Details of a Researcher - Kawakami, Yutaka

Papers - Kawakami, Yutaka

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Expression of the neural RNA- binding protein Musashi1 in human gliomas

Toda Masahiro, Iizuka Yukihiko, Yu Wangjie, Imai Takao, Ikeda Eiji, Yoshida Kazunari, Kawase Takeshi, Kawakami Yutaka, Okano Hideyuki, Uyemura Keiichi

GLIA 34 ( 1 ) 1 - 7 2001

ISSN 0894-1491

Tumor cells arising from a particular tissue may exhibit the same gene expression patterns as their precursor cells. To test this proposition, we have analyzed the expression of a neural RNA-binding protein, Musashi1, in primary human central nervous system (CNS) tumors. In rodents, Musashi1 is expressed predominantly in proliferating multipotent neural precursor cells, but not in newly generated postmitotic neurons. The expression of Musashi1 is downregulated with the successive progression of neurogenesis. In normal adult human tissues, we detected low levels of Musashi1 expression in brain and testis by RT-PCR analysis. In an RNA panel of 32 cancer tissues and cell lines, elevated expression of Musashi1 was seen in all five malignant gliomas studied, in contrast to the slight expression seen in other tumor cells, including those in several melanomas and a prostate cancer. Western blot analysis showed strong Musashi1 expression in malignant gliomas compared with nonneoplastic brain tissue. Glioblastomas, the most malignant form of glioma, showed higher Musashi1 expression than less malignant gliomas by immunohistochemical analysis. Tumors with strong Musashi1 expression tended to have high proliferative activity. Thus, the expression of Musashi1 correlated with the grade of the malignancy and proliferative activity in gliomas. These results suggest that primary CNS tumors may share gene expression patterns with primitive, undifferentiated CNS cells and that Musashi1 may be a useful marker for the diagnosis of CNS tumors.

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特発性血小板減少性紫斑病における病因的自己反応性T細胞の同定

Kuwana Masataka，Kawakami Yutaka，Ikeda Yasuo

日本臨床免疫学会雑誌 23 ( 6 ) 555-557 2000.12

Research paper (scientific journal), Joint Work

SEREX抗原によるグリオーマの血清診断

Toda Masahiro，Iiduka Yukihiko，Kawase Takeshi，Kawakami Yutaka

神経免疫研究 13 44-46 2000.12

Research paper (scientific journal), Joint Work

HLA class II alleles in Japanese patients with immune thrombocytopenic purpura: associations with anti-platelet glycoprotein antibodies and responses to splenectomy

Kuwana Masataka, Kaburaki Junichi, Pandey Janardan P, Murata Mitsuru, Kawakami Yutaka, Inoko Hidetoshi, Ikeda Yasuo

Tissue Antigens 56 ( 4 ) 337-343 2000.10

Research paper (scientific journal), Joint Work

New cancer therapy by immunomanipulation

Kawakami Yutaka

Cornea 19 ( 3 SUPPL. 1 ) 2000.05

ISSN 0277-3740

Purpose and Methods. T cells play an important role in in vivo rejection of human melanoma. Human melanoma antigens recognized by autologous T cells were identified. These antigens are classified as tissue (melanocyte)- specific proteins, cancer-testis antigens (proteins expressed in normal testis and various cancers), tumor-specific peptides derived from mutations in tumor cells, and others. Results. A variety of mechanisms generating T cell epitopes on tumor cells were discovered. Various clinical observations, including tumor regression observed in adoptive transfer of gp 100-reactive T cells suggest that these identified melanoma peptides may function as tumor rejection antigens. Immunodominant common epitopes that could expand melanoma-reactive cytotoxic T lymphocytes (CTLs) in vitro were found in the MART-1 and gp 100 antigens. New immunization protocols - including immunization with peptides, recombinant viruses, plasmid DNAs, and dendritic cells pulsed with peptides as well as adoptive transfer of in vitro-generated CTLs by stimulation with antigenic peptides - were developed (phase I clinical trials have been performed in the Surgery Branch of the National Cancer Institute, Bethesda, MD, U.S.A.). Immunization with the gp100(209(210M)) peptide that was modified to have high HLA-A2 binding affinity, along with incomplete Freund's adjuvant and interleukin (IL)-2, resulted in a 42% response rate in patients with melanoma. Conclusion. These immunotherapies need further improvement due to the mechanisms of tumor escape from T cell responses.

