title: Human Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes home preferentially to and induce selective regressions of autologous EBV-induced B cell lymphoproliferations in xenografted C.B-17 scid/scid mice.
abstract: C.B-17 scid/scid (severe combined immunodeficiency [SCID]) mice inoculated with peripheral blood lymphocytes from Epstein-Barr virus (EBV)-seropositive donors, or with EBV-transformed lymphoblastoid B cell lines (EBV-LCL), develop lethal human EBV+ B cell lymphoproliferative disorders (EBV-LPD) with characteristics similar to those arising in immunodeficient patients. Using this model, we examined the capacity of human effector cells to control human EBV-LPD. SCID mice received rabbit anti-asialo GM1 antiserum to abrogate endogenous natural killer-cell function. Preliminary experiments showed that adoptive transfer of peripheral blood mononuclear cells (PBMC), purified T cells, interleukin (IL) 2-activated PBMC or anti-CD3-activated T cells derived from EBV-seropositive donors did not result in improved survival of treated mice (in vivo effector/target ratio 2:1 to 1:1). In contrast, EBV-specific cytotoxic T lymphocytes (CTL), derived from EBV-seropositive donors and expanded in vitro, exhibited strong EBV-specific and HLA-restricted activity both in vitro and in vivo. SCID mice inoculated intraperitoneally with autologous but not with HLA-mismatched EBV-LCL had significantly improved survival relative to untreated mice after inoculation of EBV-specific CTL either intraperitoneally (P<0.001) or intravenously (P<0.001) (in vivo effector/target ratio 1:1). SCID mice bearing large subcutaneous EBV+ tumors and treated intravenously with 10(7) EBV-specific CTL achieved complete tumor regression. Both CTL- and CTL-plus-IL-2-treated mice survived significantly longer than untreated animals or animals treated with IL-2 alone (P = 0.0004 and P<0.02, respectively). SCID mice bearing two subcutaneous EBV+ tumors, one autologous and the other HLA mismatched to the EBV-specific CTL donor, had regression of only the autologous tumor after intravenous infusion of 10(7) EBV-specific CTL. Moreover, we could demonstrate preferential homing of PKH26-labeled EBV-specific CTL to autologous but not to HLA-mismatched EBV+ tumors as early as 24 h after intravenous adoptive transfer. Immunophenotypic analyses also demonstrated preferential infiltration of T cells into the autologous EBV+ tumor in SCID mice bearing both the autologous and either fully HLA-mismatched or genotypically related haplotype-sharing EBV+ tumors. The human T cells infiltrating EBV+ tumors were CD3+ and, predominantly, CD8+CD4-. Our results indicate that EBV-specific CTL preferentially localize to and infiltrate EBV+ tumors bearing the appropriate HLA antigens and thereafter induce targeted regressions of disease.
authors.affiliation: Department of Pediatrics and Medicine, Memorial Sloan-Kettering Cancer Center, New York 10021, USA.
authors.forename: J F
authors.initials: JF
authors.lastname: Lacerda
authors.forename: M
authors.initials: M
authors.lastname: Ladanyi
authors.forename: D C
authors.initials: DC
authors.lastname: Louie
authors.forename: J M
authors.initials: JM
authors.lastname: Fernandez
authors.forename: E B
authors.initials: EB
authors.lastname: Papadopoulos
authors.forename: R J
authors.initials: RJ
authors.lastname: O'Reilly
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D001402:B-Lymphocytes / Q000276:immunology; D002144:Callithrix; D002460:Cell Line; D002461:Cell Line, Transformed; D003602:Cytotoxicity, Immunologic; D006681:HLA-D Antigens / Q000032:analysis; D004854:Herpesvirus 4, Human / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation; D017710:Lymphocyte Transfusion; D008223:Lymphoma / Q000276:immunology* / Q000473:pathology*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D011817:Rabbits / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014183:Transplantation, Heterologous
chemical_list: D015703:Antigens, CD; D006681:HLA-D Antigens