title: 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 disease.
abstract: Epstein-Barr virus-associated hemophagocytic syndrome (EBV-AHS), which is often associated with fatal infectious mononucleosis or T-cell lymphoproliferative diseases (LPD), is a distinct disease characterized by high mortality. Treatment of patients with EBV-AHS has proved challenging. To develop some therapeutic interventions for EBV-AHS, we examined the effectiveness of an antiviral agent (vidarabine) or chemotherapy (CHOP), using a rabbit model for EBV-AHS. Fourteen untreated rabbits were inoculated intravenously with cell-free virions of the EBV-like virus Herpesvirus papio (HVP). All of the rabbits died of HVP-associated (LPD) and hemophagocytic syndrome (HPS) between 21 and 31 days after inoculation. Furthermore, three HVP-infected rabbits treated with vidarabine died between days 23 and 28 after inoculation, and their clinicopathological features were no different from those of untreated rabbits, indicating that this drug is not effective at all to treat HVP-induced rabbit LPD and HPS. Three of the infected rabbits that were treated with one course, with an incomplete set of three courses, or with three full courses of CHOP treatment died of HVP-induced LPD and HPS with a bleeding tendency and/or with opportunistic infections. They died on the 26th, 62nd and 105th day after virus inoculation, respectively. CHOP treatment transiently suppressed the HVP-induced LPD and contributed to the prolonged survival time of two infected rabbits. However, it did not remove all of the HVP-infected cells from the infected rabbits, and residual HVP-infected lymphocytes caused recurrences of rabbit LPD and HPS. The most interesting finding of this experiment was observed in the infected rabbit with the longest survival time of 105 days: HVP-negative lymphomas surrounded by HVP-induced LPD developed in the larynx and ileum of this rabbit, causing an obstruction of the lumen. We concluded that these were not secondary lymphomas caused by CHOP treatment, because no suspicious lesions were detected in three uninfected rabbits that were treated with three courses of CHOP for 120 days. It is therefore necessary to clarify the mechanism by which HVP-negative lymphomas associated with HVP-induced LPD can develop. 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. Further studies will therefore be required to develop better therapies to treat EBV-AHS.
authors.affiliation: Department of Pathology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan. kazuhaya@md.okayama-u.ac.jp
authors.forename: K
authors.initials: K
authors.lastname: Hayashi
authors.forename: H
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authors.lastname: Joko
authors.forename: T R
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authors.lastname: Koirala
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authors.lastname: Onoda
authors.forename: Z-S
authors.initials: ZS
authors.lastname: Jin
authors.forename: M
authors.initials: M
authors.lastname: Munemasa
authors.forename: N
authors.initials: N
authors.lastname: Ohara
authors.forename: W
authors.initials: W
authors.lastname: Oda
authors.forename: T
authors.initials: T
authors.lastname: Tanaka
authors.forename: T
authors.initials: T
authors.lastname: Oka
authors.forename: E
authors.initials: E
authors.lastname: Kondo
authors.forename: T
authors.initials: T
authors.lastname: Yoshino
authors.forename: K
authors.initials: K
authors.lastname: Takahashi
authors.forename: M
authors.initials: M
authors.lastname: Yamada
authors.forename: T
authors.initials: T
authors.lastname: Akagi
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D000998:Antiviral Agents / Q000627:therapeutic use*; D002460:Cell Line; D003520:Cyclophosphamide / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D020031:Epstein-Barr Virus Infections / Q000188:drug therapy* / Q000473:pathology*; D016679:Genome, Viral; D006561:Herpes Simplex / Q000473:pathology* / Q000821:virology; D015616:Histiocytosis, Non-Langerhans-Cell / Q000188:drug therapy* / Q000473:pathology*; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis; D008223:Lymphoma / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D008232:Lymphoproliferative Disorders / Q000473:pathology* / Q000821:virology; D010215:Papio; D010641:Phenotype; D011241:Prednisone / Q000008:administration & dosage; D011817:Rabbits; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018139:Simplexvirus / Q000235:genetics; D016019:Survival Analysis; D014740:Vidarabine / Q000627:therapeutic use*; D014750:Vincristine / Q000008:administration & dosage
chemical_list: D000914:Antibodies, Viral; D000998:Antiviral Agents; D007074:Immunoglobulin G; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D014740:Vidarabine; D011241:Prednisone