Pathological analyses and therapeutic trials of animal model of EB virus-related fatal hemophagocytic syndrome

EB病毒相关致死性噬血细胞综合征动物模型的病理分析及治疗试验

• 批准号: 14570190
• 负责人: HAYASHI Kazuhiko
• 金额: $ 2.3万
• 依托单位: Tottori University (2003)Okayama University (2002)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570190/
• 关键词: EBV; Herpesvirus papio; Rabbit; hemophagocytic syndrome; T-cell; LPDs; HVP; ウサギ; 血球貪食症候群; 治療

Epstein-Barr virus associated hemophagocytic syndrome (EBV-AHS) is often associated with fatal infectious mononucleosis or T-cell lymphoproliferative diseases (LPD). To elucidate the true nature of fatal LPD observed in Herpesvirus papio (HVP)-induced rabbit hemophagocytosis, reactive or neoplastic, we analyzed sequential development of HVP-induced rabbit LPD and their cell lines. All of the seven Japanese White rabbits inoculated intravenously with HVP died of fatal LPD 18 to 27 days after inoculation. LPD was also accompanied by hemophagocytic syndrome (HPS) in five of these seven rabbits. Sequential autopsy revealed splenomegaly and swollen lymph nodes, often accompanied by bleeding, which developed in the last week. Atypical lymphoid cells infiltrated many organs with a "starry sky" pattern, frequently involving the spleen, lymph nodes and liver. HVP-small RNA-1 expression in these lymphoid cells was clearly demonstrated by a newly developed in situ hybridization (ISH) system. HVP- … More ISH of immunomagnetic purified lymphoid cells from spleen or lymph nodes revealed HVP-EBER1+ cells in each CD4+, CD8+ or CD79a+fraction. Hemophagocytic histiocytosis was observed in the lymph nodes, spleen, bone marrow, andthymus. HVP-DNA was detected in the tissues and peripheral blood from the infected rabbits by PCR or Southern blot analysis. Clonality analysis of HVP-induced LPD by Southern blotting with TCR gene probe revealed polyclonal bands, suggesting polyclonal proliferation. Six IL-2 dependent rabbit T-cell lines were established from transplanted scid mouse tumors from LPD. These showed latency type I/II HVR infection and had normal karyotypes except for one line, and three of them showed tumorigenicity in nude mice. These data suggest that HVP-induced fatal LPD in rabbits is reactive polyclonally in nature. Our data from therapeutic trials using EBV-AHS animal models indicate that vidarabine is not effective as an agent to treat HVP-infected rabbits, and even the cytotoxic chemotherapy of CHOP is not sufficient to cure the HVP-infected rabbits or to prolong the survival time of infected rabbits. Less

EB病毒相关噬血细胞综合征(EBV-AHS)常与致死性传染性单核细胞增多症或T细胞淋巴增生性疾病(LPD)有关。为了阐明在乳头疱疹病毒(HVP)诱导的兔血吞噬反应中观察到的致死性LPD的真实性质，我们分析了HVP诱导的兔LPD及其细胞系的序贯发展。静脉接种HVP的7只日本大白兔均于接种后18~27天死于致死性LPD。7只兔中有5只还伴有吞噬血细胞综合征(HPS)。连续尸检显示脾肿大和淋巴结肿大，通常伴有出血，这是在上周发生的。异型淋巴样细胞以“星空”的方式渗入多个器官，常累及脾、淋巴结和肝脏。一种新发展的原位杂交(ISH)系统清楚地显示了这些淋巴样细胞中HVP-Small RNA-1的表达。Hvp-…免疫磁性纯化的脾或淋巴结淋巴样细胞的ISH结果显示，HVP-EBER1+细胞分布于各组分中的CD4+、CD8+或CD79a+。在淋巴结、脾、骨髓和胸腺中观察到噬血细胞组织细胞增多症。用聚合酶链式反应和Southern印迹杂交检测感染兔的组织和外周血中HVP-DNA。用TCR基因探针对HVP诱导的LPD进行Southern blotting克隆性分析，可见多克隆条带，提示存在多克隆增殖。从LPD移植的SCID小鼠肿瘤中建立了6个IL-2依赖的兔T细胞系。除1株外，其余均为正常核型，其中3株在裸鼠体内具有致瘤性。这些数据表明，HVP诱导的兔致死性LPD本质上是多克隆反应性的。我们使用EBV-AHS动物模型进行的治疗试验的数据表明，长春瑞滨不能有效地治疗HVP感染的兔，甚至CHOP的细胞毒化疗也不足以治愈HVP感染的兔或延长感染兔的生存时间。较少

项目成果

Oka T., Ouchida M., Koyama M.: "Gene silencing of the tyrosine phosphatase SHP1 gene by aberrant methylation in leukemias/lymphomas."Cancer Res.. 62(22). 6390-6394 (2002)

Oka T.、Ouchida M.、Koyama M.：“白血病/淋巴瘤中异常甲基化导致酪氨酸磷酸酶 SHP1 基因沉默。”Cancer Res.. 62(22)。

Oka T, et al.: "Abnormal expression of protein-tyrosine phosphatase SHP1 gene in malignant lymphomas and leukemias"Japanese Journal of Cancer Clinics. 48(10). 561-568 (2002)

Oka T 等人：“恶性淋巴瘤和白血病中蛋白酪氨酸磷酸酶 SHP1 基因的异常表达”日本癌症临床杂志。

Koirala TR, Hayashi K, Jin Z-S, Onoda S, Tanaka T, Oda W, Ichimura K, Ohara N, Oka T, Yamada M.: "Induction and Prevention of Virus-associated Malignant Lymphoma by Serial Transmission of EBV-related Virus from Cynomolgus by Blood Transfusion in Rabbits."

Koirala TR、Hayashi K、Jin Z-S、Onoda S、Tanaka T、Oda W、Ichimura K、Ohara N、Oka T、Yamada M.：“通过 EB 病毒相关病毒的串行传播诱导和预防病毒相关恶性淋巴瘤

K.Hayashi, Z-S Jin, T.Akagi: "Rabbit model for EBV-associated fatal lymphoproliferative disorders with hemophagocytosis ; in Research Advances in Virology 2"Global Research Network. 12 (2002)

K.Hayashi、Z-S Jin、T.Akagi：“EBV 相关致命性淋巴细胞增殖性疾病伴噬血作用的兔模型；病毒学研究进展 2”全球研究网络。

Hayashi, K, et al.: "Therapeutic trials for a rabbit model of EBV-associated hemophagocytic syndrome (HPS) : Effects of vidarabine or CHOP, and development of Herpesvirus papio (HVP)-negative lymphomas surrounded by HVP-infected lymphoproliferative diseas

Hayashi, K 等人：“EBV 相关噬血细胞综合征 (HPS) 兔模型的治疗试验：阿糖腺苷或 CHOP 的作用，以及被 HVP 感染的淋巴增殖性疾病包围的狒狒疱疹病毒 (HVP) 阴性淋巴瘤的发展