EBV-Associated B-Cell Lymphomas Following Transfer of Human Peripheral Blood Lymphocytes to Mice with Severe Combined Immune Deficiency

Mosier, Donald E.; Baird, SM; Kirven, Marybeth; Gulizia, Richard J.; Wilson, Darcy B.; Kubayashi, R.; Picchio, Gastón; Garnier, J. L.; Sullivan, John L.; Kipps, Thomas J.

doi:10.1007/978-3-642-75889-8_39

Cited by 27 publications

(15 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…EBV-related herpesviruses are found only in humans and nonhuman primates, and infection is tightly restricted to primate cells (19). Thus, models in other small laboratory animals require reconstitution of a human immune system for EBV infection (16), use of more distantly related gammaherpesviruses (32), or injection of EBV-infected B cells with tumor engraftment as the endpoint (21). Naive rhesus macaques can be experimentally infected by oral inoculation with rhesus lymphocryptovirus (rhLCV), providing a highly accurate experimental model for vaccine development and pathogenesis studies.…”

Section: Epstein-barr Virus (Ebv) Encodes Over 60 Different Proteins mentioning

confidence: 99%

Antibodies to Lytic Infection Proteins in Lymphocryptovirus-Infected Rhesus Macaques: a Model for Humoral Immune Responses to Epstein-Barr Virus Infection

Orlova

Fogg

Carville

et al. 2011

Clin. Vaccine Immunol.

View full text Add to dashboard Cite

Humoral immune responses to rhesus lymphocryptovirus (rhLCV) lytic infection proteins were evaluated in the rhesus macaque animal model for Epstein-Barr virus (EBV) infection. We found a hierarchy of humoral responses to 14 rhLCV lytic infection proteins in naturally infected rhesus macaques, with (i) widespread and robust responses to four glycoproteins expressed as late proteins, (ii) frequent but less robust responses to a subset of early proteins, and (iii) low-level responses to immediate-early proteins. This hierarchy of humoral responses was similar to that reported for EBV-infected humans, with the notable exception of the response to rhBARF1. Serum antibodies to rhBARF1 were frequently detected in healthy rhLCV-infected macaques, but in humans, anti-BARF1 antibodies have been reported primarily in patients with EBV-positive nasopharyngeal carcinoma (NPC). The macaque data accurately predicted that serum antibodies against BARF1 are a normal response to EBV infection when human serum samples are analyzed. The rhesus macaque animal provides a unique perspective on humoral responses to EBV infection in humans and can be a valuable model for EBV vaccine development. Epstein-Barr virus (EBV) encodes over 60 different proteins during lytic virus replication, including (i) immediate-early (IE) proteins that act principally as transcriptional activators to initiate the cascade of lytic gene expression, (ii) early (E)proteins directed at a variety of functions, including gene regulation, immune evasion, nucleotide metabolism, and DNA replication, and (iii) late (L) proteins, most of which are virion proteins (26). Serum antibody responses to lytic infection proteins are commonly used to diagnose EBV infection.Induction of humoral immune responses to EBV lytic infection proteins is also important for EBV vaccines. Antibodies against gp350, the major membrane glycoprotein (BLLF1), are capable of neutralizing EBV infection (24), and recent clinical trials showed that a gp350 subunit vaccine can induce EBVneutralizing antibodies (7,22) and protect humans from EBVinduced infectious mononucleosis (IM) (31). Protection was not complete, but this ground-breaking trial provided proof of principle for a vaccine strategy against EBV-induced disease. Since antibody responses are the foundation of most successful virus vaccines, it is not unreasonable to speculate that induction of better humoral immune responses against EBV gp350 or induction of antibody responses against other EBV lytic infection proteins may enhance efficacy of an EBV vaccine. However, testing these hypotheses in human studies can be prohibitive.Rhesus macaques are naturally infected with an EBV-related herpesvirus, or lymphocryptovirus (LCV), that encodes a repertoire of viral proteins identical to that of EBV and which biologically mimics EBV infection in humans with, e.g., oral transmission, asymptomatic persistent latent infections in peripheral blood B cells, lytic replication and viral shedding from the oral cavity, and association with malignant di...

show abstract

Section: Epstein-barr Virus (Ebv) Encodes Over 60 Different Proteins mentioning

confidence: 99%

Antibodies to Lytic Infection Proteins in Lymphocryptovirus-Infected Rhesus Macaques: a Model for Humoral Immune Responses to Epstein-Barr Virus Infection

Orlova

Fogg

Carville

et al. 2011

Clin. Vaccine Immunol.

