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A simple behavioral test for locomotor function after brain injury in mice

Tabuse Masanao, Yaguchi Masae, Ohta Shigeki, Kawase Takeshi, Toda Masahiro

Journal of Clinical Neuroscience 17 （ 11 ） 1412 - 1416 2010年11月

ISSN 0967-5868

To establish a simple and reliable test for assessing locomotor function in mice with brain injury, we developed a new method, the rotarod slip test, in which the number of slips of the paralytic hind limb from a rotarod is counted. Brain injuries of different severity were created in adult C57BL/6 mice, by inflicting 1-point, 2-point and 4-point cryo-injuries. These mice were subjected to the rotarod slip test, the accelerating rotarod test and the elevated body swing test (EBST). Histological analyses were performed to assess the severity of the brain damage. Significant and consistent correlations between test scores and severity were observed for the rotarod slip test and the EBST. Only the rotarod slip test detected the mild hindlimb paresis in the acute and sub-acute phase after injury. Our results suggest that the rotarod slip test is the most sensitive and reliable method for assessing locomotor function after brain damage in mice. © 2010 Elsevier Ltd. All rights reserved.

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Subtemporal approach - Venous drainage and surgical anatomy

Toda Masahiro, Yoshida Kazunari, Kawase Takeshi

Japanese Journal of Neurosurgery 19 （ 10 ） 742 - 752 2010年10月

ISSN 0917-950X

Because the temporal lobe extends deeply into the middle cranial fossa anteriorly, the procedure of the subtemporal approach should be modified so as to avoid damaging the brain and the cortical veins by compression with retractors. To minimize compression damage to the temporal lobe it is necessary to perform the craniotomy along the middle cranial fossa, and to remove the zygomatic arch for supratentorial lesions, and to remove the petrous pyramid for infratentorial lesions. An extradural approach is useful as a means of preventing damage to bridging veins including Labbe's vein, but because the superior petrosal sinus and the tentorium are transected in the procedure by the anterior transpetrosal approach, the drainage pathways of the superficial sylvian vein (especially the sphenobasal vein and the sphenopetrosal vein) should be checked preoperatively. In this article we outline the surgical anatomy of the middle cranial fossa required for the subtemporal approach and variations in the venous drainage of the superficial sylvian vein, and then we describe the treatment of petroclival lesions by the anterior transpetrosal approach.

Endoscopic skull base surgery

Toda Masahiro

Neurological Surgery 38 （ 6 ） 506 - 514 2010年06月

ISSN 0301-2603

Identification of antigen against brain tumor stem cell and application for treatment of glioma

Toda Masahiro

Gan to kagaku ryoho. Cancer & chemotherapy 37 （ 6 ） 1016 - 1018 2010年06月

ISSN 0385-0684

Isolation of cancer stem-like cells from a side population of a human glioblastoma cell line, SK-MG-1

Fukaya Raita, Ohta Shigeki, Yamaguchi Masayuki, Fujii Hirofumi, Kawakami Yutaka, Kawase Takeshi, Toda Masahiro

Cancer Letters 291 （ 2 ） 150 - 157 2010年05月

ISSN 0304-3835

Accumulating evidence suggests that in several types of brain tumors, including glioma, only a phenotypic subset of tumor cells called brain cancer stem cells (BCSCs) may be capable of initiating tumor growth. Recently, the isolation of side population (SP) cells using Hoechst dye has become a useful method for obtaining cancer stem cells in various tumors. In this study, we isolated cancer stem-like cells from human glioma cell lines using the SP technique. Flow cytometry analysis revealed that SK-MG-1, a human glioblastoma cell line, contained the largest number of SP cells among the five glioma cell lines that were analyzed. The SP cells had a self-renewal ability and were capable of forming spheres in a neurosphere culture medium containing EGF and FGF2. Spheres derived from the SP cells differentiated into three different lineage cells: neurons, astrocytes and oligodendrocytes. RT-PCR analysis revealed that the SP cells expressed a neural stem cell marker, Nestin. The SP cells generated tumors in the brains of NOD/SCID mice at 8 weeks after implantation, whereas the non-SP cells did not generate any tumors in the brain. These results indicate that SP cells isolated from SK-MG-1 possess the properties of cancer stem cells, including their self-renewal ability, multi-lineage differentiation, and tumorigenicity. Therefore, the SP cells from SK-MG-1 may be useful for analyzing BCSCs because of the ease with which they can be handled and their yield. © 2009 Elsevier Ireland Ltd. All rights reserved.

