. In contrast, there was no significant difference in renal damage between mice bearing TARC antagonist and control mice. CONCLUSION: We established a new system using MRL/N-1 cells that allows long-term observation of the effects of chemokine antagonists on lupus nephritis in MRL/lpr mice. We also showed that the MCP-1 antagonist ameliorated the initiation and progression of lupus nephritis and of renal vasculitis, which might provide a new approach to the treatment of the disease.

Animals↗
PubMed2003

Non-Hodgkin's lymphoma developing in a pacemaker pocket.

A 29-year-old man developed diffuse large B-cell lymphoma in a subpectoral pacemaker pocket that 6 years previously had been created in the chest for a titanium-covered pulse generator. The patient had an 8-cm-diameter dark red tumor with necrotic tissue on a keloidal surgical scar in the left side of the chest. Left axillary lymphadenopathy also was present. Laboratory studies showed an increased level of soluble interleukin 2 receptor and a normal level of lactose dehydrogenase. A biopsy specimen showed a diffuse large B-cell phenotype and monoclonal immunoglobulin H gene rearrangement. A gallium scintigraphy study showed abnormal accumulation in the left chest and left axilla. On the basis of these findings, we diagnosed diffuse large B-cell lymphoma, stage II. The patient received THP-COP chemotherapy (pirarubicin, cyclophosphamide, vincristine, and prednisolone) and radiotherapy, achieved complete remission, and was free of disease for 16 months after treatment. This case suggests that there was a relationship between the development of non-Hodgkin's lymphoma and the presence of chronic inflammation in the pulse generator pocket.

Adult↗
PubMed2003

Hypocellular acute promyelocytic leukemia with a tetraploid clone characterized by two t(15;17).

We describe a case of hypocellular acute promyelocytic leukemia with a tetraploid clone characterized by two t(15;17). The large leukemia cells had a bizarre nuclear configuration and multiple Auer rods. A bone marrow biopsy specimen revealed a markedly hypocellular marrow (<10% cellularity) in the absence of myelofibrosis. Myelodysplastic features were not detected. Chromosome analysis of marrow cells revealed a karyotype of 92,XXYY,del(2)(q?),t(15;17)(q22;q21)x2. Interphase fluorescence in situ hybridization revealed that the marrow cells were composed of a tetraploid clone carrying double t(15;17) and normal diploid cells. The leukemia responded well to all-trans retinoic acid. We think that the tetraploidy could be caused by endoreduplication or endomitosis of the diploid clone with single t(15;17). The unique karyotype largely contributed to the cell morphology and marrow hypoplasia, while it may not have affected on the prognosis of the acute promyelocytic leukemia.

Bone Marrow Cells↗
PubMed2003

A novel fusion variant of the MORF and CBP genes detected in therapy-related myelodysplastic syndrome with t(10;16)(q22;p13).

We report a case of therapy-related myelodysplastic syndrome (t-MDS) with t(10;16)(q22;p13), in which novel fusion transcripts of the MORF and CBP genes were detected. In one MORF-CBP fusion transcript, exon 15 of the MORF gene was fused in frame with exon 5 of the CBP gene. In a reciprocal CBP-MORF transcript, exon 4 of the CBP gene was fused in frame with exon 16 of the MORF gene. This is the first reported case of t-MDS associated with t(10;16), and provides molecular evidence that the novel MORF-CBP and/or CBP-MORF fusion protein(s) might play an important role in the development of t-MDS.

Acetyltransferases↗
PubMed2003

Aurora2/BTAK/STK15 is involved in cell cycle checkpoint and cell survival of aggressive non-Hodgkin's lymphoma.

Non-Hodgkin's lymphoma (NHL) has a wide biological heterogeneity and shows extremely variable responses to therapeutic measures. However, markers that indicate disease activity and determine treatment strategies for this malignancy are little recognized. Using the differential display method, we have identified Aurora2/BTAK/STK15, a centrosome-associated serine/threonine kinase, whose overexpression leads to centrosome amplification, chromosomal instability and transformation of mammalian solid tumours. Northern analysis with mRNA from a single tumour cell suspension of NHL confirmed that Aurora2/BTAK/STK15 was highly expressed in histologically aggressive types. To elucidate the function of Aurora2/BTAK/STK15 in NHL, Aurora2/BTAK/STK15 sense or antisense genes were transfected to B-cell lymphoma cell lines to generate overexpressed or under-regulated tumour cells. Aurora2/BTAK/STK15 antisense transfectant was barely established compared with a sense or vector-only transfectant. Two clones were finally established that exhibited a low proliferation rate and significantly increased G1 arrest compared with vector-only transfectants. Moreover, antisense oligo treatment in vitro showed that restriction of cell growth appeared in proportion to antisense oligo concentration. These results suggest that Aurora2/BTAK/STK15 is an effective candidate to indicate not only disease activity but also tumorigenesis of non-Hodgkin's lymphoma. Retardation of tumour cell growth resulting from the restriction of this gene's functions may be a novel therapeutic approach for non-Hodgkin's lymphoma.

