Rabbit model for human EBV-associated hemophagocytic syndrome (HPS)

Sequential autopsy analysis and characterization of IL-2-dependent cell lines established from Herpesvirus papio-induced fatal rabbit lymphoproliferative diseases with HPS

Kazuhiko Hayashi, Zaishun Jin, Sachiyo Onoda, Hiromasa Joko, Norihiro Teramoto, Nobuya Ohara, Wakako Oda, Takehiro Tanaka, Yi Xuan Liu, Tirtha Raj Koirala, Takashi Oka, Eisaku Kondo, Tadashi Yoshino, Kiyoshi Takahashi, Tadaatsu Akagi

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Abstract

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-ISH of immunomagnetically 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, and thymus. 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 HVP 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.

Original languageEnglish
Pages (from-to)1721-1736
Number of pages16
JournalAmerican Journal of Pathology
Volume162
Issue number5
Publication statusPublished - May 1 2003

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Hemophagocytic Lymphohistiocytosis
Papio
Herpesviridae
Human Herpesvirus 4
Interleukin-2
Autopsy
Rabbits
Cell Line
Lymph Nodes
Spleen
Lymphocytes
Southern Blotting
In Situ Hybridization
Histiocytosis
T-Lymphocytes
Herpesviridae Infections
Infectious Mononucleosis
Splenomegaly
Karyotype
Nude Mice

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Rabbit model for human EBV-associated hemophagocytic syndrome (HPS) : Sequential autopsy analysis and characterization of IL-2-dependent cell lines established from Herpesvirus papio-induced fatal rabbit lymphoproliferative diseases with HPS. / Hayashi, Kazuhiko; Jin, Zaishun; Onoda, Sachiyo; Joko, Hiromasa; Teramoto, Norihiro; Ohara, Nobuya; Oda, Wakako; Tanaka, Takehiro; Liu, Yi Xuan; Koirala, Tirtha Raj; Oka, Takashi; Kondo, Eisaku; Yoshino, Tadashi; Takahashi, Kiyoshi; Akagi, Tadaatsu.

In: American Journal of Pathology, Vol. 162, No. 5, 01.05.2003, p. 1721-1736.

Research output: Contribution to journalArticle

Hayashi, Kazuhiko ; Jin, Zaishun ; Onoda, Sachiyo ; Joko, Hiromasa ; Teramoto, Norihiro ; Ohara, Nobuya ; Oda, Wakako ; Tanaka, Takehiro ; Liu, Yi Xuan ; Koirala, Tirtha Raj ; Oka, Takashi ; Kondo, Eisaku ; Yoshino, Tadashi ; Takahashi, Kiyoshi ; Akagi, Tadaatsu. / Rabbit model for human EBV-associated hemophagocytic syndrome (HPS) : Sequential autopsy analysis and characterization of IL-2-dependent cell lines established from Herpesvirus papio-induced fatal rabbit lymphoproliferative diseases with HPS. In: American Journal of Pathology. 2003 ; Vol. 162, No. 5. pp. 1721-1736.
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abstract = "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-ISH of immunomagnetically 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, and thymus. 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 HVP 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.",
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T2 - Sequential autopsy analysis and characterization of IL-2-dependent cell lines established from Herpesvirus papio-induced fatal rabbit lymphoproliferative diseases with HPS

AU - Hayashi, Kazuhiko

AU - Jin, Zaishun

AU - Onoda, Sachiyo

AU - Joko, Hiromasa

AU - Teramoto, Norihiro

AU - Ohara, Nobuya

AU - Oda, Wakako

AU - Tanaka, Takehiro

AU - Liu, Yi Xuan

AU - Koirala, Tirtha Raj

AU - Oka, Takashi

AU - Kondo, Eisaku

AU - Yoshino, Tadashi

AU - Takahashi, Kiyoshi

AU - Akagi, Tadaatsu

PY - 2003/5/1

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N2 - 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-ISH of immunomagnetically 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, and thymus. 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 HVP 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.

AB - 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-ISH of immunomagnetically 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, and thymus. 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 HVP 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.

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