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Targeted inhibition of IL-10-secreting CD25^- Treg via p38 MAPK suppression in cancer immunotherapy

Ohkusu-Tsukada Kozo, Toda Masahiro, Udono Heiichiro, Kawakami Yutaka, Takahashi Kimimasa

European Journal of Immunology 40 （ 4 ） 1011 - 1021 2010年04月

ISSN 0014-2980

Cancer-induced immunotolerance mediated by inducible Treg (iTreg) is a major obstacle to cancer immunotherapy. In a basic study of immunotolerance, injection of an endogenous superantigen, i.e. the minor lymphocyte stimulatory (Mls)-1^a, into specific TCR Vβ8.1-Tg mice enabled generation of anergic CD25^- iTreg, the immunosuppressive function of which was maintained by IL-10 production via p38-MAPK activation. Interestingly, although p38-chemical inhibitor (p38-inhibitor) is capable of breaking CD25^- iTreg-induced immunotolerance, the p38-inhibitor had hardly any immunotolerance breaking effect when CD25⁺ Treg were present, suggesting that depletion of CD25⁺ Treg is necessary for p38-inhibitor to be effective. Peptide OVA_323-339 iv.-injection into its specific TCR-Tg (OT-II) mice also induced adaptive tolerance by iTreg. Peptide immunotherapy with p38-inhibitor after CD25⁺ Treg-depletion was performed in an OVA-expressing lymphoma E.G7-bearing tolerant model established by adoptive transfer of OT-II CD25^- iTreg, which resulted in suppression of tumor growth. Similarly, the antitumor immunity induced by peptide immunotherapy in colon carcinoma CT26-bearingmice, in which the number of IL-10-secreting iTreg is increased, was augmented by treatment with p38-inhibitor after CD25 ⁺ Treg-depletion and resulted in inhibition of tumor progression. These results suggest that simultaneous inhibition of two distinct Treg-functions may be important to the success of cancer immunotherapy. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA.

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Identification of HLA-A2- And A24-restricted T-cell epitopes derived from SOX6 expressed in glioma stem cells for immunotherapy

Ueda Ryo, Ohkusu-Tsukada Kozo, Fusaki Noemi, Soeda Akio, Kawase Takeshi, Kawakami Yutaka, Toda Masahiro

International Journal of Cancer 126 （ 4 ） 919 - 929 2010年02月

ISSN 0020-7136

Malignant gliomas are the most aggressive human primary brain tumors and are currently incurable. Immunotherapies have the potential to target glioma and glioma stem cells (GSCs) that are resistant to conventional therapies. We previously identified SOX6 as a human glioma antigen and demonstrated that vaccination with SOX6 DNA induced cytotoxic T lymphocytes (CTLs) specific for glioma, thereby exerting therapeutic antitumor responses in glioma-bearing mice. In this study, we attempted to identify SOX6-derived peptides as specific targets for effective and safe T-cell-mediated immunotherapy targeting SOX6-positive glioma and GSCs. In vitro stimulation with human leukocyte antigen (HLA)-A*2402 (A24)-restricted peptides, RFENLGPQL (SOX6₅₀₄) and PYYEEQARL (SOX6₆₂₈) or the HLA-A*0201 (A2)-restricted peptide, ALFGDQDTV (SOX6₄₄₇) was capable of inducing SOX6 peptide-specific CTLs in peripheral blood mononuclear cells derived from healthy donors and glioma patients. These CTLs were able to lyse a majority of glioma cell lines and a GSC line derived from human glioblastoma in an HLA Class I-restricted and an antigen-dependent manner. Furthermore, peptide vaccines of SOX6₆₂₈, which was conserved in the murine SOX6 protein and expected to bind to major histocompatibility complex (MHC) H-2^d, induced CTLs specific for SOX6₆₂₈ in H-2^d mice. Normal autologous cells from mice, in which SOX6-specific immune responses were generated, were not destroyed. These results suggest that these SOX6 peptides are potnetially immunogenic in HLA-A24 or -A2 positive glioma patients and should be considered as a promising strategy for safe and effective T-cell-based immunotherapy of patients with gliomas. © 2009 UICC.

