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Cytokines and Hypothalamo-Autonomic Control of Immune System

Research Project

Project/Area Number 06044180
Research Category

Grant-in-Aid for international Scientific Research

Allocation TypeSingle-year Grants
SectionJoint Research
Research InstitutionKYUSHU UNIVERSITY

Principal Investigator

HOTI Tstsuro  Kyushu University, Professor, 医学部, 教授 (00022814)

Co-Investigator(Kenkyū-buntansha) ARIMURA Akira  Tulane University, Professor, チューレン大学・米日生物医学研究所, 教授
ECKHART Simo  ドイツ国, マックスプランク生理学臨床研究所, 教授
TAKE Sachiko  Kyushu University, Associate Professor, 医学部, 助手 (80253425)
TAKAKI Atsushi  Kyushu University, Associate Professor, 医学部, 助手 (30243934)
KATAFUCHI Toshihiko  Kyushu University, Associate Professor, 医学部, 講師 (80177401)
AOU Shyuji  Kyushu University, Associate Professor, 医学部, 助教授 (40150908)
SIMON Eckhart  Max-Planck Institute, Professor
RIEDEL Walte  ドイツ国, マックスプランク生理学臨床研究所, 教授
SIMON Eckhar  ドイツ国, マックスプランク生理学臨床研究所, 教授
Project Period (FY) 1994 – 1995
Project Status Completed (Fiscal Year 1995)
Budget Amount *help
¥4,100,000 (Direct Cost: ¥4,100,000)
Fiscal Year 1995: ¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 1994: ¥2,200,000 (Direct Cost: ¥2,200,000)
KeywordsSplenic sympathetic nerve / Interleukin-1 beta / Interferon alpha / Interleukin-6 / Prostaglandin E2 / Anterventral region of the III vetricle / Endotoxin / Kupffer cell / 第3脳室壁前腹側領域 / インターロイキン-1β / 視索前野 / 細胞性免疫 / 脾臓交感神経 / PACAP
Research Abstract

What we found in this project is as follows ;
1) : Suppression of splenic natural killer (NK) cell activity by noradrenaline released from splenic sympathetic nerve (SSN) terminals is one of the mechanisms of immobilization (IM) -induced immunosppression. 2) : Brain IL-1 beta induces reduction of the SSN.3) : Immunosuppression induced by both IFN alpha and IL-1 beta in the brain is due to an sctivation of CRF system which leads to an enhancement of SSN.4) : EPI receptors for PGE2 are partly involved in the activation of the brain CRF system. 5) : The medial preoptic area (MPO), which is the most potent acting site of INF alpha, is involved in the central regulation of immunity by its suppressive influence on the SSN.6) : Splenic NK activity decreases during dynamic phase of the ventromedial hypothalamus (VMH) lesioning-induced hyperphagia, while it increases during static phase. 7) : Neurons in the anteroventromedial region of the III ventricle projecting to the MPO and the paraventricular nucleus play an important role in the blood-borne cytokine-brain signal transduction. 8) : Inhibition of the dorsal vagal motoneurons by IL-1 beta through the prostanoids is considered to be one of the mechanisms of the IL-1 beta-induced suppression of gastric acid secretion. 9) : IM stress elevates plasma IL-6 concentration. 10) : Plasma IL-6 response to IM stress was attenuated by partial hepatectomy or by partial sympathectomy in the liver. 11) : Some Kupffer (K) cells and endothelial cells in the liver obtained from rats immobilized showed significant IL-6 like immunoreactivity against anti-murine IL-6 antiserum. 12) : Norepinephrine stimulated the IL-6 production in the K cells obtained by in vitro culture preparation. 13) : The basal endotoxin (LPS) level in the portal plasma was higher than that in the systemic venous plasma. 14) : The portal LPS content increased during IM stress, whereas that in the systemic venous plasma did not change remarkably.

