研究者詳細 - 河上　裕

論文 - 河上　裕

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Development of HLA-A alleles typing in Japanese using biotinylated dideoxynucleotide and TOF-MS sequencing

Dan Katsuaki, Kawamura Miki, Miyashita Kiichi, Kawakami Yutaka

Tissue antigens 59 （ Suppl. 2 ） 111-111 2002年05月

研究論文（学術雑誌）, 共著

Development of HLA-A alleles typing in Japanese using biotinylated dideoxynucleotide and TOF- MAS sequencing

Dan Katsuaki, Kawamura Miki, Miyashita Kiichi, Kawakami Yutaka

Tissue antigens 59 （ Suppl. 2 ） 111 2002年05月

研究論文（学術雑誌）, 共著

Restricted T-cell receptor β-chain usage by T cells autoreactive to β₂-glycoprotein I in patients with antiphospholipid syndrome

Yoshida Kazue, Arai Takahide, Kaburaki Junichi, Ikeda Yasuo, Kawakami Yutaka, Kuwana Masataka

Blood 99 （ 7 ） 2499 - 2504 2002年04月

ISSN 0006-4971

We recently identified CD4⁺ T cells that are autoreactive to β₂-glycoprotein I (β₂GPI) and that promote antiphospholipid antibody production in patients with antiphospholipid syndrome (APS). In this study, T-cell receptor (TCR) β chains of β₂GPI-reactive T cells were examined in 8 β₂GPI-responders, including 5 patients with APS and 3 healthy subjects, using polymerase chain reaction and single-strand conformation polymorphism (PCRSSCP) analysis combined with in vitro stimulation of peripheral blood T cells with recombinant β₂GPI. The TCR Vβ segments that expanded oligoclonally after stimulation with β₂GPI varied among responders, but the Vβ7 and Vβ8 segments were commonly detected in 6 and 4 β2GPI-responders, respectively. Analysis of the complementarity-determining region 3 sequence of β₂GPI-reactive T cells revealed limited diversity, and all Vβ7⁺ TCRs had an amino acid motif of TGxxN/Q or minor variations. The Vβ8⁺ TCRs had another motif, PxAxxD/E. Surprisingly, an identical Vβ7⁺ TCRβ chain was used by β₂GPI-reactive T cells in 3 patients with APS. There was no apparent difference in the TCRβ usage between APS patients and healthy responders. Some of the Vβ7⁺ TCRs with the TGxxN/Q motif detected by PCR-SSCP analysis were also used by β₂GPI-specific CD4⁺ T-cell clones responsive to an immunodominant epitope containing the major phospholipid-binding site. Depletion of Vβ7+ or Vβ8⁺ T cells from the peripheral blood mononuclear cell cultures significantly inhibited in vitro anti-β₂GPI antibody production in response to β2GPI. Our results indicate preferential usage of TCRβ chains by β₂GPI-reactive T cells. These TCRβ chains can be reasonable targets for TCR-based immunotherapy for patients with APS.

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Spleen is a primary site for activation of platelet-reactive T and B cells in patients with immune thrombocytopenic purpura