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Immunotherapy targeted at brain cancer stem cells

Toda Masahiro

Open Cancer Immunology Journal 3 48 - 50 2010年

Progress in stem cell research has been associated with the discovery of the presence of cancer stem cells in a variety of malignant tumors, and because these cells are resistant to anticancer agents and radiotherapy, analysis of their properties has been rapidly pursued as an important target for the treatment of cancers, including malignant brain tumors. Brain cancer stem cells (BCSCs) have been isolated from brain tumor tissue and brain tumor cell lines by using neural stem cell culture methods. Analyzing the properties of BCSCs is extremely important to developing treatment methods that target BCSCs. Although no treatment method targeting BCSCs has yet been established, several methods have been proposed based on their cell-biological characteristics. This article describes therapeutic strategies that target drug-resistance molecules and stem-cell-associated molecules as well as immunotherapy targeted at BCSCs. © Masahiro Toda; Licensee Bentham Open.

Transplantation of dendritic cells promotes functional recovery from spinal cord injury in common marmoset

Yaguchi Masae, Tabuse Masanao, Ohta Shigeki, Ohkusu-Tsukada Kozo, Takeuchi Tamaki, Yamane Junichi, Katoh Hiroyuki, Nakamura Masaya, Matsuzaki Yumi, Yamada Masayuki, Itoh Toshio, Nomura Tatsuji, Toyama Yoshiaki, Okano Hideyuki, Toda Masahiro

Neuroscience Research 65 （ 4 ） 384 - 392 2009年12月

ISSN 0168-0102

We previously reported that implantation of dendritic cells (DCs) into the injured site activates neural stem/progenitor cells (NSPCs) and promotes functional recovery after spinal cord injury (SCI) in mice. Working toward clinical application of DC therapy for SCI, we analyzed whether DCs promote functional recovery after SCI in a non-human primate, the common marmoset (CM). CMs are usually born as dizygotic twins. They are thus natural bone marrow and peripheral blood chimeras due to sharing of the placental circulation between dizygotic twins, leading to functional immune tolerance. In this study, to identify adequate CM donor-and-host pairs, mixed leukocyte reaction (MLR) assays were performed. Then, CM-DCs were generated from the bone marrow of the twin selected to be donor and transplanted into the injured site of the spinal cord of the other twin selected to be host, 7 days after injury. Histological analyses revealed fewer areas of demyelination around the injured site in DC-treated CMs than in controls. Immunohistochemical analysis showed that more motor neurons and corticospinal tracts were preserved after SCI in DC-treated CMs. Motor functions were evaluated using three different behavior tests and earlier functional recovery was observed in DC-treated CMs. These results suggest DC therapy to possibly be beneficial in primates with SCI and that this treatment has potential for clinical application. © 2009 Elsevier Ireland Ltd and the Japan Neuroscience Society.

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Therapeutic strategies targeting brain tumor stem cells

Toda Masahiro

Brain and Nerve 61 （ 7 ） 799 - 803 2009年07月

ISSN 1881-6096

Progress in stem cell research reveals cancer stem cells to be present in a variety of malignant tumors. Since they exhibit resistance to anticancer drugs and radiotherapy, analysis of their properties has been rapidly carried forward as an important target for the treatment of intractable malignancies, including brain tumors. In fact, brain cancer stem cells (BCSCs) have been isolated from brain tumor tissue and brain tumor cell lines by using neural stem cell culture methods and isolation methods for side population (SP) cells, which have high drug-efflux capacity. Although the analysis of the properties of BCSCs is the most important to developing methods in treating BCSCs, the absence of BCSC purification methods should be remedied by taking it up as an important research task in the immediate future. Thus far, there are no effective treatment methods for BCSCs, and several treatment methods have been proposed based on the cell biology characteristics of BCSCs. In this article, I outline potential treatment methods damaging treatment-resistant BCSCs, including immunotherapy which is currently a topic of our research.

