Novel Mouse Xenograft Models Reveal a Critical Role of CD4 T Cells in the Proliferation of EBV-Infected T and NK Cells
Epstein-Barr virus (EBV), a ubiquitous B-lymphotropic herpesvirus, ectopically infects T or NK cells to cause severe diseases of unknown pathogenesis, including chronic active EBV infection (CAEBV) and EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH). We developed xenograft models of CAEBV and EBV-HLH by transplanting patients' PBMC to immunodeficient mice of the NOD/Shi-scid/IL-2Rγnull strain. In these models, EBV-infected T, NK, or B cells proliferated systemically and reproduced histological characteristics of the two diseases. Analysis of the TCR repertoire expression revealed that identical predominant EBV-infected T-cell clones proliferated in patients and corresponding mice transplanted with their PBMC. Expression of the EBV nuclear antigen 1 (EBNA1), the latent membrane protein 1 (LMP1), and LMP2, but not EBNA2, in the engrafted cells is consistent with the latency II program of EBV gene expression known in CAEBV. High levels of human cytokines, including IL-8, IFN-γ, and RANTES, were detected in the peripheral blood of the model mice, mirroring hypercytokinemia characteristic to both CAEBV and EBV-HLH. Transplantation of individual immunophenotypic subsets isolated from patients' PBMC as well as that of various combinations of these subsets revealed a critical role of CD4+ T cells in the engraftment of EBV-infected T and NK cells. In accordance with this finding, in vivo depletion of CD4+ T cells by the administration of the OKT4 antibody following transplantation of PBMC prevented the engraftment of EBV-infected T and NK cells. This is the first report of animal models of CAEBV and EBV-HLH that are expected to be useful tools in the development of novel therapeutic strategies for the treatment of the diseases.
Vyšlo v časopise:
Novel Mouse Xenograft Models Reveal a Critical Role of CD4 T Cells in the Proliferation of EBV-Infected T and NK Cells. PLoS Pathog 7(10): e32767. doi:10.1371/journal.ppat.1002326
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.ppat.1002326
Souhrn
Epstein-Barr virus (EBV), a ubiquitous B-lymphotropic herpesvirus, ectopically infects T or NK cells to cause severe diseases of unknown pathogenesis, including chronic active EBV infection (CAEBV) and EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH). We developed xenograft models of CAEBV and EBV-HLH by transplanting patients' PBMC to immunodeficient mice of the NOD/Shi-scid/IL-2Rγnull strain. In these models, EBV-infected T, NK, or B cells proliferated systemically and reproduced histological characteristics of the two diseases. Analysis of the TCR repertoire expression revealed that identical predominant EBV-infected T-cell clones proliferated in patients and corresponding mice transplanted with their PBMC. Expression of the EBV nuclear antigen 1 (EBNA1), the latent membrane protein 1 (LMP1), and LMP2, but not EBNA2, in the engrafted cells is consistent with the latency II program of EBV gene expression known in CAEBV. High levels of human cytokines, including IL-8, IFN-γ, and RANTES, were detected in the peripheral blood of the model mice, mirroring hypercytokinemia characteristic to both CAEBV and EBV-HLH. Transplantation of individual immunophenotypic subsets isolated from patients' PBMC as well as that of various combinations of these subsets revealed a critical role of CD4+ T cells in the engraftment of EBV-infected T and NK cells. In accordance with this finding, in vivo depletion of CD4+ T cells by the administration of the OKT4 antibody following transplantation of PBMC prevented the engraftment of EBV-infected T and NK cells. This is the first report of animal models of CAEBV and EBV-HLH that are expected to be useful tools in the development of novel therapeutic strategies for the treatment of the diseases.
