Molecular mechanism of thymic involution and its application to forensic diagnosis of child abuse

• Project/Area Number: 18H03067
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 58040:Forensics medicine-related
• Research Institution: Wakayama Medical University
• Principal Investigator: Kondo Toshikazu 和歌山県立医科大学, 医学部, 教授 (70251923)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,030,000 (Direct Cost: ¥13,100,000、Indirect Cost: ¥3,930,000); Fiscal Year 2021: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2019: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2018: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
• Keywords: 法医病理学 / 子どもの虐待 / 胸腺退縮 / サイトカイン / ケモカイン / アポトーシス / 副腎皮質ホルモン / 児童虐待 / 胸腺 / ストレス / 遺伝子欠損マウス / バイオマーカ / 胸腺萎縮 / バイオマーカー

Outline of Final Research Achievements

We analyzed the roles of cytokines/chemokines in thymic atrophy using murine restraint stress model. When WT mice were restrained, the thymus was significantly involuted. However,in Cx3cr1-deficient mice treated with the same manner, the thymic atrophy was significantly suppressed. Subsequently, we examined apoptotic cells in the thymus of WT and Cx3cr1-deficient mice. Restrain stress induced the apoptosis in the thymic cells of WT mice. However,the absence of Cx3cr1 significantly suppressed apoptosis of thymic cells. In line with this,the intrathymic gene expression of Fas ligand was significantly attenuated in Cx3cr1 deficient mice．Moreover, blood cortisol level was suppressed in restrain stress-treated Cx3cr1-deficient mice. These observations implied that the absence of CX3CR1 resisted stress-induced thymic atrophy. Thus, CX3CR1-mdiated signals would promote thymic involution induced by restrain stress. CX3CR1 would be a key molecule for diagnosing abuse in infants and children.

Academic Significance and Societal Importance of the Research Achievements

法医解剖例・臨床医学の現場において，虐待が疑われる事例については医学的見解を求められることが多くなってきている．そこで被虐待児の鑑別法の確立が切望されているにも関わらず被虐待児であると判断するための客観的な法医学的診断法は未だ確立されていない．CX3CR1遺伝子欠損マウスではストレスによる胸腺退縮が有意に抑制されていことから，CX3CR1がストレス誘導胸腺退縮に重要な役割を果たしていることが世界で初めて明らかとなった．法医学的に血中のCX3CL1（CX3CR1リガンド）CX3CR1が，虐待のバイオマーカーの一つとなる可能性が示され，今後の新たな虐待の法医診断法の確立に貢献するものと考えられた．