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Longitudinal analysis of autoantibody response to topoisomerase I in systemic sclerosis

Kuwana Masataka, Kaburaki Junichi, Mimori Tsuneyo, Kawakami Yutaka, Tojo Takeshi

Arthritis and Rheumatism 43 ( 5 ) 1074 - 1084 2000.05

ISSN 0004-3591

Objective. To examine serial changes in serum anti-topoisomerase I (anti-topo I) antibody levels in patients with systemic sclerosis (SSc), as well as associations with clinical features and the in vivo activation status of circulating topo I-reactive T and B cells. Methods. Serum anti-topo I antibody levels were serially measured at different time points in 28 SSc patients who were positive for anti-topo I antibody at their first visit (range of followup 6-29 years). The patients were subgrouped according to the disappearance (group 1) or persistence (group 2) of anti-topo I antibody. Clinical findings as well as T and B cell responses to topo I were compared between these 2 groups. Results. Serum anti-topo I antibody disappeared during the period of followup in 6 patients (group 1), but persisted in 22 patients (group 2). Loss of anti-topo I antibody occurred within 10 years after the first visit and independently of treatment. Group I patients had less extensive skin and lung involvement and better survival rates than did group 2 patients. Complete loss of anti-topo I antibody followed a reduction in isotype expression and epitope reactivities. The kinetics of in vitro T cell proliferation induced by topo I were delayed and circulating topo I- reactive T Cells were less frequently detected in group I versus group 2 patients, suggesting that the disappearance of anti-topo I antibody was due to loss of activation of topo I-reactive T cells. In vitro production of anti-topo I antibody in peripheral blood mononuclear cell cultures in response to antigenic stimulation in both group 1 and group 2 patients indicated persistence of anti-topo I antibody-producing 'memory' B cells even after the loss of serum anti-topo I antibody. Conclusion. Our results indicate that there is a distinct subset of anti-topo I-positive SSc patients who lose anti-topo I antibody during the disease course and have a favorable outcome. In vivo production of anti-topo I autoantibody may require antigenic stimulation that activates topo I-reactive T and B cells.

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T cells that are autoreactive to β₂-glycoprotein I in patients with antiphospholipid syndrome and healthy individuals

Hattori Noriko, Kuwana Masataka, Kaburaki Junichi, Mimori Tsuneyo, Ikeda Yasuo, Kawakami Yutaka

Arthritis and Rheumatism 43 ( 1 ) 65 - 75 2000.01

ISSN 0004-3591

Objective. To identify the T cells responsive to β₂-glycoprotein I (β₂GPI) that mediate antiphospholipid antibody production in patients with antiphospholipid syndrome (APS). Methods. In vitro proliferative responses and anti-β₂GPI antibody production induced by β₂GPI were examined in peripheral blood mononuclear cell (PBMC) cultures from 12 APS patients, 13 systemic lupus erythematosus patients without APS, and 12 healthy donors. Results. Peripheral blood T cells from all subjects failed to respond to β₂GPI in its native form. In contrast, reduced β₂GPI was able to stimulate T cells not only from all 12 patients with anti-β₂GPI antibodies, but also from 10 of 25 individuals without anti-β₂GPI antibodies. The specificity of the responses to β₂GPI was confirmed by activation of the reduced β₂GPI-primed T cells by recombinant β₂GPI in secondary cultures. Characterization of the T cell response induced by β₂GPI revealed that the response was associated with the presence of the DR53-associated alleles, the responding T cells were CD4+ and restricted by HLA class II, and antigenic peptides were located in domains IV and/or V. Anti-β₂GPI antibody production was induced specifically in anti-β₂GPI antibody-positive patients, in PBMC cultures with reduced β₂GPI. Anti-β₂GPI antibodies produced in vitro recognized β₂GPI immobilized with cardiolipin or β₂GPI coated on 'high-binding' polystyrene plates. Conclusion. These results strongly suggest that CD4+ and HLA class II-restricted T cells responsive to β₂GPI are involved in the production of antiphospholipid antibodies in APS patients.

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T cells that are autoreactive to β₂-glycoprotein I in patients with antiphospholipid syndrome and healthy individuals

Hattori Noriko, Kuwana Masataka, Kaburaki Junichi, Mimori Tsuneyo, Ikeda Yasuo, Kawakami Yutaka

Arthritis and Rheumatism 43 ( 1 ) 65-75 2000.01

Research paper (scientific journal), Joint Work

Recognition of shared melanoma antigens in association with major hla-a alleles by tumor infiltrating t lymphocytes from 123 patients with melanoma

Kawakami Yutaka, Dang Nita, Wang Xiang, Tupesis Janis, Robbins Paul F., Wang Rong Fu, Wunderlich John R., Yannelli John R., Rosenberg Steven A.

