The functional human immune system, including T, B, and natural killer lymphocytes, is reconstituted in NOD/Shi-scid/IL-2Rgamma(null) (NOG) mice that receive hematopoietic stem cell transplants. Here, we show that these humanized mice can recapitulate key aspects of Epstein-Barr virus (EBV) infection in humans. Inoculation with approximately 1 x 10(3) TD(50) (50% transforming dose) of EBV caused B cell lymphoproliferative disorder, with histopathological findings and latent EBV gene expression remarkably similar to that in immunocompromised patients. Inoculation with a low dose of virus (
Systemic chronic active Epstein-Barr virus infection (sCAEBV) was defined as a T- or NK-cell neoplasm in the 2017 World Health Organization (WHO) classification. To clarify the clinical features of sCAEBV under this classification and review the effects of chemotherapy, we performed a nationwide survey in Japan from 2016 through 2018 of patients with sCAEBV newly diagnosed from January 2003 through March 2016. One hundred cases were evaluated. The patients were aged 1 to 78 years (median, 21) and included 53 males and 47 females. Spontaneous regression was not observed in patients with active disease. In the childhood-onset group (age, <9 years), 78% of the patients were male. In contrast, 85% of the patients in the elderly-onset group (age, >45 years) were female. The prognosis of the childhood-onset group was better than those of the adolescent/adult- and elderly-onset groups. The main chemotherapies used were a combination of cyclosporine A, steroids, and etoposide (cooling therapy) in 52 cases and cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) in 45 cases. The rate of complete response (CR), defined as complete resolution of disease activity, was 17% for cooling therapy and 13% for CHOP. Virological CR was not observed. The 3-year overall survival rates in patients treated with chemotherapy only (n = 20), chemotherapy followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT; n = 47), and allo-HSCT only (n = 12) were 0%, 65%, and 82%, respectively. Distinct characteristics were observed between childhood- and elderly-onset sCAEBV, and they appeared to be different disorders. Chemotherapy is currently insufficient to resolve disease activity and eradicate infected cells. The development of an effective treatment is urgently needed.
The expression of ets genes has been studied in mouse tissues and regenerating murine liver, an in vivo model for cell proliferation. Our results indicate that (i) the ets-1 and ets-2 loci are transcriptionally active; (ii) the ets-2 locus encodes a major mRNA (3.5 kilobases) and is expressed in most of the tissues examined, whereas the ets-l locus encodes a major 5.3-kilobase and minor 4.0-, 2.5-, and 2.2-kilobase RNA species and is expressed at a high level in thymus; (iii) both ets-1 and ets-2 mRNA are abundant in young proliferating tissues and are greatly reduced in terminally differentiated tissues, except thymus; (iv) compensatory growth of liver induces ets-2 mRNA before DNA synthesis, but after fos and myc induction; and (v) ets-2 mRNA, but not ets-1 mRNA, is stabilized in the presence of cycloheximide during hepatic regeneration. These results suggest that ets-2 gene expression is intrinsically linked with cell proliferation. Thus, ets-2 expression follows a pattern similar to other members of the nuclear oncogene family. During hepatic regeneration, the ets-1 and ets-2 loci are subject to differential regulation.Retroviral oncogenes are derived from normal cellular genes that may be actively involved in cell proliferation and differentiation. Avian erythroblastosis virus, E26, is a replication-defective virus that contains tripartite oncogenes Agag-mybE-ets-Aenv (1, 2). We have previously shown (3,4) that (i) v-ets has two cellular homologues, ets-J and ets-2, localized on two different chromosomes in higher mammals;(ii) the ets-l locus has been mapped to human chromosome 11, mouse chromosome 9, and feline chromosome Dl; the ets-2 locus has been assigned to human chromosome 21, mouse chromosome 16, and feline chromosome C2; (iii) both human ets-J and ets-2 loci are transcriptionally active; and (iv) in acute human leukemia, the ets-J locus has been translocated from chromosome 11 to 4 in t(4;11) (q21;23) region, whereas the ets-2 locus has been translocated from chromosome 21 to chromosome 8 in t(8;21) (q22;23), indicating ets gene products may play a significant role in leukemogenesis (refs. 5-8; for a review, see ref. 8). In contrast to the mammalian genes, the chicken proto-ets locus appears to be contiguous and encodes a major transcript of 7.5 kilobases (kb) (2,3).Using temperature-sensitive mutants of E26 virus, Beug et al. (9) have shown that the v-ets domain of the E26 virus retains the capacity to transform erythroblasts and fibroblasts in vitro. From these results, it has been concluded that products derived from the ets gene loci are involved in erythroid differentiation. However, as indicated, the ets loci in higher mammals are very complex. We do not know how many polypeptides are encoded by the ets gene loci and what function they perform in the cell. To understand the biological function and regulation of the ets genes in higher eukaryotes, we have studied the expression of the ets gene loci in various murine tissues and in liver following partial hepatectomy. Our results indica...
Humanized NOD/Shi-scid/interleukin-2Rgamma(null) (NOG) mice with full T cell development had significantly longer life span after Epstein-Barr virus (EBV) infection, compared with those with minimal T cell development. Removing CD3(+) or CD8(+) T cells from EBV-infected humanized mice by administration of anti-CD3 or anti-CD8 antibodies reduced their life span. CD8(+) T cells obtained from EBV-infected mice suppressed the outgrowth of autologous B cells isolated from uninfected mice and inoculated with EBV in vitro. These results indicate that humanized NOG mice are capable of T cell-mediated control of EBV infection and imply their usefulness as a tool to evaluate immunotherapeutic and prophylactic strategies for EBV infection.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.