title: Immune surveillance and therapy of lymphomas driven by Epstein-Barr virus protein LMP1 in a mouse model.
abstract: B cells infected by Epstein-Barr virus (EBV), a transforming virus endemic in humans, are rapidly cleared by the immune system, but some cells harboring the virus persist for life. Under conditions of immunosuppression, EBV can spread from these cells and cause life-threatening pathologies. We have generated mice expressing the transforming EBV latent membrane protein 1 (LMP1), mimicking a constitutively active CD40 coreceptor, specifically in B cells. Like human EBV-infected cells, LMP1+ B cells were efficiently eliminated by T cells, and breaking immune surveillance resulted in rapid, fatal lymphoproliferation and lymphomagenesis. The lymphoma cells expressed ligands for a natural killer (NK) cell receptor, NKG2D, and could be targeted by an NKG2D-Fc fusion protein. These experiments indicate a central role for LMP1 in the surveillance and transformation of EBV-infected B cells in vivo, establish a preclinical model for B cell lymphomagenesis in immunosuppressed patients, and validate a new therapeutic approach.
authors.affiliation: Program of Cellular and Molecular Medicine, Children's Hospital and Immune Disease Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Baochun
authors.initials: B
authors.lastname: Zhang
authors.forename: Sven
authors.initials: S
authors.lastname: Kracker
authors.forename: Tomoharu
authors.initials: T
authors.lastname: Yasuda
authors.forename: Stefano
authors.initials: S
authors.lastname: Casola
authors.forename: Matthew
authors.initials: M
authors.lastname: Vanneman
authors.forename: Cornelia
authors.initials: C
authors.lastname: Hömig-Hölzel
authors.forename: Zhe
authors.initials: Z
authors.lastname: Wang
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Derudder
authors.forename: Shuang
authors.initials: S
authors.lastname: Li
authors.forename: Tirtha
authors.initials: T
authors.lastname: Chakraborty
authors.forename: Shane E
authors.initials: SE
authors.lastname: Cotter
authors.forename: Shohei
authors.initials: S
authors.lastname: Koyama
authors.forename: Treeve
authors.initials: T
authors.lastname: Currie
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.forename: Jeffery L
authors.initials: JL
authors.lastname: Kutok
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Rodig
authors.forename: Glenn
authors.initials: G
authors.lastname: Dranoff
authors.forename: Klaus
authors.initials: K
authors.lastname: Rajewsky
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D004854:Herpesvirus 4, Human; D006801:Humans; D007157:Immunologic Surveillance; D007167:Immunotherapy; D008223:Lymphoma / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C037662:EBV-associated membrane antigen, Epstein-Barr virus; C527086:Klrk1 protein, mouse; D055655:NK Cell Lectin-Like Receptor Subfamily K; D014763:Viral Matrix Proteins