Research Products

• [Journal Article] A case of necrotizing fasciitis following intra-articular injections ? Iatrogenic or spontaneous? (2022)
  • Author(s): Matsuki Jumpei、Ishigami Akiko、Tanaka Motonari、Hata Satoshi、Ishida Yuko、Nosaka Mizuho、Kuninaka Yumi、Yamamoto Hiroki、Shimada Emi、Hashizume Yumiko、Takayasu Tatsunori、Kimura Akihiko、Furukawa Fukumi、Kondo Toshikazu
  • Journal Title: Legal Medicine Volume: 54 Pages: 101989-101989
  • DOI: 10.1016/j.legalmed.2021.101989
  • Peer Reviewed / Open Access
• [Journal Article] Complete decapitation by a self-constructed guillotine in a burned body ? complex suicide or postmortem burning? (2021)
  • Author(s): Ishigami A, Hata S, Ishida Y, Nosaka M, Kuninaka Y, Yamamoto H, Shimada E, Hashizume Y, Takayasu T, Kimura A, Furukawa F, Kondo T
  • Journal Title: Int J Legal Med Volume: 135 Issue: 1 Pages: 301-305
  • DOI: 10.1007/s00414-020-02323-y
  • Peer Reviewed / Open Access
• [Journal Article] Intrathrombotic appearances of AQP-1 and AQP-3 in relation to thrombus age in murine deep vein thrombosis model (2021)
  • Author(s): Nosaka M, Ishida Y, Kuninaka Y,Ishigami A, Taruya A, Shimada E, Hashizume Y, Yamamoto H, Kimura A, Furukawa F, Kondo T
  • Journal Title: Int J Legal Med Volume: 135 Issue: 2 Pages: 547-553
  • DOI: 10.1007/s00414-020-02482-y
  • Peer Reviewed / Open Access
• [Journal Article] A comparative study of pleural effusion in water area, water temperature and postmortem interval in forensic autopsy cases of drowning (2021)
  • Author(s): Ishigami Akiko、Kashiwagi Masayuki、Ishida Yuko、Hara Kenji、Nosaka Mizuho、Matsusue Aya、Yamamoto Hiroki、Waters Brian、Kondo Toshikazu、Kubo Shin-ichi
  • Journal Title: Scientific Reports Volume: 11 Issue: 1
  • DOI: 10.1038/s41598-021-01047-2
  • Peer Reviewed
• [Journal Article] Forensic significance of intracardiac heme oxygenase-1 expression in acute myocardial ischemia (2021)
  • Author(s): Kuninaka Yumi、Ishida Yuko、Nosaka Mizuho、Ishigami Akiko、Taruya Akira、Shimada Emi、Kimura Akihiko、Yamamoto Hiroki、Ozaki Mitsunori、Furukawa Fukumi、Kondo Toshikazu
  • Journal Title: Scientific Reports Volume: 11 Issue: 1
  • DOI: 10.1038/s41598-021-01102-y
  • Peer Reviewed / Open Access
• [Journal Article] Fatal injury by high-pressure water jet unit ? A case report (2021)
  • Author(s): Ishigami Akiko、Iwahashi Yumi、Ishida Yuko、Nosaka Mizuho、Kuninaka Yumi、Yamamoto Hiroki、Hashizume Yumiko、Kondo Toshikazu
  • Journal Title: Journal of Forensic and Legal Medicine Volume: 84 Pages: 102270-102270
  • DOI: 10.1016/j.jflm.2021.102270
  • Peer Reviewed
• [Presentation] 法医学から見た虐待による小児頭部外傷について (2022)
  • Author(s): 近藤稔和
  • Organizer: 第45回日本脳神経外傷学会
  • Invited
• [Presentation] 新生児・乳児を取り巻く法医学的諸問題－虐待例を中心に－ (2021)
  • Author(s): 近藤稔和
  • Organizer: 第73回日本産科婦人科学会学術講演会
  • Invited
• [Presentation] Immunohistochemical detection of heme oxygenase-1 in acute myocardial infarction. (2021)
  • Author(s): Ishida Y, Kuninaka Y, Nosaka M, Shimada E, Ishigami A, Kimura A, Yamamoto H, Furukawa F, Kawaguchi M, Kondo T.
  • Organizer: 25th Congress of the International Academy of Legal Medicine (IALM2021)
  • Int'l Joint Research
• [Presentation] Forensic pathological study on temporal appearance of dendritic cells in skin wounds. (2021)
  • Author(s): Kuninaka Y, Ishida Y, Nosaka M, Shimada E, Kimura A, Yamamoto H, Furukawa F, Kawaguchi M, Eisenmenger W, Kondo T.
  • Organizer: 25th Congress of the International Academy of Legal Medicine (IALM2021)
  • Int'l Joint Research
• [Presentation] Fibrinolytic role of CX3CR1 and its application to thrombus age estimation in deep vein thrombosis model mice. (2021)