Journal of Immunotherapy 23 ( 1 ) 50817 2000

ISSN 1524-9557

In situ cancer vaccination with a mutant HSV for the treatment of liver metastasis of colon cancer

Endo T, Toda M, Watanabe M, Iizuka Y, Kubota T, Kitajima M, Kawakami Y

Proceedings of the American Association for Cancer Research 41 798 2000

Research paper (scientific journal), Joint Work

Multiple in situ cancer vaccinations with HSV and IL-12 synergize to facilitate tumor regression

Suzuki A, Toda M, Iizuka Y, Kitagawa Y, Kawakami Y

Proceedings of the American Association for Cancer Research 41 469 2000

Research paper (scientific journal), Joint Work

Characterization of tumor antigens recognized by IgG antibody in patients with glioma using SEREX

Takahashi S, Toda M, Iizuka Y, Yoshida K, Kawase T, Kawakami Y

Proceedings of the American Association for Cancer Research 41 880 2000

Research paper (scientific journal), Joint Work

Identification and characterization of human brain tumor antigens: a potential target for specific immunotherapy and diagnostic marker

Toda M, Iizuka Y, Takahashi S, Fujita T, Ikeda E, Yoshida K, Kawase T, Okano H, Uyemura K, Kawakami Y

Proceedings of the American Association for Cancer Research 41 710 2000

Research paper (scientific journal), Joint Work

Cancer immunotherapy with dendritic cells engineered to express tumor antigens

Sumimoto H., Kawakami Y.

Biotherapy 14 ( 12 ) 1197 - 1204 2000

ISSN 0914-2223

Dendritic cells engineered to express tumor-associated antigens can be used to prime and potentiate cytotoxic T cell responses against cancer cells. Numerous delivery systems for introducing genes to dendritic cells have been examined, which include (I) Viral vector systems such as Moloney leukemia virus vector (MLV), human immunodeficiency virus (HIV) vector, and adenovirus vector, vaccinia virus vector, canarypox virus vector and herpes simplex virus (HSV) vector, and (II) Non-viral vector systems such as cationic liposome, particle bombardment (gene gun) and electroporation methods. In this review, we adress several issues regarding these gene delivery systems in terms of genetic modification of dendritic cells. Since every method has advantages and/or disadvantages, the optimal methods for presenting antigen epitopes to dendritic cells need to be clarified. Several animal models by using dendritic cells transduced with model tumor antigens have shown in vivo antitumor effects, suggesting the potential clinical usefulness of this strategy.

HLA class II alleles in Japanese patients with immune thrombocytopenic purpura. Associations with anti-platelet glycoprotein autoantibodies and responses to splenectomy

Kuwana M., Kaburaki J., Pandey J. P., Murata M., Kawakami Y., Inoko H., Ikeda Y.

Tissue Antigens 56 ( 4 ) 337 - 343 2000

ISSN 0001-2815

HLA class II alleles and immunoglobulin allotypes were determined in 83 Japanese patients with immune thrombocytopenic purpura (ITP) and 114 race-matched healthy controls. Distribution of DRB and DQB1 alleles as well as G1M(f, z), G2M(n+, n-), and KM(1, (1,2), 3) were not different between ITP patients and healthy controls, while DPB1*0201 was marginally increased in ITP patients vs. healthy controls (51% vs. 28%, Pc = 0.04, OR = 2.6 [1.4-4.8]). In contrast, strong associations between anti-glycoprotein autoantibodies and HLA class II genes were found as follows: Anti-GPIIb-IIIa antibody with DRB1*0405 and DQB1*0401; and anti-GPIb-IX antibody with DRB1*0803 and DQB1*0601. When factors influencing therapeutic responses to splenectomy were examined, a poor response was correlated with the presence of DRB1*0405, DQB1*0401 and anti-GPIIb-IIIa antibody (P = 0.01, 0.002, and 0.03, respectively). Our results indicate that HLA class II genes influence the production of anti-glycoprotein antibody specificities rather than the development of ITP. In addition, HLA class II genotyping could be useful in predicting therapeutic responses to splenectomy in Japanese patients with ITP.

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Identification and characterization of pathogenic autoreactive T cells in patients with idiopathic thrombocytopenic purpura

Kuwana M., Kawakami Y., Ikeda Y.

Nihon Rinshō Men'eki Gakkai kaishi = Japanese journal of clinical immunology 23 ( 6 ) 555 - 557 2000

ISSN 0911-4300

Recognition of shared melanoma antigens in association with major HLA-A alleles by tumor infiltrating T lymphocytes from 123 patients with melanoma

Kawakami Yutaka, Dang Nita, Wang Xiang, Tupesis Janis, Robbins Paul F., Wang Rong Fu, Wunderlich John R., Yannelli John R., Rosenberg Steven A.