Report

(2 results)
  • 1995 Final Research Report Summary
  • 1994 Annual Research Report
  • Research Products

    (74 results)

All Other

All Publications (74 results)

  • [Publications] Hori,T: "The hypothalamo-sympathetic nervous ststem modulates peripheral cellular immunity." Neurobiology. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Hori,T: "The autonomic nervous system as a communication channel between the brain and the immune system" Neuroimmunomodulation. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Katafuchi,T.: "Roles of cytokines in the neural-immune interactions : modulation of NMDA responses by IFNα." Neurobiology. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Katafuchi,T.: "Cerebellar afferents to neuroendocrine cells : implications for adaptive responses to simulated weightlessness" Endocrine.J. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Ando,T.: "Intracerebroventricular injection of prostaglandin E2 increases splenic sympathetic nerve activity in rats" Am.J.Physiol.(Regulatory Integrative Comp.Physiol.). 269. R662-R668 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Niijima,A.: "The effect of interleukin-1β on the efferent activity of the vagus nerve to the thymus" J.Auton.Nerv.Sys.54. 137-144 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Take,S.: "Interferon-α acts at the preoptic hypothalamus to reduce natural killer cytotoxicity in rats" Am.J.Physiol.(Regulatory Integrative Comp.Physiol.). 268. R1406-R1410 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Nakashima,T.: "Naloxone suppresses the rising phase of fever induced by interferon-α" Br.Res.Bull.37. 61-66 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Matsui,H.: "The central action of parathyroid hormone on blood calcium and hypothalamicd neuronal activity in the rat" Am.J.Physiol.268. R21-R27 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Oka,T.: "The opposing effects of interleukin-1b microinjected into the preoptic hypothalamus and the ventromdial hypothalamus on nociceptive behavior in rats" Brain Res.700. 271-278 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Aou,S.: "Hypothalamus regulates calcium metabolism in rats" Neurobiology. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Aou,S.: "Hypothalamo-vagal control of calcium metabolism in rats" J.Auton.Nerv.Sys.(in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Suzuki,K.: "Repetitively firing neurons in the rat medial nucleus tractus solitarius is invoved in cholecystokinin type-A receptor mediated functions" J.Auton.Nerv.Sys.(in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Li,A.-J.: "Fibroblast growthfactor receptor-1 in the lateral hypothalamic area regulates food intake" Exp.Neurol. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Takaki,A.: "Immobilization stress may increases plasma interleukin (IL)-6 via central and peripheral catecholamines" Neuroimmunomoduration. 1. 335-342 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Takaki,A.: "Immobilization-induced plasma IL-6 elevation is mediated by endogenous catecholamines." Pathophysiology. 1. 457-457 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Arimura,A.: "Interactions between cytokines and the hypothalamic-pituitary-adrenal axis during stress" Annals of New York Academy of Sciences. 739. 270-281 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 粟生修司: "視床下部を中心とする性行動・情動行動制御機構:視床下部機能の新しい側面" 日本生理誌. 57. 155-163 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 粟生修司: "肥満症、II.摂食、食欲調節系、摂食、食欲調節系概論" 日本臨床. 53. 13-18 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 粟生修司: "肥満症、II.摂食、食欲調節系、調節因子概論" 日本臨床. 53. 19-25 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 粟生修司: "肥満症、II.摂食、食欲調節系、調節因子の受容体と作用機序:グルコース(グルコース受容ニューロン、グルコース感受性ニューロン)" 日本臨床. 53. 26-32 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 粟生修司: "肥満症、II.摂食、食欲調節系、調節因子の受容体と作用機序:その他の有機化合物(有機酸、ラクトンなど)" 日本臨床. 53. 85-89 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 堀哲郎: "脳・免疫系関連の発熱" 第24回日本医学会総会会誌. (印刷中).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 片渕俊彦: "ストレス応答と免疫系-交感神経系を介する免疫調節" 第24回日本医学会総会会誌. (印刷中).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 片渕俊彦: "脳-免疫系関連とサイトカイン:免疫疾患-state of arts" 別冊 医学のあゆみ. 94-97 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Takaki,A.: "Is immobilization-induced plasma IL-6 elevation regulated by hepatic innervation? In : Liver Innervation,ed.T.Shimazu" John Libbey & Company Ltd.,London, 221-226 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 粟生修司: "視床下部におけるホメオスタシス機能とストレス応答:視床下部機能の新しい側面.視床下部、板倉徹、前田敏博編" プレーン出版、東京(印刷中),

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 粟生修司: "情動と生理.心身医学標準テキスト" 医学書院、東京(印刷中),