  • Author(s): Nosaka M, Ishida Y, Ishigami A, Kuninaka Y, Yamamoto H, Shimada E, Hashizume Y, Kawaguchi M, Kimura A, Kondo T.
  • Organizer: 25th Congress of the International Academy of Legal Medicine (IALM2021)
  • Int'l Joint Research
• [Presentation] A comparative study of pleural effusion in water area, water temperature and postmortem interval in forensic autopsy cases of drowning. (2021)
  • Author(s): Ishigami A, Kashiwagi M, Ishida Y, Hara K, Nosaka M, Matsusue A, Yamamoto H, Waters B, Kubo, Kondo T.
  • Organizer: 25th Congress of the International Academy of Legal Medicine (IALM2021)
  • Int'l Joint Research
• [Presentation] Crucial role of IL-6 in murine DVT model via macrophage recruitment and the induction of proteolytic enzymes. (2021)
  • Author(s): Nosaka M, Ishida Y, Kimura A, Ishigami A, Kuninaka Y, Yamamoto H, Hashizume Y, Kimura A, Mukaida N, Kondo T.
  • Organizer: The 27th International Symposium on Molecular Cell Biology of Macrophages 2020+1 (MMCB2020+1)
  • Int'l Joint Research
• [Presentation] Prevention of CaCl2-induced aortic inflammation and subsequent aneurysm formation by CCL3. (2021)
  • Author(s): Ishida Y, Kuninaka Y, Nosaka M, Kimura A, Taruya A, Furuta M, Mukaida N, Kawaguchi M, Kondo T.
  • Organizer: The 27th International Symposium on Molecular Cell Biology of Macrophages 2020+1 (MMCB2020+1)
  • Int'l Joint Research
• [Presentation] Spi-B plays a protective role in pressure overload-induced heart failure through the proliferation of resident macrophages. (2021)
  • Author(s): Kimura A, Ishida Y, Nosaka M, Kuninaka Y, Taruya A, Sasaki I, Kaisho T, Kondo T.
  • Organizer: The 27th International Symposium on Molecular Cell Biology of Macrophages 2020+1 (MMCB2020+1)
  • Int'l Joint Research
• [Presentation] CCL3-CCR5 axis exacerbate acetaminophen-induced liver injury in mice. (2021)
  • Author(s): 石田裕子，國中由美，石部琢也，野坂みずほ，山本寛記，石上安希子，島田栄美，木村章彦，川口真理子，向田直史，近藤稔和．
  • Organizer: 第42回日本炎症・再生医学会
• [Presentation] 深部静脈血栓症モデルにおけるCCR5システムの病態生理学的役割の解明（第3報） (2021)
  • Author(s): 野坂みずほ，石田裕子，石上安希子，山本寛記，國中由美，橋爪佑示子，木村章彦，向田直史，近藤稔和．
  • Organizer: 第42回日本炎症・再生医学会
• [Presentation] Absence of CCL5/CCR5 axis inhibits thrombus resolution through reduced uPA, tPA and VEGF expressions in DVT model. (2021)
  • Author(s): Nosaka M, Ishida Y, Ishigami A, Kuninaka Y. Yamamoto H, Shimada E, Hashizume Y, Kawaguchi M, Kimura A, Mukaida N, Kondo T.
  • Organizer: ISTH2021
  • Int'l Joint Research
• [Presentation] The involvement of CX3CR1 in stress-induced thymic atrophy. (2021)
  • Author(s): Kondo T, Ishida Y, Kuninaka Y, Nosaka M, Yamamoto H, Shimada E, Kawaguchi M, Kimura A, Furukawa F, Mukaida N.
  • Organizer: 100th Annual Conference German Society of Legal Medicine
  • Int'l Joint Research
• [Presentation] Forensic examination of complex suicide cases. (2021)
  • Author(s): Ishigami A, Tanaka M, Hashizume Y, Matsuki J, Ishida Y, Nosaka M, Yamamoto H, Kuninaka Y, Shimada E, Kawaguchi M, Kimura A, Furukawa F, Kondo T.
  • Organizer: 100th Annual Conference German Society of Legal Medicine
  • Int'l Joint Research
• [Presentation] Forensic significance of intracardiac heme oxygenase-1 expression in acute myocardial ischemia. (2021)
  • Author(s): Ishida Y, Kuninaka Y, Nosaka M, Ishigami A, Taruya A, Shimada E, Kimura A, Yamamoto H, Ozaki M, Furukawa F, Matsuki J, Kawaguchi M, Kondo T.
  • Organizer: 100th Annual Conference German Society of Legal Medicine
  • Int'l Joint Research
• [Presentation] Forensic pathological study on temporal appearance of dendritic cells in skin wounds. (2021)