Activation of dendritic-like cells and neural stem/progenitor cells in injured spinal cord by GM-CSF

Hayashi Kaori, Ohta Shigeki, Kawakami Yutaka, Toda Masahiro

Neuroscience Research 64 （ 1 ） 96 - 103 2009年05月

ISSN 0168-0102

Previously, we demonstrated that implanted dendritic cells (DCs) in the injured spinal cord of adult mice exert a neurotrophic effect, resulting in the activation of endogenous neural stem/progenitor cells (NSPCs) and neurogenesis. Granulocyte-macrophage colony stimulating factor (GM-CSF), which is an essential cytokine for the generation of DCs from haematopoietic progenitor cells, has been shown to be beneficial for the treatment of spinal cord injury (SCI). In the present study, to evaluate the mechanisms underlying this therapeutic efficacy of GM-CSF, we investigated the effects of GM-CSF on the DC-like cells and NSPCs in the injured spinal cord. When GM-CSF was injected into the injured spinal cords of mice, the numbers of DC-like cells and activated microglia/macrophages around the lesion site increased, accompanied by an increase in BDNF expression. A significant increase in endogenous NSPCs was observed around the lesion site in the GM-CSF-treated mice compared with that in the controls. A neurosphere forming assay revealed that GM-CSF also induced the proliferation of NSPCs in vitro. Moreover, injection of GM-CSF into the lesion immediately after the SCI resulted in early recovery of the locomotor function of the injured mice. In conclusion, GM-CSF activated DC-like cells and NSPCs in the injured spinal cord, which was probably involved in its beneficial effects in cases of spinal cord injury. © 2009 Elsevier Ireland Ltd and the Japan Neuroscience Society.

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Intraoperative navigation and fluorescence imagings in malignant glioma surgery

Toda Masahiro

Keio Journal of Medicine 57 （ 3 ） 155 - 161 2008年09月

ISSN 0022-9717

The current basic goals in glioma surgery are radical tumor resection without triggering the development of new neurological deficits. Although complete removal of malignant gliomas is extremely difficult because of the tumors' infiltrative characteristics, gross total resection of the tumor is known to be associated with improved outcome in the patients. To enable safe and radical resection of malignant gliomas, especially those adjacent to eloquent brain areas, rapid progress has been made in the development of operative support techniques; e.g., navigation systems to provide information about the anatomical and functional locations in the brain and a fluorescence imaging technique for differentiating brain tumors from normal brain tissue. These intraoperative imaging techniques in glioma surgery have improved the functional outcomes of glioma patients.

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Functional recovery after spinal cord injury in mice through activation of microglia and dendritic cells after IL-12 administration

Yaguchi Masae, Ohta Shigeki, Toyama Yoshiaki, Kawakami Yutaka, Toda Masahiro

Journal of Neuroscience Research 86 （ 9 ） 1972 - 1980 2008年07月

ISSN 0360-4012

We have previously reported that the transplantation of dendritic cells (DCs) brings about functional recovery after spinal cord injury in mice through the activation of endogenous microglia/macrophages and neural stem/progenitor cells. In this study, the effect of interleukin-12 (IL-12), which is secreted from DCs, was evaluated for the treatment of spinal cord injury in mice. Administration of IL-12 into the injured site significantly increased the number of activated microglia/macrophages and DCs as well as the expression of brain-derived neurotrophic factor surrounding the lesion site. Immunohistochemical analyses showed that de novo neurogenesis and remyelination were induced by IL-12 treatment. Furthermore, an open field test using Basso-Beattie-Brenham scoring revealed a significant improvement of locomotor function in mice treated with IL-12. These results suggest that IL-12 administration into the injured spinal cord results in a functional recovery through the activation of microglia/macrophages and DCs. © 2008 Wiley-Liss, Inc.

