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) 通常与致命性传染性单核细胞增多症或 T 细胞淋巴细胞增殖性疾病 (LPD) 相关。或肿瘤，我们分析了 HVP 诱导的兔 LPD 及其细胞系的顺序发育。所有七只日本白兔静脉注射。接种 HVP 后 18 至 27 天，这 7 只兔子中的 5 只还伴有噬血细胞综合征 (HPS)，随后尸检显示脾肿大和淋巴结肿大，通常伴有出血。非典型淋巴细胞呈“星空”状浸润许多器官，经常累及脾脏、淋巴结和肝脏。新开发的原位杂交 (ISH) 系统清楚地证明了这些淋巴细胞中的 RNA-1 表达，对来自脾脏或淋巴的免疫磁性纯化淋巴细胞进行 ISH 分析，结果显示每个 CD4+、CD8+ 或 CD79a+ 中都有 HVP-EBER1+ 细胞。在淋巴结、脾脏、骨髓中观察到噬血细胞组织细胞增生症，并在组织和胸腺中检测到 HVP-DNA。通过 PCR 或 Southern 印迹分析对感染兔的外周血进行 TCR 基因探针的 Southern 印迹分析，结果显示多克隆条带，表明从移植的 scid 中建立了 6 种依赖 IL-2 的兔 T 细胞系。来自 LPD 的小鼠肿瘤显示出潜伏的 I/II 型 HVR 感染，并且除 1 个系外具有正常的核型，其中 3 个在裸鼠中显示出致瘤性。这些数据表明 HVP 诱导致命。兔子体内的 LPD 本质上是多克隆反应，我们使用 EBV-AHS 动物模型进行的治疗试验数据表明，阿糖腺苷作为治疗 HVP 感染兔子的药物无效，甚至 CHOP 的细胞毒性化疗也不足以治愈 HVP。 - 感染兔或延长感染兔的生存时间。

项目成果

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。

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)。

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。

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

Oka T 等人：“白血病/淋巴瘤中异常甲基化对酪氨酸磷酸酶 SHP1 基因的基因沉默”Cancer Res.. 62(22)。