Rabbit Model for Human EBV-Associated Hemophagocytic Syndrome (HPS)

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.

Successful treatment of refractory hyperferritinemic syndromes with canakinumab: a report of two cases

“…By contrast, substantial benefit from ANK treatment in sJIA-associated MAS after inadequate response to glucocorticoids and CSA has been described in many case reports [ 24 , 25 ]. Notably, occurrence of MAS was occasionally seen in children treated with doses of 1–2 mg/kg daily [ 26 , 27 ]. In some of these patients, however, features of MAS improved after the dose of ANK was escalated.…”

EBNA-2-Deleted Epstein-Barr Virus from P3HR-1 Can Infect Rabbits with Lower Efficiency than Prototype Epstein-Barr Virus from B95-8

“…ISH was performed as described previously [11,12,13] using routinely processed sections of paraffin-embedded samples of EBV-positive gastric cancer as a positive control and samples from the spleen, mesenteric lymph nodes, appendix, tonsils and liver of the autopsied rabbits. The DAKO ISH detection kit was used with the FITC-labeled DNA probes (Code No.…”

“…These animals are precious and it is difficult to use them in general laboratories because of problems with breeding, handling techniques and costs. It has been reported that rabbits can be infected with herpesvirus papio, which is a type of lymphocryptovirus that affects baboons, and that they develop herpesvirus papio-associated LPD and hemophagocytic syndrome [11,12,13]. Rabbits are easy to maintain and it is straightforward to collect blood from their ear veins.…”

Epstein-Barr Virus (HHV-4) Inoculation to Rabbits by Intranasal and Oral Routes Results in Subacute and/or Persistent Infection Dissimilar to Human Disease

“…mice with severe combined immunodeficiency disease) or animals inoculated with gammaherpesviruses distinct from the original virus [1]. Rabbits infected with EBV-related herpesviruses were examined by several authors [2,3,4,5,6]. These experiments mainly resulted in the establishment of lymphoproliferative disease and/or formation of malignant lymphomas.…”