Aurora Kinase A↗
PubMed2003

[A case of pyomyositis following influenza virus infection].

A 45-year-old man visited the first hospital complained of high fever on January 2003. He was diagnosed as having Influenza virus type A infection and prescribed of Oseltamivir. He was afebrile next day, but severe myalgia of neck, shoulder, lumbar region and right femoral region was appeared. His illness was considered as polymyalgia rheumatica and started of oral steroid therapy. His symptom was deteriorated and transferred to our hospital. Echography, Ga scintigraphy, computed tomography and magnetic resonance imaging revealed the multiple abscesses and the diagnosis of pyomyositis was made. Pyomyositis following Influenza virus infection must be considered as a differential diagnosis of myalgia after Influenza virus infection.

Diagnosis, Differential↗
PubMed2002

Constitutive expression of SOCS3 confers resistance to IFN-alpha in chronic myelogenous leukemia cells.

Because suppressor of cytokine signaling (SOCS) proteins are negative regulators of cytokine-induced signaling, it has been hypothesized that aberrant SOCS expression confers resistance against cytokine therapy. This study reports on the constitutive expression of SOCS3 in most chronic myelogenous leukemia (CML) cell lines, which are resistant to treatment with interferon alpha (IFN-alpha). In contrast, the KT-1/A3 cell line, in which constitutive expression of SOCS3 is barely detectable, is sensitive to IFN-alpha treatment. Forced expression of SOCS3 in the KT-1/A3 cell line confers resistance to IFN-alpha treatment. Furthermore, most of the blast cells from patients in CML blast crisis, which are usually resistant to IFN-alpha therapy, showed constitutive expression of SOCS3. These findings indicate that constitutive SOCS3 expression affects the IFN-alpha sensitivity of CML cell lines and blast cells from patients with CML blast crisis.

Base Sequence↗
PubMed2002

Essential role of NF-kappa B-inducing kinase in T cell activation through the TCR/CD3 pathway.

NF-kappa B-inducing kinase (NIK) is involved in lymphoid organogenesis in mice through lymphotoxin-beta receptor signaling. To clarify the roles of NIK in T cell activation through TCR/CD3 and costimulation pathways, we have studied the function of T cells from aly mice, a strain with mutant NIK. NIK mutant T cells showed impaired proliferation and IL-2 production in response to anti-CD3 stimulation, and these effects were caused by impaired NF-kappa B activity in both mature and immature T cells; the impaired NF-kappa B activity in mature T cells was also associated with the failure of maintenance of activated NF-kappa B. In contrast, responses to costimulatory signals were largely retained in aly mice, suggesting that NIK is not uniquely coupled to the costimulatory pathways. When NIK mutant T cells were stimulated in the presence of a protein kinase C (PKC) inhibitor, proliferative responses were abrogated more severely than in control mice, suggesting that both NIK and PKC control T cell activation in a cooperative manner. We also demonstrated that NIK and PKC are involved in distinct NF-kappa B activation pathways downstream of TCR/CD3. These results suggest critical roles for NIK in setting the threshold for T cell activation, and partly account for the immunodeficiency in aly mice.

Animals↗
PubMed2002

CD151 enhances cell motility and metastasis of cancer cells in the presence of focal adhesion kinase.

