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) 通常与致命的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。为了阐明在狒狒疱疹病毒 (HVP) 诱导的兔噬血细胞反应性或肿瘤性中观察到的致命性 LPD 的真实性质，我们分析了 HVP 诱导的兔 LPD 及其细胞系的顺序发育。静脉注射 HVP 的 7 只日本白兔在接种后 18 至 27 天全部死于致命的 LPD。这七只兔子中有五只患有 LPD，并伴有噬血细胞综合征 (HPS)。随后的尸检显示上周出现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 HVP-小 RNA-1 的表达。对来自脾脏或淋巴结的免疫磁性纯化淋巴细胞进行 HVP-… 更多 ISH，结果显示每个 CD4+、CD8+ 或 CD79a+ 组分中都有 HVP-EBER1+ 细胞。在淋巴结、脾脏、骨髓和胸腺中观察到噬血细胞组织细胞增多症。通过PCR或Southern印迹分析在感染兔的组织和外周血中检测到HVP-DNA。使用 TCR 基因探针通过 Southern 印迹对 HVP 诱导的 LPD 进行克隆性分析，结果显示多克隆条带，表明存在多克隆增殖。从 LPD 移植的 scid 小鼠肿瘤中建立了 6 种 IL-2 依赖性兔 T 细胞系。这些细胞表现出潜伏的I/II型HVR感染，并且除1个品系外具有正常的核型，其中3个在裸鼠中表现出致瘤性。这些数据表明，HVP 诱导的兔致命性 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 感染兔子或延长感染兔子的生存时间。较少的

项目成果

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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

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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