Lymphoproliferative disease in human peripheral blood mononuclear cell-injected SCID mice. I. T lymphocyte requirement for B cell tumor generation.

Veronese, Maria Luisa; Veronesi, Arianna; D’Andrea, Emma; Mistro, Annarosa Del; Indraccolo, Stefano; Mazza, Maria Rosaria; Mion, Marta; Zamarchi, Rita; Menin, Chiara; Panozzo, Marina

doi:10.1084/jem.176.6.1763

Cited by 83 publications

(60 citation statements)

References 28 publications

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“…However, in contrast to LCL, tumour outgrowth in SCID mice is not blocked by acyclovir (Boyle et al, 1992). The presence of CD4 + or CD8 + T cells in the inoculum is an absolute requirement for their growth (Veronese et al, 1992 ;I. Johannessen, unpublished results), suggesting that SCID tumours arise from a subpopulation of EBV-carrying B cells which have the capacity for direct outgrowth in vivo if supplied with T cell-derived soluble factors and which are quite distinct from the EBV-carrying cells which give rise to spontaneous LCL.…”

Section: Discussionmentioning

confidence: 98%

Non-correlation of in vivo and in vitro parameters of Epstein-Barr virus persistence suggests heterogeneity of B cell infection.

Johannessen

Haque²,

Njie-Jobe³

et al. 1998

Journal of General Virology

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Section: Discussionmentioning

confidence: 98%

Non-correlation of in vivo and in vitro parameters of Epstein-Barr virus persistence suggests heterogeneity of B cell infection.

Johannessen

Haque²,

Njie-Jobe³

et al. 1998

Journal of General Virology

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“…Treatment of SCID/hu mice with CsA, which blocks T-cell activation, was also able to block EBV-driven tumorigenesis. 22,23 Collectively, these observations point to a model in which viral reactivation and outgrowth of transformed B cells is dependent on T-cell help for activation of latently infected resting B cells.If B-cell activation is the initiating event, how does the latent virus respond to this stimulus? One possibility is that B-cell activation induces expression of all the viral latent genes (a latency III phenotype), resulting in transformation and direct outgrowth of infected B cells.…”

mentioning

confidence: 93%

mentioning

confidence: 93%

“…In a remarkable counterpoint to the critical role played by EBV-specific CD8 + CTL in control of latent infection in healthy individuals, studies in SCID/hu mice have revealed that EBV-driven tumorigenesis is T-cell dependent. Veronese et al 22 found that SCID mice engrafted with T-cell-depleted PBL from EBV-positive donors failed to develop tumors, whereas the presence of CD4 + or CD8 + T cells resulted in disease progression, with CD4 + T cells being the more efficient in providing helper function for viral pathogenesis. Treatment of SCID/hu mice with CsA, which blocks T-cell activation, was also able to block EBV-driven tumorigenesis.…”

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confidence: 99%

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Skipping the two-step? Possible mechanisms of Epstein–Barr virus reactivation

Cannon

Rochford

2003

Leukemia

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Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus that is associated with several malignant diseases of B-cell or epithelial cell origin, including endemic Burkitt's lymphoma, nasopharyngeal carcinoma, Hodgkin's disease, and the lymphoproliferative disorders (LPD) that arise in immunocompromised individuals. In this issue of Leukemia, Piovan co-workers address a long-standing question concerning the pathogenesis of EBV-associated LPD -what is the mechanism of viral reactivation from latency and subsequent outgrowth of transformed B cells? They present intriguing evidence that suggests that LPD may arise by virtue of direct outgrowth of transformed B cells, rather than a two-step process involving viral lytic cycle reactivation followed by de novo infection and transformation of bystander B cells. 1 EBV infection of B cells in vitro results in transformation and rapid outgrowth of lymphoblastoid cell lines (LCL) with a latency III phenotype, encompassing expression of six viral nuclear antigens (EBNA1, 2, 3A, 3B, 3C and LP), three latent membrane proteins (LMP1, LMP2A and LMP2B), and two small untranslated RNA species (EBER1 and EBER2). 2 In contrast with the ready transformation and outgrowth of latently infected B cells in vitro, infection of healthy individuals results in an asymptomatic carrier state in which EBV resides within resting B cells with an IgD À , CD27 + memory phenotype. 3,4 Prevailing opinion is that viral gene expression in resting B cells is limited to LMP2A, the EBERs and possibly EBNA1, 5-7 although expression of the latter is a point of some debate. LMP2A is thought to play a role in the maintenance of latency through inhibition of surface immunoglobulin-mediated signalling and B-cell activation and may also help EBV-infected cells to persist in vivo. 8 An alternative view, proposed by Babcock et al, 9 is that most latently infected resting B cells are transcriptionally silent with respect to viral gene expression. EBV-specific CD8 + cytotoxic T lymphocytes (CTL) play a pivotal role in the control of asymptomatic latent infections through their ability to recognize viral latent antigens associated with B-cell transformation. 10 EBV-specific CD8 + CTL responses are inhibited in cyclosporin A (CsA)-treated transplant patients, 11,12 who are accordingly at high risk of developing EBV-associated posttransplant LPD and lymphoma. 13,14 In contrast with the phenotype of latently infected resting B cells in the peripheral blood, LPD express a full complement of latent genes, including EBNA2, the EBNA3 antigens, LMP1 and LMP2, 15,16 all of which are major targets for virus-specific CTL surveillance. Evidence of viral lytic gene expression in LPD has also been documented. 17,18 Valuable information regarding the pathogenesis of EBV and the mechanisms of viral reactivation has been gained from studies with severe combined immunodeficient (SCID) mice engrafted with human peripheral blood lymphocytes (PBL) from EBV-positive donors. The initial observation that chimeric SCID/ hu mice were suscep...

