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 Journal Article

   

Authors:	Lacerda, J. F.; Ladanyi, M.; Louie, D. C.; Fernandez, J. M.; Papadopoulos, E. B.; O'Reilly, R. J.
Article 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 107 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 = 0.004 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 107 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.
Keywords:	survival; controlled study; human cell; nonhuman; cd3 antigen; cd8 antigen; t-lymphocytes; mouse; animals; mice; cell line; animal experiment; animal model; tumor regression; mice, scid; b-lymphocytes; lymphocyte activation; immunotherapy; xenograft; cytotoxic t lymphocyte; t-lymphocytes, cytotoxic; lymphoma; transplantation, heterologous; cell line, transformed; effector cell; cytotoxicity, immunologic; immunophenotyping; lymphoproliferative disease; cd4 antigen; antigens, cd; immune deficiency; hla-d antigens; t lymphocyte subpopulation; hla antigen; t lymphocyte activation; scid mouse; epstein barr virus; herpesvirus 4, human; lymphocyte transfusion; rabbits; humans; human; male; priority journal; article; callithrix
Journal Title:	Journal of Experimental Medicine
Volume:	183
Issue:	3
ISSN:	0022-1007
Publisher:	Rockefeller University Press
Date Published:	1996-03-01
Start Page:	1215
End Page:	1228
Language:	English
PUBMED:	8642263
PROVIDER:	scopus
PMCID:	PMC2192329
DOI:	10.1084/jem.183.3.1215
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-0029917128&partnerID=40&md5=c66e9bd0d51d9c8a8858ed8cb1aa5ce7
Notes:	Article -- Export Date: 22 November 2017 -- Source: Scopus

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