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/

C.B-17 scid/scid (severe combined immunodeficiency [SCID]) mice inocul ated with peripheral blood lymphocytes from Epstein-Barr virus (EBV)-s eropositive donors, or with EBV-transformed lymphoblastoid B cell line s (EBV-LCL), develop lethal human EBV(+) B cell lymphoproliferative di sorders (EBV-LPD) with characteristics similar to those arising in imm unodeficient patients. Using this model, we examined the capacity of h uman effector cells to control human EBV-LPD. SCID mice received rabbi t anti-asialo GM1 antiserum to abrogate endogenous natural killer-cell function. Preliminary experiments showed that adoptive transfer of pe ripheral 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 mic e (in vivo effector/target ratio 2:1 to 1:1). In contrast, EBV-specifi c cytotoxic T lymphocytes (CTL), derived from EBV-seropositive donors and expanded in vitro, exhibited strong EBV-specific and HLA-restricte d activity both in vitro and in vivo. SCID mice inoculated intraperito neally with autologous but not with HLA-mismatched EBV-LCL. had signif icantly improved survival relative to untreated mice after inoculation of EBV-specific CTL either intraperitoneally (P <0.001) or intravenou sly (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 a nimals or animals treated with IL-2 alone (P = 0.004 and P <0.02, resp ectively). SCID mice bearing two subcutaneous EBV(+) tumors, one autol ogous 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 ho ming of PKH26-labeled EBV-specific CTL to autologous but not to HLA-mi smatched EBV(+) tumors as early as 24 h after intravenous adoptive tra nsfer. Immnunophenotypic analyses also demonstrated preferential infil tration of T cells into the autologous EBV(+) tumor in SCID mice beari ng both the autologous and either fully HLA-mismatched or genotypicall y related haplotype-sharing EBV(+) tumors. The human T cells infiltrat ing EBV(+) tumors were CD3(+) and, predominantly, CD8(+)CD4(-). Our re sults indicate that EBV-specific CTL preferentially localize to and in filtrate EBV(+) tumors bearing the appropriate HLA antigens and therea fter induce targeted regressions of disease.