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.
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.
Hayashi
Kazuhiko
K
Department of Pathology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan. kazuhaya@md.okayama-u.ac.jp
Jin
Zaishun
Z
Onoda
Sachiyo
S
Joko
Hiromasa
H
Teramoto
Norihiro
N
Ohara
Nobuya
N
Oda
Wakako
W
Tanaka
Takehiro
T
Liu
Yi-Xuan
YX
Koirala
Tirtha Raj
TR
Oka
Takashi
T
Kondo
Eisaku
E
Yoshino
Tadashi
T
Takahashi
Kiyoshi
K
Akagi
Tadaatsu
T
D000818:Animals; D001344:Autopsy; D002460:Cell Line; D020031:Epstein-Barr Virus Infections / Q000235:genetics / Q000473:pathology*; D019309:Epstein-Barr Virus Nuclear Antigens / Q000235:genetics; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000302:isolation & purification*; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D008214:Lymphocytes / Q000276:immunology / Q000473:pathology; D010215:Papio; D011817:Rabbits; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D013577:Syndrome; D014763:Viral Matrix Proteins / Q000235:genetics
C037662:EBV-associated membrane antigen, Epstein-Barr virus; D019309:Epstein-Barr Virus Nuclear Antigens; D007376:Interleukin-2; D016693:Receptors, Antigen, T-Cell, alpha-beta; D014763:Viral Matrix Proteins