View full text Add to dashboard Cite

show abstract

“…However, in this model system, host cells are never infected with EBV, and tumorigenesis in the immunodeficient animal is inevitable if sufficient numbers of EBV-infected B cells are inoculated. 9 EBV infection of cotton-top tamarins, a New World nonhuman primate, can induce lymphomagenesis in some animals in which the tamarin B cells are infected and immortalized by EBV. 10,11 This is an important animal model for establishing the oncogenic potential of EBV infection, but the tamarin immune response to a cross-species virus infection may not accurately model the human immune response to EBV infection.…”

Section: Introductionmentioning

confidence: 99%

Experimental rhesus lymphocryptovirus infection in immunosuppressed macaques: an animal model for Epstein-Barr virus pathogenesis in the immunosuppressed host

Rivailler

Carville²,

Kaur³

et al. 2004

Blood

View full text Add to dashboard Cite

“…Here, we used the well-established PTLD-SCID mouse model [23], [24], that permits to assess efficacy of T-cell preparations in a preclinical setting [25], to comparatively evaluate the tumor-protective potential of different CD4+ T-cell specificities in vivo .…”

Section: Introductionmentioning

confidence: 99%

Virus and Autoantigen-Specific CD4+ T Cells Are Key Effectors in a SCID Mouse Model of EBV-Associated Post-Transplant Lymphoproliferative Disorders

et al. 2014

View full text Add to dashboard Cite

Polyclonal Epstein-Barr virus (EBV)-infected B cell line (lymphoblastoid cell lines; LCL)-stimulated T-cell preparations have been successfully used to treat EBV-positive post-transplant lymphoproliferative disorders (PTLD) in transplant recipients, but function and specificity of the CD4+ component are still poorly defined. Here, we assessed the tumor-protective potential of different CD4+ T-cell specificities in a PTLD-SCID mouse model. Injection of different virus-specific CD4+ T-cell clones showed that single specificities were capable of prolonging mouse survival and that the degree of tumor protection directly correlated with recognition of target cells in vitro. Surprisingly, some CD4+ T-cell clones promoted tumor development, suggesting that besides antigen recognition, still elusive functional differences exist among virus-specific T cells. Of several EBV-specific CD4+ T-cell clones tested, those directed against virion antigens proved most tumor-protective. However, enriching these specificities in LCL-stimulated preparations conferred no additional survival benefit. Instead, CD4+ T cells specific for unknown, probably self-antigens were identified as principal antitumoral effectors in LCL-stimulated T-cell lines. These results indicate that virion and still unidentified cellular antigens are crucial targets of the CD4+ T-cell response in this preclinical PTLD-model and that enriching the corresponding T-cell specificities in therapeutic preparations may enhance their clinical efficacy. Moreover, the expression in several EBV-negative B-cell lymphoma cell lines implies that these putative autoantigen(s) might also qualify as targets for T-cell-based immunotherapy of virus-negative B cell malignancies.

show abstract

EBV-Associated B-Cell Lymphomas Following Transfer of Human Peripheral Blood Lymphocytes to Mice with Severe Combined Immune Deficiency

Cited by 27 publications

References 23 publications

Antibodies to Lytic Infection Proteins in Lymphocryptovirus-Infected Rhesus Macaques: a Model for Humoral Immune Responses to Epstein-Barr Virus Infection

Antibodies to Lytic Infection Proteins in Lymphocryptovirus-Infected Rhesus Macaques: a Model for Humoral Immune Responses to Epstein-Barr Virus Infection

Experimental rhesus lymphocryptovirus infection in immunosuppressed macaques: an animal model for Epstein-Barr virus pathogenesis in the immunosuppressed host

Virus and Autoantigen-Specific CD4+ T Cells Are Key Effectors in a SCID Mouse Model of EBV-Associated Post-Transplant Lymphoproliferative Disorders

Contact Info

Product

Resources

About