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論文 - 戸田　正博

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Application of the endoscopic transsphenoidal approach to true type transsellar transsphenoidal meningoencephalocele in an adult

Saito Katsuya, Toda Masahiro, Sano Keisho, Tomita Toshiki, Ogawa Kaoru, Yoshida Kazunari

Acta Neurochirurgica 154 （ 8 ） 1511 - 1515 2012年08月

ISSN 0001-6268

Of the transsellar transsphenoidalmeningoencephaloceles (TTSMEs), the true type presents with the hernial sac extending from the intracranium to the epipharynx through the sellar floor. The true type is the most serious and difficult to manage, especially when the hernial sac contains vital structures, such as the anterior cerebral artery, pituitary gland, optic nerve, hypothalamus, and third ventricle. Surgical outcome for true type TTSME is reported to be poor. We describe a successful case of endoscopic repair for a 36-year-old man with true type TTSME. Our success with endoscopic repair for true type TTSME in an adult is the first reported case. We believe that the endoscopic transsphenoidal approach allows less invasive surgery and provides an acceptable operative outcome in comparison with other microsurgical approaches. © Springer-Verlag 2012.

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Surgical results of an endoscopic endonasal approach for clival chordomas

Saito Katsuya, Toda Masahiro, Tomita Toshiki, Ogawa Kaoru, Yoshida Kazunari

Acta Neurochirurgica 154 （ 5 ） 879 - 886 2012年05月

ISSN 0001-6268

Background The surgical approaches for clival chordomas remain controversial, although the extent of resection is one of the most important factors for long survival rates. Recently an endoscopic endonasal approach in good collaboration with otolaryngologists has attracted major attention as a surgical approach for clival chordomas. We describe our experience with the endoscopic endonasal approach and provide a review of the literature. Methods Between 2008 and 2011, six operations were performed via the endoscopic endonasal approach for clivus chordomas. The mean tumor size was 35 mm in diameter. The tumor location was mainly from the upper to middle clivus. The tumor extended into the cavernous sinus in five cases and intradurally in three cases. A binostril approach was performed in four cases, while a one nostril approach was performed in two cases. Results Gross total removal was achieved in three cases. The analysis of cases with incomplete resection suggested that residual tumors were observed epidurally and subdurally. The residual on the epidura was observed from the posterior clinoid to the posterior compartment of the cavernous sinus. On the other hand, the residual on the subdural was observed behind the upper part of the pituitary gland. There was no postoperative cerebrospinal fluid (CSF) leakage using vascularized nasoseptal flaps in any of the cases. Conclusions The endoscopic endonasal transclival approach allows an appropriate extent of resection with acceptable complication rates in comparison with other approaches. In our series, the accomplishment of gross total removal was associated with the relationship between the tumors and surrounding structures, such as the pituitary gland and the cavernous portion of the intracranial carotid artery (ICA). © Springer-Verlag 2012.

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Downregulation of KIF23 suppresses glioma proliferation

Takahashi Satoshi, Fusaki Noemi, Ohta Shigeki, Iwahori Yoshihiro, Iizuka Yukihiko, Inagawa Kohei, Kawakami Yutaka, Yoshida Kazunari, Toda Masahiro

Journal of Neuro-Oncology 106 （ 3 ） 519 - 529 2012年02月

ISSN 0167-594X

To identify therapeutic molecular targets for glioma, we performed modified serological identification of antigens by recombinant complementary DNA (cDNA) expression cloning using sera from a mouse glioma model. Two clones, kinesin family member 23 (Kif23) and structural maintenance of chromosomes 4 (Smc4), were identified as antigens through immunological reaction with sera from mice harboring synergic GL261 mouse glioma and intratumoral inoculation with a mutant herpes simplex virus. The human Kif23 homolog KIF23 is a nuclear protein that localizes to the interzone of mitotic spindles, acting as a plus-end-directed motor enzyme that moves antiparallel microtubules in vitro. Expression analysis revealed a higher level of KIF23 expression in glioma tissues than in normal brain tissue. The introduction of small interfering RNA (siRNA) targeting KIF23 into two different glioma cell lines, U87MG and SF126, downregulated KIF23 expression, which significantly suppressed glioma cell proliferation in vitro. KIF23 siRNA-treated glioma cells exhibited larger cell bodies with two or more nuclei compared with control cells. In vivo analysis using mouse xenograft showed that KIF23 siRNA/DNA chimeratreated tumors were significantly smaller than tumors treated with control siRNA/DNA chimera. Taken together, our results indicate that downregulation of KIF23 decreases proliferation of glioma cells and that KIF23 may be a novel therapeutic target in malignant glioma. © 2011 Springer Science+Business Media, LLC.

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Macrophage migration inhibitory factor (MIF) promotes cell survival and proliferation of neural stem/progenitor cells.

