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: Baochun Zhang, Sven Kracker, Tomoharu Yasuda, Stefano Casola, Matthew Vanneman, Cornelia Hömig-Hölzel, Zhe Wang, Emmanuel Derudder, Shuang Li, Tirtha Chakraborty, Shane E Cotter, Shohei Koyama, Treeve Currie, Gordon J Freeman, Jeffery L Kutok, Scott J Rodig, Glenn Dranoff, Klaus Rajewsky
• Journal: Cell (Cell) Vol. 148 Issue 4 Pg. 739-51 (Feb 17 2012) ISSN: 1097-4172 [Electronic] United States
• PMID: 22341446 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• EBV-associated membrane antigen, Epstein-Barr virus
• Klrk1 protein, mouse
• NK Cell Lectin-Like Receptor Subfamily K
• Viral Matrix Proteins

Topics

• Animals
• B-Lymphocytes (immunology, pathology)
• Disease Models, Animal
• Herpesvirus 4, Human
• Humans
• Immunologic Surveillance
• Immunotherapy
• Lymphoma (immunology, pathology, therapy)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• NK Cell Lectin-Like Receptor Subfamily K (immunology)
• T-Lymphocytes (immunology, pathology)
• Viral Matrix Proteins (genetics, metabolism)