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

EB病毒相关噬血细胞综合征（EBV-AHS）常与致命的传染性单核细胞增多症或T细胞淋巴组织增生性疾病（LPD）相关。为了阐明在乳头疱疹病毒（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及其细胞系的顺序发展。7只日本白色家兔静脉接种HVP后18 ~ 27天全部死于致死性LPD。在这7只家兔中，有5只还伴有噬血细胞综合征（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。非典型淋巴样细胞以“星空”模式浸润许多器官，经常累及脾脏、淋巴结和肝脏。HVP-小RNA-1表达在这些淋巴样细胞清楚地表明了一个新开发的原位杂交（ISH）系统。HVP- ...更多信息 免疫磁性纯化的脾或淋巴结淋巴样细胞的ISH显示每个CD 4+、CD 8+或CD 79 a+部分中的HVP-EBER 1+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生症。用PCR和Southern blot方法检测感染兔组织和外周血中HVP-DNA。用TCR基因探针通过Southern印迹分析HVP诱导的LPD的克隆性，显示多克隆条带，表明多克隆增殖。从LPD移植的scid小鼠肿瘤中建立了6个IL-2依赖性兔T细胞系。这些细胞表现为潜伏性I/II型HVR感染，除一个细胞系外核型正常，其中三个细胞在裸鼠体内表现出致瘤性。这些数据表明，HVP诱导的兔致死性LPD本质上是反应性多克隆。使用EBV-AHS动物模型的治疗试验数据表明，阿糖腺苷作为治疗HVP感染兔的药物无效，即使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存活时间。少

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