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Hori, T., Katafuchi, T., Take, S., Kaizuka, Y., Ichijo, T.and Shimizu, N.: "The hypothalamo-sympathetic nervous ststem modulates peripheral cellular immunity." Neurobiology. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Hori, T., Katafuchi, T., Take, S., Shimizu, N.and NIIJIMA,A: "The autonomic nervous system as a communication channel between the brain and the immune system" Neuroimmunomodulation. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Katafuchi, T., Take, S., Li, A.and Hori, T: "Roles of cytokines in the neural-immune interactions : modulation of NMDA responses by IFNalpha." Neurobiology. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Katafuchi, T., Hori, T., Oomura, Y.and Koizumi, K: "Cerebellar afferents to neuroendocrine cells : implications for adaptive responses to simulated weighliessness" Enocrine.J. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Ando, T., Ichijo, T., Katafuchi, T.adn Hori, T: "Intracerebroventricular injection of prostaglandin E2 increases splenic sympathetic nerve activity in rats" 269. R662-R668 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Niijima, A., Hori, T., Katafuchi, T.and Ichijo T: "The effect of interleukin-1beta on the efferent activity of the vagus nerve to the thymus" J.Auton.Nerv.Sys.54. 137-144 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Take, S., Uchimura, D., Kanemitsu, Y., Katafuchi, T.and Hori, T: "Interferon-alpha acts at the preoptic hypothalamus to reduce natural killer cytotoxicity in rats" Am.J.Physiol.(Regulatory Integrative Comp.Physiol.). 268. R1406-R1410 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Nakashima, T., Murakami, T., Murai, T., Hori, T.and Kiyohara, T: "Naloxone suppresses the rising phase of fever induced by interferon alpha" Br.Res.Bull.37. 61-66 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Matsui, H., Aou, S., Ma, J.and Hori, T: "The central action of parathyroid hormone on blood calcium and hypothalamicd neuronal activity in the rat" Am.J.Physiol. (Regulatory Integrative copm.Physiol.). 268. R21-R27 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Oka, T.Oka, K., Hosoi, M., Aou, S.and Hori, T: "The opposing effects of interleukin-1b microinjected into the preoptic hypothalamus and the ventromdial hypothalamus on nociceptive behavior in rats" Brain Res.700. 271-278 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Aou, S., Shiramine, K., Ma, J., Matsui, H., and hori, T.: "Hypothalamus regulates calcium metabolism in rats" Neurobiology. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Aou, S., Ma, J., Matsui, H., Shiramine, K., and hori, T: "Hypothalamo-vagal control of calcium metabolism in rats" J.Auton.Nerv.Sys.(in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Suzuki, K., Aou, S., Shimizu, N., and Hori, T: "Repetitively firing neurons in the rat medial nucleus tractus solitarius is invoved in cholecystokinin type-A receptor mediated functions" J.Auton.Nerv.Sys.(in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Li, A,-J., Oomura, Y., Hori, T., Aou, S., Sasaki, K., Kimura, H., and Tooyama, I: "Fibroblast growthfactor receptor-1 in the lateral hypothalamic area regulates food intake" Exp.Neurol. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] A.Takaki, Q.-H.Huang, A.Somogyvai-Vigh and A.Arimura: "Immobilization stress may increases plasma interleukin (IL) -6 via central and peripheral catecholamines" Neuroimmunomodulation. 1. 335-342 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] A.Takaki, Q.-H.Huang, A.Somogyvari-Vigh, and A.Arimura: "Immobilization-induced plasma IL-6 elevation is mediated by endogenous catecholamines." Pathophysiology. 1. 457 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] A.Arimura, A.Takaki and G.Komaki.: "Interactions between cytokines and the hypothalamic-pituitary-adrenal axis during stress" Annals of New York Academy of Sciences. 739. 270-281 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Takaki, A., et al.: John Libbey & Company Ltd, London. Is immobilization-induced plasma IL-6 elevation regulated by hepatic innervation? In : Liver Innervation, ed.T.Shimazu, 221-226 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Ma,J.,et al.: "Hypothalamic stimulation induces vagally mediated hypocalcemia in therat." Brain Research Bulletin. 33. 4-23 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Shimizu,N.,et al: "An IL-1β-induced noradrenaline release in the spleen is mediated by brain corticotropin-releasing factor:anin vivo microdialysis study with conscious rats." Brain,Behavior & Immunity. 7. 65-69 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Szreder,Z.,et al.: "Thermoregulatory effect of intracerebral injections of neuropeptide Yin rats at different environmental temperatures." General Pharmacology. 25. 85-91 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Ma,J.,et al.: "Linkage of stress-induced hypocalcemia,gastric lesions and emotional behavior in Wistar Kyoto rats." American Journal of Physiology. 266. R960-R965 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Kuroda,Y.,et al.: "Restraint stress suppresses experimental allergic encephalomyelitis in Lewis rats." Brain Research Bulletin. 34. 15-17 (1994)