Kuwana Masataka, Okazaki Yuka, Kaburaki Junichi, Kawakami Yutaka, Ikeda Yasuo

Journal of Immunology 168 （ 7 ） 3675 - 3682 2002年04月

ISSN 0022-1767

We have recently reported that in patients with chronic immune thrombocytopenic purpura (IMTP), circulating T and B cells that are responsive to gpIIb-IIIa can induce anti-platelet autoantibody production. In this study, the frequencies and activation status of gpIIb-IIIa-reactive T and B cells were evaluated in the peripheral blood and spleen obtained from nine IMTP patients undergoing splenectomy. There was no difference in gpIIb-IIIa-reactive T cell frequencies between peripheral blood and spleen (6.4 ± 2.6 vs 5.2 ± 2.4 per 10⁵ T cells), as determined by limiting dilution analysis, but activated T cells responsive to gpIIb-IIIa showing accelerated proliferation kinetics and those expressing CD154 were more frequent in spleen than in peripheral blood. The frequencies of anti-gpIIb-IIIa Ab-producing B cells, as determined by ELISPOT assay, were also similar in peripheral blood and spleen (61.2 ± 24.0 vs 77.7 ± 45.3 per 10⁵ B cells); however, an anti-gpIIb-IIIa Ab was spontaneously produced by splenocytes in vitro, but scarcely secreted by PBMCs. CD19^-/surface Ig^-/CD38⁺/CD138⁺ plasma cells secreting anti-gpIIb-IIIa Ab were exclusively detected in the spleen. In serial analysis, the frequencies of circulating gpIIb-IIIa-reactive T and B cells were decreased after splenectomy in patients with a complete response, but were unchanged in nonresponders. These findings indicate that an interaction between gpIIb-IIIa-reactive T and B cells inducing anti-platelet Ab production in IMTP patients occurs primarily in the spleen and that the significant number of gpIIb-IIIa-reactive T and B cells activated in the spleen are released into the circulation as memory cells.

Restricted T cell receptor _-chain usage by T cells autoreactive to _2-glycoprotein I in patients with antiphospholipid syndrome

Yoshida Kazue, Araki Takashi, Kaburaki J, Ikeda Yasuo, Kawakami Yutaka, Kuwana Masataka

Blood 99 （ 7 ） 2499-2504 2002年04月

研究論文（学術雑誌）, 共著

ミニ移植 ―Con―

山崎理絵，河上裕

血液・免疫・腫瘍 7 （ 2 ） 202-206 2002年04月

研究論文（学術雑誌）, 共著

Spleen is a primary site for activation of platelet-reactive T and B cells in patients with immune thrombocytopenic purpura¹

Kuwana Masataka, Okazaki Yuka, Kaburaki Junichi, Kawakami Yutaka, Ikeda Yasuo

The journal of immunology 168 （ 7 ） 3675-3682 2002年04月

研究論文（学術雑誌）, 共著

In situcancer vaccination with a replication-conditional HSV for the treatment of liver metastasis of colon cancer

Endo Takashi, Toda Masahiro, Watanabe Masahiko, Iizuka Yukihiko, Kubota Tetsuro, Kitajima Masaki, Kawakami Yutaka

Cancer Gene Therapy 9 （ 2 ） 142-148 2002年02月

研究論文（学術雑誌）, 共著

In situ cancer vaccination with a replication-conditional HSV for the treatment of liver metastasis of colon cancer

Endo Takashi, Toda Masahiro, Watanabe Masahiko, Iizuka Yukihiko, Kubota Tetsuro, Kitajima Masaki, Kawakami Yutaka

Cancer gene therapy 9 （ 2 ） 142-148 2002年02月

研究論文（学術雑誌）, 共著

Immuno-viral therapy of brain tumors by combination of viral therapy with cancer vaccination using a replication-conditional HSV

Toda Masahiro, Iizuka Yukihiko, Kawase Takeshi, Uyemura Keiichi, Kawakami Yutaka

Cancer Gene Therapy 9 （ 4 ） 356 - 364 2002年

ISSN 0929-1903

Here we developed an effective therapeutic approach using a replication-conditional mutant of herpes simplex virus (HSV), G207, for the treatment of metastatic tumors in the immunologically privileged central nervous system. An experimental model of brain metastasis was developed using BALB/c mice that harbored both intracranial (i.c.) and subcutaneous (s.c.) mouse CT26 colon adenocarcinoma tumors. Intratumoral injections of G207 into s.c. tumors elicited cytotoxic T-cell responses not only to HSV but also to a tumor antigen; however, only a limited antitumor effect was observed on metastatic brain tumors. To improve this antitumor effect, G207 was also injected into the brain tumor. After intratumoral injections of G207 into both i.c. and s.c. CT26 tumors, a significant antitumor effect was observed in the metastatic brain tumors. This therapeutic efficacy was absent in athymic mice, indicating that the antitumor effect could be mediated by T cells. Cytotoxic T-cell responses to HSV and the tumor antigen were induced by injections of G207 into i.c. and s.c. CT26 tumors. These results suggest that HSV-infected brain tumors may be efficiently eliminated by the induced anti-HSV T cells as well as by antitumor T cells. Therefore, this strategy of immuno-viral therapy, involving direct viral oncolytic activities and inducing antitumor and antiviral immune responses, may be useful for the treatment of tumors in the immunologically privileged central nervous system.