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Induction of protective and therapeutic antitumor immunity by a DNA vaccine with a glioma antigen, SOX6

Ueda Ryo, Kinoshita Eiko, Ito Rena, Kawase Takeshi, Kawakami Yutaka, Toda Masahiro

International Journal of Cancer 122 （ 10 ） 2274 - 2279 2008年05月

ISSN 0020-7136

We previously reported identifying SOX6 as a glioma antigen by serological screening using a testis cDNA library. Its preferential expression and frequent IgG responses in glioma patients indicate that SOX6 may be a useful target for immunotherapy. To examine whether cytotoxic T-lymphocyte (CTL) responses specific for SOX6 to destroy glioma can be generated in vivo, we treated glioma-bearing mice by vaccination with a plasmid DNA encoding murine full-length SOX6 protein. Following SOX6-DNA vaccination, CTLs specific for SOX6-expressing glioma cells were induced, while normal autologous-cells that had restrictedly expressed SOX6 during embryogenesis were not destroyed. Furthermore, DNA vaccination with SOX6 exerted protective and therapeutic antitumor responses in the glioma-bearing mice. This antitumor activity was abrogated by the depletion of CD4 positive T cells and/or CD8 positive T cells. These results suggest that the SOX6 protein has multiple CTL and helper epitopes to induce antitumor activity and the effectiveness of SOX6-DNA vaccine for the prevention and treatment of glioma. © 2008 Wiley-Liss, Inc.

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Isolation and characterization of dendritic cells from common marmosets for preclinical cell therapy studies

Ohta Shigeki, Ueda Yoko, Yaguchi Masae, Matsuzaki Yumi, Nakamura Masaya, Toyama Yoshiaki, Tanioka Yoshikuni, Tamaoki Norikazu, Nomura Tatsuji, Okano Hideyuki, Kawakami Yutaka, Toda Masahiro

Immunology 123 （ 4 ） 566 - 574 2008年04月

ISSN 0019-2805

Dendritic cells (DCs) have important functions as modulators of immune responses, and their ability to activate T cells is of great value in cancer immunotherapy. The isolation of DCs from the peripheral blood of rhesus and African green monkeys has been reported, but the immune system in the common marmoset remains poorly characterized, although it offers many potential advantages for preclinical studies. In the present study, we devised methods, based on techniques developed for mouse and human DC preparation, for isolating DCs from three major tissue sources in the common marmoset: bone marrow (BM), spleen and peripheral blood. Each set of separated cells was analysed using the cell surface DC-associated markers CD11c, CD80, CD83, CD86 and human leucocyte antigen (HLA)-DR, all of which are antibodies against human antigens, and the cells were further characterized both functionally and morphologically as antigen-presenting cells. BM proved to be an excellent cell source for the isolation of DCs intended for preclinical studies on cell therapy, for which large quantities of cells are required. In the BM-derived CD11c⁺ cell population, cells exhibiting the characteristic features of DCs were enriched, with the typical DC morphology and the abilities to undergo endocytosis, to secrete interleukin (IL)-12, and to stimulate Xenogenic T cells. Moreover, BM-derived DCs produced the neurotrophic factor NT-3, which is also found in murine splenic DCs. These results suggest that BM-derived DCs from the common marmoset may be useful for biological analysis and for preclinical studies on cell therapy for central nervous system diseases and cancer. © 2007 Blackwell Publishing Ltd.