We have examined the role of the protein CD151 in cell motility, invasion and metastasis of cancer cells by using CD151-overexpressing cells prepared by transfection of CD151 cDNA into three cancer cell lines established from different origins; a human colon cancer RPMI4788, a human glioblastoma A172 and a human fibrosarcoma HT1080. Invasion into Matrigel and cell motility of all 3 CD151-overexpressing cancer cells were enhanced significantly when compared to control parental cells. Pulmonary metastasis of 2 metastatic CD151-overexpressing cancer cell lines, RPMI4788/CD151 and HT1080/CD151, was higher than that of control parental cells and was markedly inhibited by anti-CD151 monoclonal antibody (MAb), SFA1.2B4. To examine whether focal adhesion kinase (FAK) is associated with promotion of cell motility and invasion of cancer cells through CD151, we transfected human CD151 cDNA into FAK (+/+) or FAK (-/-) fibroblasts that were isolated from embryos in FAK-deficient mice and compared invasion into Matrigel and cell motility between each CD151-transfected cells and controls. The invasion into Matrigel and cell motility of CD151-transfected FAK (+/+) fibroblasts increased significantly above those of parental cells and were inhibited by anti-CD151 MAb, whereas those of CD151-transfected FAK (-/-) fibroblasts were not enhanced at all and were not blocked by anti-CD151 MAb. These findings indicate that the CD151 molecule enhances cell motility, invasion and metastasis of cancer cells and that FAK is needed for these events through CD151.

Antibodies, Monoclonal↗
PubMed2002

Dramatic efficacy of fludarabine in the treatment of an aggressive case of splenic lymphoma with villous lymphocytes.

Splenic lymphoma with villous lymphocytes (SLVL) is an indolent lymphoproliferative disorder of mature B lymphocytes. Splenectomy is primarily recommended for treating this disease, and splenic irradiation or alkylating agents may be effective; however, frequent recurrence is observed after these therapies. We report here an unusual case of SLVL in which the degree of splenomegaly and the serum IgM level increased rapidly. Although the effects of splenic irradiation and combination chemotherapy were both unsatisfactory and transient, complete remission lasting for more than 15 months was achieved after two courses of treatment with low-dose fludarabine (15 mg m(-2) daily for 3 d). The present case indicates that treatment with fludarabine is effective for SLVL and recommended as the first-line therapy for elderly patients and those with an aggressive form of the disease.

Aged↗
PubMed2002

Identification of a novel WT1-derived peptide which induces human leucocyte antigen-A24-restricted anti-leukaemia cytotoxic T lymphocytes.

We previously reported the establishment of a Wilms' tumour (WT)1-derived peptide (CMTWNQMNL)-specific and human leucocyte antigen (HLA)-A24-restricted anti-leukaemia cytotoxic T lymphocyte (CTL) line, TAK-1. In this study, we have established a novel WT1-derived peptide (RWPSCQKKF)-specific CD8+ CTL line, designated NIM-1. NIM-1 lysed HLA-A24-positive leukaemia cells, but not HLA-A24-negative leukaemia cells or normal cells. The effects of TAK-1 and NIM-1 on cytotoxicity against leukaemia cells were not synergistic, suggesting that recognition of a single epitope on the tumour-specific antigen by CTLs is sufficient to exert maximal cytotoxic activity against tumour cells.

CD8-Positive T-Lymphocytes↗
PubMed2002

Phenotypic and functional alterations of dendritic cells induced by human herpesvirus 6 infection.

Human herpesvirus 6 (HHV-6) has a tropism for T lymphocytes and monocytes/macrophages, suggesting that HHV-6 infection affects the immunosurveillance system. In the present study, we investigated the HHV-6-induced phenotypic and functional alterations of dendritic cells (DCs), which are professional antigen-presenting cells. HHV-6 infection of monocyte-derived immature DCs appeared to induce the up-regulation of CD80, CD83, CD86, and HLA class I and class II molecules, suggesting that HHV-6 infection induces the maturation of DCs. In addition, the antigen capture capacity of DCs was found to decrease following infection with HHV-6. In contrast to up-regulation of mature-DC-associated surface molecules on HHV-6-infected DCs, their capacity for presentation of alloantigens and exogenous virus antigens to T lymphocytes decreased significantly from that of uninfected DCs. In contrast, there appeared to be no reduction in the capacity for presentation of an HLA class II-binding peptide to the peptide-specific CD4(+) T lymphocytes. These data indicate that HHV-6 infection induces phenotypic alterations and impairs the antigen presentation capacity of DCs. The present data also suggest that the dysfunction of HHV-6-infected DCs is attributable mainly to impairment of the antigen capture and intracellular antigen-processing pathways.

Antigens, CD↗
PubMed2002

Identification of critical residues for ligand binding in the integrin beta3 I-domain by site-directed mutagenesis.