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      1994 Annual Research Report
  • [Publications] Ma,J.,et al: "Ventromedial hypothalamus mediates stress-in-duced hypocalcemia via the gastric vagus in rats." Brain Research Bulletin. 34. 41-45 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Aou,S.,et al.: "The effect of B-HT920,a dopamine D2 agonist,on bar-press feeding in the monkey." Physiology & Behavior. 55. 1125-1130 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Ichijo,T., et al.: "Central interleukin-1β enhancessplenic sympathetic nerve activity in rats." Brain Research Bulletin. 34. 547-553 (1994)

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      1994 Annual Research Report
  • [Publications] Katafuchi,T.,et al.: "The biphasic changes in splenicnatural killer cell activity followingventromedial hypothalamic lesions in rats." Brain Research. 652. 164-168 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Oka,T.,et al.: "EP1-receptor mediation of prostaglandin E2-induced hyperthermia in rats." American Journal of Physiology. 267. R289-R294 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Shimizu,N.,et al.: "CRF receptor antagonist attenuates stress-in-duced noradrenaline release in the medial prefrontal cortex ofrats." Brain Research. 654. 145-148 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Oka,T.,et al.: "Intracerebroventricular injection of interleukin1β enhances nociceptive neuronal responses of the trigeminal nucleus caudalis in rats." Brain Research. 656. 236-244 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Oka,T.,et al.: "Intracerebroventricular injection of prostaglandin E2 induces thermalhyperalgesia in rats:the possible involvement of EP3 receptors." Brain Research. 663. 287-292 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Aou,S.,et al.: "Hypothalamic linkage in stress-induced hypocalcemia,gastric damage,and emotional behavior in rats." American Journal of Physiology. 267. R38-R43 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Kanemitsu,Y.,et al.: "Production of antisense DNA probe by asymmetric PCR and its application to in situ hybridization." Nucleic Acids Sympsium Series. 31. 57-59 (1994)

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      1994 Annual Research Report
  • [Publications] Nakane,H.,et al.: "Stress-induced noradrenaline release in the rat prefrontal cortex measured by microdialysis." American Journal of Physiology. 267. R1559-R1566 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Sasaki,K.,et al.: "Effects of fibroblast growth factors and related peptides on food intake by rats." Physiology & Behavior. 56. 211-218 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Matsui,H.,et al: "The central action of parathyroid hormone on blood calcium and hypothalamic neuronal activity in the rat." American Journal of Physiology. 268. R21-R27 (1995)

    • Related Report
      1994 Annual Research Report
  • [Publications] 堀 哲郎: "神経系と免疫系の対話" 日本臨床. 52. 55-61 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] 片渕俊彦,堀 哲郎: "生理活性物質の生理学" 臨床検査. 38. 20-24 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] 堀 哲郎,武 幸子: "脳と免疫系" 日本サイコオンコロジー学会誌. 7. 35-37 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Hori,T.,et al.: "Immune cytokines modulate peripheral cellular immunity through the hypothalamo-sympathetic nervous system.,Integrative and Cellular Aspects of Autonomic Functions." John Libbey Eurotext(Eds Pleschka,K.& Gerstberger,R.), 554 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] 堀 哲郎: "代謝と体温.現代の生理学" 金原出版(古河太郎,本田良行編), 920 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] 堀 哲郎: "温・冷覚の生理学,新編感覚・知覚心理学ハンドブック" 誠信書房(大山正,今井正吾,和気典二編), 1741 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] 堀 哲郎: "脳と免疫,精神活動の流れを遡る機能・構造・物質" メディカル・ジャーナル社(早石修,伊藤正男編), 156 (1994)

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      1994 Annual Research Report
  • [Publications] 堀 哲郎,武 幸子: "脳・免疫系連関の諸問題,感染症と生体防御の基本原理-統合的視点を中心として" 第67回日本細菌学会総会事務局編, 135 (1994)

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      1994 Annual Research Report
  • [Publications] 片渕俊彦,堀 哲郎: "脳・免疫系連関における最近の進歩,第11回「ニューロトランスミッターと疾患研究会」ワークショッププロシ-ディングス" エクセプタ・メディカ社(佐藤公道編), 89 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] 片渕俊彦,堀 哲郎: "脳-免疫系連関,脳機能の解明-分子から病態まで-" 創風社(赤池紀扶,小暮久也編), 286 (1994)

    • Related Report
      1994 Annual Research Report

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Published: 1994-04-01   Modified: 2016-04-21  

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