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Identification of a neuron-specific human gene, KIAA1110, that is a guanine nucleotide exchange factor for ARF1

Hattori Yujiro, Ohta Shigeki, Hamada Kenji, Yamada-Okabe Hisafumi, Kanemura Yonehiro, Matsuzaki Yumi, Okano Hideyuki, Kawakami Yutaka, Toda Masahiro

Biochemical and Biophysical Research Communications 364 （ 4 ） 737 - 742 2007年12月

ISSN 0006-291X

To identify neuron-specific genes, we performed gene expression profiling, cDNA microarray and in silico ESTs (expressed sequence tags) analyses. We identified a human neuron-specific gene, KIAA1110 (homologue of rat synArfGEF (Po)), that is a member of the guanine nucleotide exchange factor (GEF) for the ADP-ribosylation factor (ARF). RT-PCR analysis showed that the KIAA1110 gene was expressed specifically in the brain among adult human tissues, whereas no apparent expression was observed in immature neural tissues/cells, such as fetal brain, glioma tissues/cells, and neural stem/precursor cells (NSPCs). The KIAA1110 protein was shown to be expressed in mature neurons but not in undifferentiated NSPCs. Immunohistochemical analysis also showed that KIAA1110 was expressed in neurons of the human adult cerebral cortex. Furthermore, the pull-down assay revealed that KIAA1110 has a GEF activity toward ARF1 that regulates transport along the secretion pathway. These results suggest that KIAA1110 is expressed specifically in mature neurons and may play an important role in the secretion pathway as a GEF for ARF1. © 2007 Elsevier Inc. All rights reserved.

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Preferential expression and frequent IgG responses of a tumor antigen, SOX5, in glioma patients

Ueda Ryo, Yoshida Kazunari, Kawase Takeshi, Kawakami Yutaka, Toda Masahiro

International Journal of Cancer 120 （ 8 ） 1704 - 1711 2007年04月

ISSN 0020-7136

We previously reported to identify SOX5 as a glioma antigen by serological screening using a testis cDNA library. The present study was designed to analyze SOXS expression, its immunoreactivity, and the correlation between SOX5 IgG responses and clinical features in glioma patients to evaluate the possibility of its use as a diagnostic marker. Quantitative RT-PCR and Western blot analysis revealed that SOX5 was expressed in glioma tissues, but not in normal adult tissues, except in the testis. An immunohistochemical analysis showed that SOX5 was expressed in glioma cells, but only a few SOX5-positive cells were detected in non-neoplastic tissues from the cerebral cortex. IgG antibodies against SOX5 were detected in sera from 8 of the 27 glioma patients (27.6%), 0 of the 14 patients with other brain diseases (0%), 1 of the 54 other cancer patients (1.9%) and 1 of the 37 healthy individuals (2.7%). Patients with glioblastotna (GBM) who showed IgG responses against SOX5 exhibited significantly better survival periods than GBM patients without SOX5 antibodies. In summary, SOX5 is aberrantly expressed in glioma and can be recognized as a glioma antigen using IgGs from the sera of glioma patients. Furthermore, there is a statistically significant correlation between the presence of SOX5 IgGs and survival in GBM patients, suggesting that the glioma antigen SOX5 may be useful not only as a diagnostic marker, but also as a prognostic marker in glioma patients. © 2007 Wiley-Liss, Inc.

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Enhancement of immunologic tumor regression by intratumoral administration of dendritic cells in combination with cryoablative tumor pretreatment and Bacillus Calmette-Guerin cell wall skeleton stimulation

Udagawa Masaru, Kudo-Saito Chie, Hasegawa Go, Yano Kazuhito, Yamamoto Aiko, Yaguchi Masae, Toda Masahiro, Azuma Ichiro, Iwai Takehisa, Kawakami Yutaka