Zdroje
1. RickinsonABKieffED 2007 Epstein-Barr virus. KnipeDMHowleyPM Fields Virology 5. ed Philadelphia Lippincott Williams and Wilkins 2655 2700
2. KieffEDRickinsonAB 2007 Epstein-Barr virus and its replication. KnipeDMHowleyPM Fields Virology Philadelphia Lippincott Williams and Wilkins 2603 2654
3. FujiwaraSOnoY 1995 Isolation of Epstein-Barr virus-infected clones of the human T-cell line MT-2: use of recombinant viruses with a positive selection marker. J Virol 69 3900 3903
4. WatryDHedrickJASiervoSRhodesGLambertiJJ 1991 Infection of human thymocytes by Epstein-Barr virus. J Exp Med 173 971 980
5. KikutaHSakiyamaYMatsumotoSOh-IshiTNakanoT 1993 Fatal Epstein-Barr virus-associated hemophagocytic syndrome. Blood 82 3259 3264
6. KawaguchiHMiyashitaTHerbstHNiedobitekGAsadaM 1993 Epstein-Barr virus-infected T lymphocytes in Epstein-Barr virus-associated hemophagocytic syndrome. J Clin Invest 92 1444 1450
7. Kawa-HaKIshiharaSNinomiyaTYumura-YagiKHaraJ 1989 CD3-negative lymphoproliferative disease of granular lymphocytes containing Epstein-Barr viral DNA. J Clin Invest 84 51 55
8. JonesJFShurinSAbramowskyCTubbsRRSciottoCG 1988 T-cell lymphomas containing Epstein-Barr viral DNA in patients with chronic Epstein-Barr virus infections. N Engl J Med 318 733 741
9. KikutaHTaguchiYTomizawaKKojimaKKawamuraN 1988 Epstein-Barr virus genome-positive T lymphocytes in a boy with chronic active EBV infection associated with Kawasaki-like disease. Nature 333 455 457
10. IshiharaSTawaAYumura-YagiKMurataMHaraJ 1989 Clonal T-cell lymphoproliferation containing Epstein-Barr (EB) virus DNA in a patient with chronic active EB virus infection. Jpn J Cancer Res 80 99 101
11. JaffeES 2009 The 2008 WHO classification of lymphomas: implications for clinical practice and translational research. Hematology Am Soc Hematol Educ Program 2009 523 531
12. OkanoM 2002 Overview and problematic standpoints of severe chronic active Epstein-Barr virus infection syndrome. Crit Rev Oncol Hematol 44 273 282
13. StrausSE 1992 Acute progressive Epstein-Barr virus infections. Annu Rev Med 43 437 449
14. KimuraH 2006 Pathogenesis of chronic active Epstein-Barr virus infection: is this an infectious disease, lymphoproliferative disorder, or immunodeficiency? Rev Med Virol 16 251 261
15. KimuraHMorishimaTKaneganeHOhgaSHoshinoY 2003 Prognostic factors for chronic active Epstein-Barr virus infection. J Infect Dis 187 527 533
16. TsugeIMorishimaTKimuraHKuzushimaKMatsuokaH 2001 Impaired cytotoxic T lymphocyte response to Epstein-Barr virus-infected NK cells in patients with severe chronic active EBV infection. J Med Virol 64 141 148
17. SugayaNKimuraHHaraSHoshinoYKojimaS 2004 Quantitative analysis of Epstein-Barr virus (EBV)-specific CD8+ T cells in patients with chronic active EBV infection. J Infect Dis 190 985 988
18. AoukatyALeeIFWuJTanR 2003 Chronic active Epstein-Barr virus infection associated with low expression of leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) on natural killer cells. J Clin Immunol 23 141 145
19. HenterJIHorneAAricoMEgelerRMFilipovichAH 2007 HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 48 124 131
20. LayJDTsaoCJChenJYKadinMESuIJ 1997 Upregulation of tumor necrosis factor-alpha gene by Epstein-Barr virus and activation of macrophages in Epstein-Barr virus-infected T cells in the pathogenesis of hemophagocytic syndrome. J Clin Invest 100 1969 1979