  • Author(s): Kuninaka Y, Ishida Y, Nosaka M, Ishigami A, Shimada E, Kimura A, Ozaki M, Yamamoto H, Furukawa F, Matsuki J, Kawaguchi M, Eisenmenger W, Kondo T.
  • Organizer: 100th Annual Conference German Society of Legal Medicine
  • Int'l Joint Research
• [Presentation] Absence of CCR5/CCL5 axis exaggerates thrombus formation through reduced uPA, tPA and VEGF expression in murine DVT model. (2021)
  • Author(s): Nosaka M, Ishida Y, Ishigami A, Kuninaka Y, Shimada E, Hashizume Y, Yamamoto H, Kimura A, Furukawa F, Mukaida N, Kondo T.
  • Organizer: 100th Annual Conference German Society of Legal Medicine
  • Int'l Joint Research
• [Presentation] A case of necrotizing fasciitis following intra-articular injections-iatrogenic or spontaneous? (2021)
  • Author(s): Matsuki J, Ishigami A, Ishida Y, Nosaka M, Kuninaka Y, Yamamoto H, Shimada E, Hashizume Y, Kimura A, Furukawa F, Kondo T.
  • Organizer: 100th Annual Conference German Society of Legal Medicine
  • Int'l Joint Research
• [Presentation] 分子細胞生物学と生活反応 (2021)
  • Author(s): 近藤稔和
  • Organizer: 第105次日本法医学会学術全国集会
• [Presentation] 深部静脈血栓における熱ショック蛋白の動態と法医診断学的応用に関する研究 (2021)
  • Author(s): 野坂みずほ，石田裕子，國中由美，石上安希子，山本寛記，橋爪佑示子，島田栄美，川口真理子，木村章彦，近藤稔和．
  • Organizer: 第105次日本法医学会学術全国集会
• [Presentation] これからの死因究明についてー現代社会における法医学の役割― (2021)
  • Author(s): 近藤稔和
  • Organizer: 第38回日本法医学会学術中四国地方集会
  • Invited
• [Presentation] Crucial role of IL-6 in thrombus resolution in DVT model mouse via induction of proteolytic enzymes. (2021)
  • Author(s): Nosaka M, Ishida Y, Ishigami A, Kuniinaka Y, Yamamoto H, Kimura A, Mukaida N, Kondo T.
  • Organizer: 9th Annual Meeting of the International Cytokine & Interferon Society (Cytokines2021)
  • Int'l Joint Research
• [Presentation] Oncostatin M receptor β mediates skin wound healing by regulating HGF synthesis in fibroblasts. (2021)
  • Author(s): 石田裕子，國中由美，小森忠祐，野坂みずほ，木村章彦，宮島 篤，森川吉博，川口真理子，近藤稔和．
  • Organizer: 第51回日本創傷治癒学会
• [Presentation] 熱傷におけるXCL1およびXCR1の発現解析 (2021)
  • Author(s): 野坂みずほ，石田裕子，石上安希子，國中由美，山本寛記，木村章彦，近藤稔和．
  • Organizer: 第51回日本創傷治癒学会
• [Presentation] CCL3-CCR5 axis exacerbate acetaminophen-induced liver injury in mice. (2021)
  • Author(s): Ishida Y, Kuninaka Y, Nosaka M, Kimura A, Mukaida N, Kondo T.
  • Organizer: 第50回日本免疫学会学術集会
• [Presentation] CCL3-CCR5 axis improve innate immune responses during septic peritonitis. (2021)
  • Author(s): Kuninaka Y, Ishida Y, Nosaka M, Kimura A, Mukaida N, Kondo T.
  • Organizer: 第50回日本免疫学会学術集会
• [Presentation] Expressions of intrathrombotic CX3CR1 and fractalkine and their possible role in thrombolysis on murine DVT model. (2021)
  • Author(s): Nosaka M, Ishida Y, Kimura A, Kuninaka Y, Mukaida N, Kondo T.
  • Organizer: 第50回日本免疫学会学術集会
• [Presentation] 法医実務における再鑑定の現状と今後の在り方について (2021)
  • Author(s): 近藤稔和
  • Organizer: 第4回日本法医病理学会学術全国集会
• [Presentation] The involvement of CX3CR1 in stress-induced thymic atrophy (2021)
  • Author(s): Kondo T, Ishida Y, Kuninaka Y, Nosaka M, Ishigami A, Kawaguchi M,
  • Organizer: 100th Annual Meeting of German Society of Legal Medicine
  • Int'l Joint Research
• [Presentation] マウス拘束モデルにおける胸腺萎縮へのCX3CR1の関与 (2020)
  • Author(s): 石田裕子，國中由美，野坂みずほ，石上安希子，島田栄美，山本寛記，川口真理子，近藤稔和
  • Organizer: 第104次日本法医学会学術全国集会
• [Presentation] The involvement of CCR5 in stress-induced thymic atrophy (2018)
  • Author(s): T. Kondo, T. Kawaguchi, M. Kawaguchi, Y. Ishida, M. Nosaka, Y. Kuninaka, H. Yamamoto, S. Sakamoto, E. Shimada, A. Kimura
  • Organizer: 98th Annual Meeting of German Society of Legal Medicine
  • Int'l Joint Research
• [Book] 死体検案ハンドブック (2020)
  • Author(s): 福永龍繁，近藤稔和
  • Total Pages: 7
  • Publisher: 金芳堂
  • ISBN: 9784765318235