Expansion of EBNA1-specific effector T cells in posttransplantation lymphoproliferative disorders

• Published in: Blood 2010-09, Vol.116 (13), p.2245-2252
• Main Authors: Jones, Kimberley, Nourse, Jamie P., Morrison, Leanne, Nguyen-Van, Do, Moss, Denis J., Burrows, Scott R., Gandhi, Maher K.
• Format: Article
• Language: English
• Subjects: Adult; Alleles; Base Sequence; Biological and medical sciences; Case-Control Studies; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - virology; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - virology; Child; DNA Primers - genetics; Epitopes - genetics; Epstein-Barr Virus Nuclear Antigens - genetics; Epstein-Barr Virus Nuclear Antigens - immunology; Female; Hematologic and hematopoietic diseases; Herpesvirus 4, Human - genetics; Herpesvirus 4, Human - immunology; HLA-B35 Antigen - genetics; Humans; Immunotherapy, Adoptive - methods; Infant, Newborn; Interferon-gamma - biosynthesis; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphoproliferative Disorders - etiology; Lymphoproliferative Disorders - immunology; Lymphoproliferative Disorders - therapy; Lymphoproliferative Disorders - virology; Lysosomal-Associated Membrane Protein 1 - biosynthesis; Lysosomal-Associated Membrane Protein 2 - biosynthesis; Male; Medical sciences; Middle Aged; Polymorphism, Genetic; T-Lymphocytes - immunology; T-Lymphocytes - virology; Transplants - adverse effects; Young Adult
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2010-03-274076

Immunosuppression resulting in impaired Epstein-Barr virus (EBV)–specific T-cell immunity is involved in the pathogenesis of EBV-positive post-transplantation lymphoproliferative disorder (EBV+ PTLD). Restoration of EBV-specific T-cell immunity by adoptive immunotherapy can induce remission. EBV-nuclear antigen-1 (EBNA1) is unique in being expressed in all cases of EBV+ PTLD. Recent data demonstrate that EBNA1 is not immunologically silent and can be exploited as a T-cell target. There are no data on EBNA1-specific T cells in PTLD. EBNA1-specific T cells capable of proliferation, interferon-γ release, and CD107a/b degranulation were assayed in 14 EBV+ PTLD diagnostic blood samples and 19 healthy controls. EBNA1-specific CD4+ T cells predominated and were expanded in 10 of 14 patients and 19 of 19 controls. Although human leukocyte antigen class I alleles influenced the magnitude of the response, EBNA1-specific CD8+ effector T cells were successfully generated in 9 of 14 EBV+ PTLD patients and 16 of 19 controls. The majority of PTLD patients had a polymorphism in an EBNA1 epitope, and T-cell recognition was greatly enhanced when EBNA1 peptides derived from the polymorphic epitope were used. These results indicate that EBNA1-specific T cells should be included in adoptive immunotherapy for PTLD. Furthermore, expansion protocols should use antigenic sequences from relevant EBV strains.