To define the structural basis of ligand recognition by alphaIIb beta3, we conducted site-directed mutagenesis of residues located on the top surface of the beta3 I-domain that is homologous to the I-domain of several alpha subunits and contains a putative ligand binding site. Here we identify D158 and N215 in beta3 as novel residues critical for ligand binding. Alanine substitution of D158 or N215 abolished binding of a ligand-mimetic antibody and fibrinogen to alphaIIb beta3 induced by different types of integrin activation. CHO cells expressing recombinant alphaIIb beta3 bearing D158A or N215A mutation did not adhere to fibrinogen. These mutations had the same effect on ligand binding to another beta3 integrin, alphaVbeta3. Compared to the alphaI-domain structure, the betaB-betaC loop containing D158 in the beta3 I-domain is quite different in length and sequence. These results suggest that the structure for ligand recognition is different in the betaI- and alphaI-domains.

Animals↗
PubMed2002

[Granulocytic sarcoma developing in lymph nodes].

A 77-year-old man was admitted to a hospital because of a left cervical tumor. He was initially diagnosed as having non-Hodgkin lymphoma, diffuse large cell type, Ann Arbor stage IV, and transferred to our hospital for chemotherapy. Flow cytometric analysis of the left axillary lymph node cells derived from a biopsy specimen showed that in addition to lymphoid surface markers (CD5, 7, 21), myeloid surface markers (CD11b, 33, 34) were also positive. The diagnosis of malignant lymphoma was therefore confirmed. The patient, was treated with THP-COP therapy, which proved very effective. Thereafter, a biopsy specimen was found to be positive for MT1 (CD43) staining but negative for myeloperoxidase and chloroacetate esterase staining on immunohistochemistry. Furthermore, no rearrangement of the IgH JH, TCR C beta 1 or TCR J gamma gene was detected by Southern blot analysis. On basis of these findings and the previous results of flow cytometry, we changed the diagnosis from malignant lymphoma to granulocytic sarcoma. THP-COP therapy was continued, and complete remission was achieved. Two months later, however, the patient developed acute myelocytic leukemia (AML M1) and received DCP therapy, but he died of pneumonia.

Aged↗
PubMed2002

Antilung cancer effect of WT1-specific cytotoxic T lymphocytes.

We and other groups have recently reported that CTLs that specifically recognize a peptide derived from WT1 lyse leukemia cells in a HLA class I-restricted manner. Because WT1 is expressed in various solid tumors as well as in leukemic cells, we investigated whether WT1-specific CTLs can also inhibit the growth of lung cancer by examining their cytotoxic activity against lung cancer cell lines in vitro and their inhibitory effect on the growth of human lung cancer cells engrafted into nude mice. The WT1 transcript was detected in most of the lung cancer cell lines examined. A WT1-specific, HLA-A24-restricted CTL clone (designated TAK-1) exhibited cytotoxicity against lung cancer cell lines bearing HLA-A24 but did not lyse cells lacking this HLA. This suggests that the target antigen for TAK-1 on HLA-A24-positive lung cancer cells is the naturally processed WT1 peptide. Adoptive transfer of TAK-1 into nude mice that had been engrafted with a HLA-A24-positive lung cancer cell line resulted in inhibition of cancer cell growth and prolonged survival. These findings strongly suggest that WT1 is a universal tumor-associated antigen and that WT1-targeting immunotherapy offers a potentially effective treatment option for lung cancer as well as leukemia.

Animals↗
PubMed2002

[Epstein-Barr virus-associated posttransplant lymphoproliferative disease after renal transplantation].

A 24-year-old Japanese male was admitted to our hospital because of lymphadenopathy in his left neck. He had a nine-year history of chronic renal failure, and had received an ABO-mismatched renal allograft and splenectomy in August 2000 after one year of hemodialysis treatment. After renal transplantation, he was treated with FK506, methylprednisolone (mPSL), and mycophenolate mofetil (MMF) as an immunosuppressants for his graft maintenance. On admission, April 2001, he underwent lymphadenectomy, and the immunohistochemical studies revealed that the tumor cells expressed EBV-LMP and EBNA-2 antigens with the histology of diffuse large B-cell lymphoma. Our diagnosis was an Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disease (PTLD), and we reduced the dose of immunosuppressive agents and treated the patient with rituximab. In this case, there may have been two principal risk factors associated with PTLD: first, the patient was treated with higher levels of immunosuppressive agents because of the ABO-mismatched transplantation, and second, he was an EBV-seronegative recipient at the time of pretransplantation.

ABO Blood-Group System↗