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Dry eye associated with chronic graft-versus-host disease

Ogawa Y., Kuwana M., Yamazaki K., Mashima Y., Okamoto S., Tsubota K., Oguchi Y., Kawakami Y.

Advances in Experimental Medicine and Biology 506 B 1041 - 1045 2002年

ISSN 0065-2598

In situ cancer vaccination with a replication-conditional HSV for the treatment of liver metastasis of colon cancer

Endo Takashi, Toda Masahiro, Watanabe Masahiko, Iizuka Yukihiko, Kubota Tetsuro, Kitajima Masaki, Kawakami Yutaka

Cancer Gene Therapy 9 （ 2 ） 142 - 148 2002年

ISSN 0929-1903

In this study, we investigated the therapeutic efficacy of a replication-conditional mutant HSV, G207, for the treatment of liver metastasis of colon carcinoma. Three liver metastasis models in syngeneic BALB/c mice were developed: (i) splenic injection, (ii) splenic and subcutaneous (s.c.) injection, and (iii) orthotopic implantation of CT26 colon carcinoma. In the splenic injection model, G207 was injected into the established splenic tumor on day 7. In the splenic and s.c. injection model, G207 were injected into the established s.c. tumor on days 5 and 8. In the orthotopic implantation model, a piece of CT26 tumor tissue was transplanted onto the wall of the cecum and G207 was injected in the established cecum tumor on day 7. On day 21 or 28, animals were sacrificed and liver metastases were evaluated. In all three models in immunocompetent mice, liver metastases were significantly reduced by intratumoral inoculation with G207 compared to the control. In athymic mice, however, there was no significant therapeutic effect of intratumoral inoculation with G207 on liver metastases. Tumor-specific cytotoxic T-lymphocyte responses were induced in mice treated with G207 in the orthotopic implantation model. These results suggest that intratumoral inoculation of G207, as an in situ cancer vaccine, can be an effective approach against liver metastasis of colon cancer and the efficacy involves tumor-specific T-cell responses.

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A simple and reliable behavioral analysis of locomotor function after spinal cord injury in mice

Mikami Yuji, Toda Masahiro, Watanabe Masahiko, Nakamura Masaya, Toyama Yoshiaki, Kawakami Yutaka

Journal of Neurosurgery 97 （ 1 SUPPL. ） 142 - 147 2002年

ISSN 0022-3085

To establish a simple and reliable method to assess the behavioral function after spinal cord injury (SCI) in mice, the authors used an automated animal movement analysis system, SCANET. Two different SCI lesions were created in adult female BALB/c and C57BL/6 mice by transecting both the posterior columns and the left lateral and anterior funiculi or only the left lateral and anterior funiculi at T-8. Control mice underwent laminectomy only. The SCANET system consists of a cage equipped with two crossing sensor frames arranged at different heights, by which small (MI) and large (M2) horizontal movements and the vertical movement involved in rearing (RG) can be monitored. The authors assessed locomotor function by determining the M1, M2, and RG scores; to this end, they used the SCANET system and a previously established behavior test, the 21-point open-field Basso-Beattie-Bresnahan (BBB) Locomotor Rating Scale. The results indicated that the RG scores were significantly and consistently different between the spinal cord-injured and control mice, irrespective of the mouse strain or injury model, but that MI and M2 scores were not. Moreover, there was a statistically positive correlation between the RG score and the BBB Scale score. For the assessment of locomotor function after SCI, use of the SCANET sytem in behavioral analysis is simple and the method is highly reproducible. The analysis of vertical movement is useful for assessing the recovery of limb function in mice following thoracic hemisection.