21. ImashukuSHibiSOharaTIwaiASakoM 1999 Effective control of Epstein-Barr virus-related hemophagocytic lymphohistiocytosis with immunochemotherapy. Histiocyte Society. Blood 93 1869 1874
22. ItoMHiramatsuHKobayashiKSuzueKKawahataM 2002 NOD/SCID/gamma(c)(null) mouse: an excellent recipient mouse model for engraftment of human cells. Blood 100 3175 3182
23. ShultzLDLyonsBLBurzenskiLMGottBChenX 2005 Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2R gamma null mice engrafted with mobilized human hemopoietic stem cells. J Immunol 174 6477 6489
24. StrowigTGurerCPlossALiuYFArreyF 2009 Priming of protective T cell responses against virus-induced tumors in mice with human immune system components. J Exp Med 206 1423 1434
25. WatanabeSTerashimaKOhtaSHoribataSYajimaM 2007 Hematopoietic stem cell-engrafted NOD/SCID/IL2Rgamma null mice develop human lymphoid systems and induce long-lasting HIV-1 infection with specific humoral immune responses. Blood 109 212 218
26. YajimaMImadomeKNakagawaAWatanabeSTerashimaK 2008 A new humanized mouse model of Epstein-Barr virus infection that reproduces persistent infection, lymphoproliferative disorder, and cell-mediated and humoral immune responses. J Infect Dis 198 673 682
27. TraggiaiEChichaLMazzucchelliLBronzLPiffarettiJC 2004 Development of a human adaptive immune system in cord blood cell-transplanted mice. Science 304 104 107
28. MelkusMWEstesJDPadgett-ThomasAGatlinJDentonPW 2006 Humanized mice mount specific adaptive and innate immune responses to EBV and TSST-1. Nat Med 12 1316 1322
29. BaenzigerSTussiwandRSchlaepferEMazzucchelliLHeikenwalderM 2006 Disseminated and sustained HIV infection in CD34+ cord blood cell-transplanted Rag2-/-gamma c-/- mice. Proc Natl Acad Sci U S A 103 15951 15956
30. ZhangLKovalevGISuL 2007 HIV-1 infection and pathogenesis in a novel humanized mouse model. Blood 109 2978 2981
31. DewanMZWatanabeMAhmedSTerashimaKHoriuchiS 2005 Hodgkin's lymphoma cells are efficiently engrafted and tumor marker CD30 is expressed with constitutive nuclear factor-kappaB activity in unconditioned NOD/SCID/gammac(null) mice. Cancer Sci 96 466 473
32. IshikawaFYoshidaSSaitoYHijikataAKitamuraH 2007 Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region. Nat Biotechnol 25 1315 1321
33. DurigJEbelingPGrabellusFSorgURMollmannM 2007 A novel nonobese diabetic/severe combined immunodeficient xenograft model for chronic lymphocytic leukemia reflects important clinical characteristics of the disease. Cancer Res 67 8653 8661
34. NakagawaAItoMSagaS 2002 Fatal cytotoxic T-cell proliferation in chronic active Epstein-Barr virus infection in childhood. Am J Clin Pathol 117 283 290
35. NagataHKonnoAKimuraNZhangYKimuraM 2001 Characterization of novel natural killer (NK)-cell and gammadelta T-cell lines established from primary lesions of nasal T/NK-cell lymphomas associated with the Epstein-Barr virus. Blood 97 708 713
36. ImaiSSugiuraMOikawaOKoizumiSHiraoM 1996 Epstein-Barr virus (EBV)-carrying and -expressing T-cell lines established from severe chronic active EBV infection. Blood 87 1446 1457
37. YoshiokaMIshiguroNIshikoHMaXKikutaH 2001 Heterogeneous, restricted patterns of Epstein-Barr virus (EBV) latent gene expression in patients with chronic active EBV infection. J Gen Virol 82 2385 2392
38. KimuraHHoshinoYHaraSSugayaNKawadaJ 2005 Differences between T cell-type and natural killer cell-type chronic active Epstein-Barr virus infection. J Infect Dis 191 531 539