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“…Of note, in the SCID/hu model, lymphoma generation strongly depends on the presence of T lymphocytes; in fact, tumor masses only develop when T cells are coinjected with EBV-infected precursors, and cyclosporine administration to the animals paradoxically prevents tumor development. 10,11 In a human setting, several observations also point to an involvement of activated T cells in non-Hodgkin's B-cell lymphoma generation, and the correlation of gastrointestinal B cell lymphomas with Helicobacter pylori-specific T lymphocytes is well-known. 12 The mechanisms underlying this T-cell-mediated promotion of lymphomagenesis are far from clear; in particular, it is not known whether lymphoma originates from the very few latently infected B-cell precursors injected, which are calculated in a range of 2-60 10 6 B lymphocytes, 13 or whether EBV reactivation and virus spread to bystander B cells also occurs.…”

Section: Introductionmentioning

confidence: 99%

Tumor outgrowth in peripheral blood mononuclear cell-injected SCID mice is not associated with early Epstein–Barr virus reactivation

et al. 2003

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Epstein-Barr virus (EBV)-positive B-cell lymphoproliferative disease develops in severe combined immunodeficient (SCID) mice inoculated with peripheral blood mononuclear cells (PBMC) from EBV + individuals (SCID/hu mice). In this study, we investigated the contribution of EBV reactivation and de novo infection of B lymphocytes to tumor outgrowth in SCID/hu mice. Evaluation of BZLF-1, an early EBV activation transcript, in cells recovered from the mouse peritoneal cavity within 16 days following PBMC transfer did not reveal EBV reactivation, while BZLF-1 expression was only detected in tumor masses or in vitro established lymphoblastoid cell lines. To confirm these data by a different strategy, we coinjected PBMC from seropositive donors with purified B cells from seronegative donors of different sex. Fluorescence in situ hydridization analysis of the resulting tumor masses disclosed that the overwhelming majority of lymphoma cells originated from the seropositive donor, implying that no substantial in vivo production and transmission of virus had occurred. Further, treatment of SCID/hu mice with ganciclovir did not prevent lymphoma development. Our results suggest that in the SCID/ hu mouse, early EBV replication and secondary infection of bystander B cells does not occur, and that the direct outgrowth of the transformed B lymphocytes present within the PBMC inoculum is the predominant mechanism, which leads to lymphoma generation in this experimental model.

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Lymphoproliferative disease in human peripheral blood mononuclear cell-injected SCID mice. I. T lymphocyte requirement for B cell tumor generation.

Cited by 83 publications

References 28 publications

Non-correlation of in vivo and in vitro parameters of Epstein-Barr virus persistence suggests heterogeneity of B cell infection.

Non-correlation of in vivo and in vitro parameters of Epstein-Barr virus persistence suggests heterogeneity of B cell infection.

Skipping the two-step? Possible mechanisms of Epstein–Barr virus reactivation

Tumor outgrowth in peripheral blood mononuclear cell-injected SCID mice is not associated with early Epstein–Barr virus reactivation

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