Tumor antigens isolated from a patient with vitiligo and T-cell-infiltrated melanoma

Kiniwa Y., Fujita T., Akada M., Ito K., Shofuda T., Suzuki Y., Yamamoto A., Saida T., Kawakami Y.

Cancer Research 61 （ 21 ） 7900 - 7907 2001年11月

ISSN 0008-5472

Serological identification of tumor antigens by cDNA expression cloning is a technique used to isolate cDNAs encoding tumor antigens that are recognized by IgG antibodies in sera from cancer patients. It is also useful for the isolation of tumor antigens recognized by T cells. We applied this method to identify melanoma antigens recognized by the serum from a patient with a good prognosis who had T-cell-infiltrated melanoma and vitiligo. By screening a λ phage cDNA library constructed from a highly pigmented melanoma cell line, SKme123, with the patient's serum, 50 positive cDNA clones consisting of 26 distinct antigens were isolated. Of these, 20 encoded known proteins, and 6 encoded previously uncharacterized ones. The most frequently isolated clone, which we named KU-MEL-1, was unknown previously but was homologous to partial cDNA sequences registered in the expressed sequence tag database. Reverse transcription-PCR and Northern blot analysis demonstrated that KU-MEL-1 was strongly expressed in most melanoma cell lines, melanoma tissue samples, and cultured melanocytes and weakly expressed in cell lines derived from other types of tumors, as well as in some normal tissues, including testis. Western blot analysis with polyclonal murine antibody generated by immunization with the recombinant KU-MEL-1 protein demonstrated that the KU-MEL-1 protein was preferentially expressed in melanoma cells and melanocytes IgG antibodies against KU-MEL-1 were detected in the sera from 9 of 26 melanoma patients and from some patients with other cancers including brain tumor, esophageal cancer, colon cancer, and chronic myelogenous leukemia, but were not detected in sera from 30 healthy individuals. Although the IgG specific for KU-MEL-1 was not detected in sera from 12 vitiligo patients, it was detected in sera from 7 of 11 patients with Vogt-Koyanagi-Harada disease that is thought to be an autoimmune disease against melanocytes. These results suggest that KU-MEL-1 may be a useful target for the development of diagnostic and therapeutic methods for patients with various cancers, particularly with melanoma as well as patients with autoimmune diseases against melanocytes.

Autoantibodies to the amino-terminal fragment of β-fodrin expressed in glandular epithelial cells in patients with Sjögren's syndrome

Kuwana M., Okano T., Ogawa Y., Kaburaki J., Kawakami Y.

Journal of Immunology 167 （ 9 ） 5449 - 5456 2001年11月

ISSN 0022-1767

Sjögrens's syndrome (SS) is an autoimmune disease characterized by destruction of lacrimal and salivary glands, but the mechanisms underlying the disease process are unclear. By immunoscreening a HepG2 cDNA library with serum from an SS patient we isolated a cDNA encoding amino-terminal 616 aa of β-fodrin, a membrane skeleton protein associated with ion channels and pumps. Serum Ab to the amino-terminal fragment of β-fodrin was frequently detected in SS patients compared with rheumatic disease patients without SS or healthy controls (70 vs 12 or 4%; p < 0.00001). All the anti-β-fodrin-positive sera recognized the amino-terminal fragment with no homology to α-fodrin. Anti-β-fodrin Abs in patients' sera as well as mouse polyclonal sera raised against the amino-terminal β-fodrin fragment did not react with intact β-fodrin, but recognized the 65-kDa amino-terminal fragment generated through cleavage by caspase-3 or granzyme B. When expression of intact and fragmented β-fodrin in lacrimal glands was assessed by immunohistochemistry, the antigenic amino-terminal fragment was distributed diffusely in acinar epithelial cell cytoplasm, whereas the carboxyl-terminal fragment and/or intact β-fodrin were localized in peripheral cytoplasm, especially at the basal membrane, in SS patients. In contrast, intact β-fodrin was detected primarily at the apical membrane of epithelia, and the amino-terminal fragment was scarcely detected in control patients with chronic graft-vs-host disease. These findings suggest that cleavage and altered distribution of β-fodrin in glandular epithelial cells may induce impaired secretory function and perpetuate an autoimmune response to β-fodrin, leading to autoantibody production and glandular destruction in SS.