39. XuJAhmadAJonesJFDolcettiRVaccherE 2000 Elevated serum transforming growth factor beta1 levels in Epstein-Barr virus-associated diseases and their correlation with virus-specific immunoglobulin A (IgA) and IgM. J Virol 74 2443 2446
40. OhgaSNomuraATakadaHIharaKKawakamiK 2001 Epstein-Barr virus (EBV) load and cytokine gene expression in activated T cells of chronic active EBV infection. J Infect Dis 183 1 7
41. HayashiKOharaNTeramotoNOnodaSChenHL 2001 An animal model for human EBV-associated hemophagocytic syndrome: herpesvirus papio frequently induces fatal lymphoproliferative disorders with hemophagocytic syndrome in rabbits. Am J Pathol 158 1533 1542
42. VeroneseMLVeronesiAD'AndreaEDel MistroAIndraccoloS 1992 Lymphoproliferative disease in human peripheral blood mononuclear cell-injected SCID mice. I. T lymphocyte requirement for B cell tumor generation. J Exp Med 176 1763 1767
43. JohannessenIAsgharMCrawfordDH 2000 Essential role for T cells in human B-cell lymphoproliferative disease development in severe combined immunodeficient mice. Br J Haematol 109 600 610
44. SutkowskiNPalkamaTCiurliCSekalyRPThorley-LawsonDA 1996 An Epstein-Barr virus-associated superantigen. J Exp Med 184 971 980
45. AnagnostopoulosIHummelMKreschelCSteinH 1995 Morphology, immunophenotype, and distribution of latently and/or productively Epstein-Barr virus-infected cells in acute infectious mononucleosis: implications for the interindividual infection route of Epstein-Barr virus. Blood 85 744 750
46. HudnallSDGeYWeiLYangNPWangHQ 2005 Distribution and phenotype of Epstein-Barr virus-infected cells in human pharyngeal tonsils. Mod Pathol 18 519 527
47. HislopADTaylorGSSauceDRickinsonAB 2007 Cellular responses to viral infection in humans: lessons from Epstein-Barr virus. Annu Rev Immunol 25 587 617
48. KatanoHAliMAPateraACCatalfamoMJaffeES 2004 Chronic active Epstein-Barr virus infection associated with mutations in perforin that impair its maturation. Blood 103 1244 1252
49. van RijnRSSimonettiERHagenbeekAHogenesMCde WegerRA 2003 A new xenograft model for graft-versus-host disease by intravenous transfer of human peripheral blood mononuclear cells in RAG2-/- gammac-/- double-mutant mice. Blood 102 2522 2531
50. ItoRKatanoIKawaiKHirataHOguraT 2009 Highly sensitive model for xenogenic GVHD using severe immunodeficient NOG mice. Transplantation 87 1654 1658
51. KawaKSawadaASatoMOkamuraTSakataN 2011 Excellent outcome of allogeneic hematopoietic SCT with reduced-intensity conditioning for the treatment of chronic active EBV infection. Bone Marrow Transplant 46 77 83
52. SatoEOhgaSKurodaHYoshibaFNishimuraM 2008 Allogeneic hematopoietic stem cell transplantation for Epstein-Barr virus-associated T/natural killer-cell lymphoproliferative disease in Japan. Am J Hematol 83 721 727
53. OkanoMKawaKKimuraHYachieAWakiguchiH 2005 Proposed guidelines for diagnosing chronic active Epstein-Barr virus infection. Am J Hematol 80 64 69
54. KimuraHMoritaMYabutaYKuzushimaKKatoK 1999 Quantitative analysis of Epstein-Barr virus load by using a real-time PCR assay. J Clin Microbiol 37 132 136
55. NakamuraHIwakiriDOnoYFujiwaraS 1998 Epstein-Barr-virus-infected human T-cell line with a unique pattern of viral-gene expression. Int J Cancer 76 587 594
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Hygiena a epidemiológia Infekčné lekárstvo LaboratóriumČlánok vyšiel v časopise
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