Ohta S, Misawa A, Fukaya R, Inoue S, Kanemura Y, Okano H, Kawakami Y, Toda M

J Cell Sci 125 3210 - 3220 2012年

研究論文（学術雑誌）, 共著, 査読有り

Downregulation of uPARAP mediates cytoskeletal rearrangements and decreases invasion and migration properties in glioma cells

Takahashi Satoshi, Yamada-Okabe Hisafumi, Hamada Kenji, Ohta Shigeki, Kawase Takeshi, Yoshida Kazunari, Toda Masahiro

Journal of Neuro-Oncology 103 （ 2 ） 267 - 276 2011年06月

ISSN 0167-594X

To identify molecular therapeutic targets for glioma, we performed gene expression profiling by using a complementary DNA (cDNA) microarray method and identified the urokinase plasminogen activator receptor-associated protein (uPARAP/Endo180) as a gene expressed highly in glioma tissue compared with the normal brain tissue. The uPARAP is an endocytic receptor for collagen. In certain cell types, uPARAP occurs in a complex with the urokinase plasminogen activator receptor (uPAR) where it fulfills other functions in addition to collagenolysis. Quantitative PCR analysis using a cDNA panel revealed higher expression levels of uPARAP in glioma tissue compared with normal brain tissue. Western blot analysis revealed that the uPARAP protein was expressed in glioma samples and two glioma cell lines, KNS42 and KNS81, but not expressed in control tissue from the normal brain. Introduction of small interfering RNA-targeted uPARAP into the two different glioma cell lines, KNS42 and KNS81, resulted in downregulation of uPARAP expression, and it significantly suppressed glioma cell migration and invasion in vitro. Control glioma cells showed small cell bodies, whereas uPARAP siRNA-treated glioma cells exhibited large and flat morphology. Most of the polymeric actin in the control glioma cells was concentrated in the lamellipodia that are observed in mobile cells. In contrast, in the uPARAP siRNA-treated glioma cells, polymeric actin became organized in stress fibers and the lamellipodia disappeared, characteristic of immobile cells. Our present study suggests that uPARAP may be involved in glioma cell invasiveness through actin cytoskeletal rearrangement. downregulation of uPARAP may be a novel anti-invasion therapeutic strategy for malignant gliomas. © 2010 Springer Science+Business Media, LLC.

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Functional analysis of HOXD9 in human gliomas and glioma cancer stem cells

Tabuse Masanao, Ohta Shigeki, Ohashi Yohei, Fukaya Raita, Misawa Aya, Yoshida Kazunari, Kawase Takeshi, Saya Hideyuki, Thirant Cécile, Chneiweiss Hérve, Matsuzaki Yumi, Okano Hideyuki, Kawakami Yutaka, Toda Masahiro

Molecular Cancer 10 2011年05月

Background: HOX genes encode a family of homeodomain-containing transcription factors involved in the determination of cell fate and identity during embryonic development. They also behave as oncogenes in some malignancies.Results: In this study, we found high expression of the HOXD9 gene transcript in glioma cell lines and human glioma tissues by quantitative real-time PCR. Using immunohistochemistry, we observed HOXD9 protein expression in human brain tumor tissues, including astrocytomas and glioblastomas. To investigate the role of HOXD9 in gliomas, we silenced its expression in the glioma cell line U87 using HOXD9-specific siRNA, and observed decreased cell proliferation, cell cycle arrest, and induction of apoptosis. It was suggested that HOXD9 contributes to both cell proliferation and/or cell survival. The HOXD9 gene was highly expressed in a side population (SP) of SK-MG-1 cells that was previously identified as an enriched-cell fraction of glioma cancer stem-like cells. HOXD9 siRNA treatment of SK-MG-1 SP cells resulted in reduced cell proliferation. Finally, we cultured human glioma cancer stem cells (GCSCs) from patient specimens found with high expression of HOXD9 in GCSCs compared with normal astrocyte cells and neural stem/progenitor cells (NSPCs).Conclusions: Our results suggest that HOXD9 may be a novel marker of GCSCs and cell proliferation and/or survival factor in gliomas and glioma cancer stem-like cells, and a potential therapeutic target. © 2011 Tabuse et al; licensee BioMed Central Ltd.

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Adjuvant effects of formalin-inactivated HSV through activation of dendritic cells and inactivation of myeloid-derived suppressor cells in cancer immunotherapy

Ohkusu-Tsukada Kozo, Ohta Shigeki, Kawakami Yutaka, Toda Masahiro

International Journal of Cancer 128 （ 1 ） 119 - 131 2011年01月

ISSN 0020-7136

Use of adequate adjuvant is necessary for induction of effective antitumor immune responses. To develop an effective adjuvant for cancer immunotherapy, we selected formalin-inactivated (f)-HSV as an adjuvant component, and analyzed the mechanisms underlying its adjuvant effects. First, we found that f-HSV can induce the tumor antigen-specific CTLs by enhancing antigen cross-presentation by dendritic cells (DCs), mainly through TLR2, but not TLR9. Next, f-HSV was also found to prevent the accumulation of myeloid-derived suppressor cells (MDSCs). We demonstrated that the expansion of MDSCs in the blood and spleen during tumor progression required B cells producing the inflammatory angiogenesis factors, vascular endothelial growth factor (VEGF)-A and neuropilin-1 (NRP-1), a co-receptor for VEGF receptor-2 (VEGFR-2). Interestingly, the transmembrane-type NRP-1 on B cells changed to soluble-type NRP-1 (sNRP-1) by f-HSV treatment. We further showed that the sNRP-1 and VEGF-A secreted from B cells by f-HSV treatment could abrogate the immunosuppressive ability of MDSCs. These results suggest that f-HSV can enhance antitumor immune responses as an adjuvant, not only through activation of DCs, but also inactivation of MDSCs via B cells. © 2010 UICC.

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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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