Tumor antigens isolated from a patient with vitiligo and T-cell-infiltrated melanoma

Kiniwa Yukiko, Fujita Tomonobu, Akada M, Ito Keiich, Shofuda Tomoko, Suzuki Yuriko, Yamamoto Akifumi, Saida Toshiaki, Kawakami Yutaka

Cancer Research 61 （ 21 ） 7900-7907 2001年11月

研究論文（学術雑誌）, 共著

Graft versus leukemia (GVL) 効果の免疫制御

山崎理絵，河上裕

血液フロンティア 11 （ 11 ） 1399-1408 2001年11月

研究論文（学術雑誌）, 共著

Recent topics on basic research for idiopathic thrombocytopenic purpura

Kuwana M., Kawakami Y., Ikeda Y.

Rinsho byori. The Japanese journal of clinical pathology 49 （ 10 ） 992 - 995 2001年10月

ISSN 0047-1860

Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disease characterized by increased platelet clearance caused by anti-platelet autoantibodies, which bind to circulating platelets resulting in destruction. by the reticuloendothelial system. We have recently developed enzyme-linked immunospot assay to detect circulating B cells secreting anti-platelet antibody. An increase in anti-platelet antibody-producing B cells in peripheral blood was specifically detected in ITP patients, but in none of thrombocytopenic patients without ITP or healthy donors. While earlier studies reported the presence of platelet-reactive T cells in ITP patients, we have recently found that GPIIb-IIIa is one of major target antigens recognized by platelet-reactive CD4+ T cells. Since GPIIb-IIIa-reactive CD4+ T cells had helper activity promoting production of anti-platelet antibody, these autoreactive T cells are involved in production of pathogenic anti-platelet autoantibody in ITP patients. Suppression of GPIIb-IIIa-reactive CD4+ T cells may be of therapeutic use in treating refractory patients.

特発性血小板減少性紫斑病

桑名正隆，河上裕，池田康夫

臨床病理 49 （ 10 ） 992-995 2001年10月

研究論文（学術雑誌）, 共著

Increase of oligodendrocyte progenitor cells after spinal cord injury

Ishii Ken, Toda Masahiro, Nakai Yoko, Asou Hiroaki, Watanabe Masahiko, Nakamura Masaya, Yato Yoshiyuki, Fujimura Yoshikazu, Kawakami Yutaka, Toyama Yoshiaki, Uyemura Keiichi

Journal of Neuroscience Research 65 （ 6 ） 500 - 507 2001年09月

ISSN 0360-4012

The reaction of oligodendrocyte progenitor cells (OPCs) after spinal cord injury (SCI) is poorly understood. In this study, we examined oligodendroglial reactions after contusion SCI in adult rats by immunohistochemistry. OPCs were identified by staining with monoclonal antibodies (mAbs) A2B5 and O4. Each of the A2B5-, O4-positive OPCs and galactocerebroside-positive oligodendrocytes dramatically increased in the lesion of the dorsal posterior funiculus. Bromodeoxyuridine (BrdU) incorporation studies showed that most O4-positive cells in the lesion were labeled with BrdU, suggesting that these OPCs were proliferative. In contrast, the expression of myelin basic protein was decreased in the lesion compared with controls that received laminectomy only. From the injured cord, OPCs were isolated by immunopanning with mAb A2B5. We observed an increased number of OPCs from the injured spinal cords compared with those isolated from controls and unoperated animals. After several days in culture, the OPCs from the lesion expressed galactocerebroside. These results suggest that OPCs are induced and can differentiate following SCI in the adult rat.

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