Clinical Cancer Research 12 （ 24 ） 7465 - 7475 2006年12月

ISSN 1078-0432

Purpose: We developed an effective immunotherapy, which could induce antitumor immune responses against shared and unique tumor antigens expressed in autologous tumors. Experimental Design: Intratumoral administration of dendritic cells is one of the individualized immunotherapies; however, the antitumor activity is relatively weak. In this study, we attempted to enhance the antitumor efficacy of the i.t. dendritic cell administration by combining dendritic cells stimulated with Bacillus Calmette-Guerin cell wall skeleton (BCG-CWS) additionally with cryoablative pretreatment of tumors and analyzed the therapeutic mechanisms. Results: These two modifications (cryoablation of tumors and BCG-CWS stimulation of dendritic cells) significantly increases the antitumor effect on both the treated tumor and the untreated tumor, which was distant at the opposite side, in a bilateral s.c. murine CT26 colon cancer model. Further analysis of the augmented antitumor effects revealed that the cryoablative pretreatment enhances the uptake of tumor antigens by the introduced dendritic cells, resulting in the induction of tumor-specific CD8⁺ T cells responsible for the in vivo tumor regression of both treated and remote untreated tumors. This novel combination i.t. dendritic cell immunotherapy was effective against well-established large tumors. The antitumor efficacy was further enhanced by depletion of CD4⁺CD25 ⁺FoxP3⁺ regulatory T cells. Conclusions: This novel dendritic cell immunotherapy with i.t. administration of BCG-CWS-treated dendritic cells following tumor cryoablation could be used for the therapy of cancer patients with multiple metastases. © 2006 American Association for Cancer Research.

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Intracarotid injection of granulocyte-macrophage colony-stimulating factor induces neuroprotection in a rat transient middle cerebral artery occlusion model

Nakagawa Toru, Suga Sadao, Kawase Takeshi, Toda Masahiro

Brain Research 1089 （ 1 ） 179 - 185 2006年05月

ISSN 0006-8993

Granulocyte-macrophage colony-stimulating factor (GM-CSF) was found to promote collateral flow in patients with coronary artery disease and also to induce arteriogenesis in a rat hypoperfusion brain model. Activated macrophages have been shown to induce vascular proliferation and play an important role in ischemic stroke. In this study, we examined the therapeutic effect of GM-CSF on the ischemic brain by activating microglia/macrophages. Rats were subjected to 1-h intraluminal middle cerebral artery occlusion (MCAO) and received an intracarotid injection of GM-CSF (5 ng) or saline immediately after reperfusion. Infarct volume, neurological function and histological findings were assessed 48 h later. An intracarotid injection of GM-CSF reduced the infarct volume and improved neurological function at 48 h after reperfusion. Histological analysis revealed that the number of activated microglia/macrophages to be increased and the number of apoptotic cells to be decreased in the area of the penumbra. These results suggest that intracarotid injection of GM-CSF may have a therapeutic effect on brain ischemia via activation of microglia/macrophages. © 2006 Elsevier B.V. All rights reserved.

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Identification of a glioma antigen, GARC-1, using cytotoxic T lymphocytes induced by HSV cancer vaccine

Iizuka Yukihiko, Kojima Hidefumi, Kobata Tetsuji, Kawase Takeshi, Kawakami Yutaka, Toda Masahiro

International Journal of Cancer 118 （ 4 ） 942 - 949 2006年02月

ISSN 0020-7136

Despite several ongoing clinical trials of immunotherapies against glioma, few glioma-specifk antigens recognized by cytotoxic T lymphocytes (CTLs) have been identified. We recently demonstrated that intratumoral inoculation with herpes simplex virus (HSV) as a cancer vaccine activates tumor-specific CTLs. To identify glioma antigens recognized by CTLs, we used the HSV cancer vaccine to vaccinate mice harboring a syngeneic mouse glioma cell line, GL261. From the splenocytes of the immunized mice, we generated an H-2D^b-restricted CTL line, GCL-1, that was specific for GL261. Then, a cDNA expression library generated from GL261 was screened with GCL-1, and a new gene encoding glioma antigen, GARC-1, was isolated. Sequence analysis revealed that the GARC-1 gene isolated from GL261 had a point mutation causing an amino acid change (Asp to Asn at position 81). T-cell epitope analysis revealed that the mutated peptide GARC-1_77-85 (AALLNKLYA) but not the wild-type peptide (AALLDKLYA), was recognized by GCL-1. These results suggest that HSV cancer vaccination may be a useful method for inducing tumor-specific CTLs and identifying tumor antigens. Furthermore, this GL261/GARC-1 murine glioma model may be useful for the development of immunotherapy for brain tumors. © 2005 Wiley-Liss, Inc.

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