Journal of Immunotherapy 23 ( 1 ) 17 - 27 2000

ISSN 1053-8550

A total of 123 tumor-infiltrating T lymphocyte (TIL) cultures established from patients with HLA-A1, -A2, -A3, -A24, or -A31 metastatic melanoma in the Surgery Branch, National Cancer Institute, were screened for recognition of shared melanoma antigens including five melanosomal proteins (tyrosinase, MART-1/melan-A, gp100, TRP1, TRP2) as well as peptides derived from MAGE-1 and MAGE-3. Examination of the specificity of these T cells indicated that 16% of HLA-A1 TIL, 57% of HLA-A2 TIL, 7% of HLA-A3 TIL, 13% of HLA-A24 TIL, and 27% of HLA-A31 TIL recognized shared melanoma antigens restricted by major histocompatibility complex class I. Melanosomal proteins were frequently recognized by these TIL, and MART- 1_27-35, gp100_154- ₁₆₂, gp100_209-217, and gp100_280-288 represent highly immunogenic epitopes that were recognized by a high percentage of HLA-A2 restricted melanoma reactive TIL. Recognition of gp100 by HLA-A2 restricted TIL significantly correlated with clinical response to adoptive immunotherapy with TIL in 21 HLA-A2 melanoma patients (p = 0.024). Four HLA-A1, two HLA-A2, two HLA-A3, one HLA-A24, and two HLA-A31 restricted shared antigen-specific TIL did not recognize the previously identified antigens tested in this study, and may be useful for the identification of new melanoma antigens. The observation that TILs isolated from patients with metastatic melanoma recognized melanosomal proteins in the context of predominant HLA-A alleles implies that it may be possible to develop immunotherapies for patients with melanoma expressing diverse HLA types.

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T cell immune responses against melanoma and melanocytes in cancer and autoimmunity

Kawakami Yutaka, Suzuki Yuriko, Shofuda Tomoko, Kiniwa Yukiko, Inozume Takashi, Dan Katsuaki, Sakurai Toshiharu, Fujita Tomonobu

Pigment Cell Research 13 ( SUPPL. 8 ) 163 - 169 2000

ISSN 0893-5785

T cell responses specific for melanoma cells and melanocytes appear to be involved in the rejection of melanoma tumors, as well as in the development of autoimmune reactions in patients with Vogt-Koyanagi-Harada disease (VKH), sympathetic ophthalmia, or autoimmune vitiligo. Some of the target antigens for those T cells have been isolated using cDNA expression cloning with melanoma reactive T cells derived from tumor infiltrating lymphocytes (TIL) of patients with melanoma. These include melanocyte specific proteins, such as tyrosinase, TRP1, TRP2, gp100, and MART-1, cancer-testis antigens, and mutated peptidcs derived from genetic alterations in melanoma cells. Some of the melanoma reactive T cells appear to respond to cryptic or subdominant self epitopes in melanosomal proteins. Modification of those epitopes to increase their immunogenicity by replacement of amino acids at primary anchor residues for peptide/MHC binding, allowed an improvement in immunotherapy for patients with melanoma. Targets for autoreactive T cells against melanocytes in those autoimmune disorders remain to be identified. Isolation of novel target antigens is important for understanding these pathological T cell responses, as well as for developing new diagnostic and treatment methods for these diseases. A variety of techniques, including cDNA expression cloning with T cells, serological analysis of recombinant cDNA expression libraries (SEREX), cDNA subtraction with representational differential analysis (RDA), and serial analysis of gene expression (SAGE) are now being applied to identify novel melanoma/melanocyte antigens recognized by T cells and antibodies.

Immuno-gene therapy for cancer

Kawakami Y.

Biotherapy 14 ( 4 ) 345 - 350 2000

ISSN 0914-2223

A variety of molecules involved in the immune system have recently been isolated. These molecules have allowed the design of immunological interventions of immune responses to human cancer, or so called immuno-gene therapy. Clinical trials have been performed in Europe and the U.S. using various protocols, including gene-modified T cells; highly immunogenic cancer cells transfected with genes encoding cytokines, co-stimulatory molecules, and foreign antigens; immunization with tumor antigen genes as forms of plasmids and recombinant viruses; and immunization with dendritic cells transduced with tumor antigen genes. However, the anti-tumor effects observed in these reports have been limited. Improvement of various points will be necessary to establish immuno-gene therapy for cancer on the basis of fundamental research on immunoregulation against cancer, including isolation of tumor antigens and analysis of tumor escape mechanisms.

転移性脳腫瘍に対する癌ワクチン療法の試み

Toda Masahiro, Iizuka Yukihiko, Yazaki Takahito, Uemura Keiichi, Kawase Takeshi, Kawakami Yutaka

Neurologia medico-chirurgica 10 ( abstr ) 80-80 1999.10

Research paper (scientific journal), Joint Work

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