title: Allogeneic T cells treated with amotosalen prevent lethal cytomegalovirus disease without producing graft-versus-host disease following bone marrow transplantation.
abstract: Infusion of donor antiviral T cells can provide protective immunity for recipients of hemopoietic progenitor cell transplants, but may cause graft-vs-host disease (GVHD). Current methods of separating antiviral T cells from the alloreactive T cells that produce GVHD are neither routine nor rapid. In a model of lethal murine CMV (MCMV) infection following MHC-mismatched bone marrow transplantation, infusion of MCMV-immune donor lymphocytes pretreated with the DNA cross-linking compound amotosalen prevented MCMV lethality without producing GVHD. Although 95% of mice receiving 30 x 10(6) pretreated donor lymphocytes survived beyond day +100 without MCMV disease or GVHD, all mice receiving equivalent numbers of untreated lymphocytes rapidly died of GVHD. In vitro, amotosalen blocked T cell proliferation without suppressing MCMV peptide-induced IFN-gamma production by MCMV-primed CD8(+) T cells. In vivo, pretreated lymphocytes reduced hepatic MCMV load by 4-log(10) and promoted full hemopoietic chimerism. Amotosalen-treated, MCMV tetramer-positive memory (CD44(high)) CD8(+) T cells persisted to day +100 following infusion, and expressed IFN-gamma when presented with viral peptide. Pretreated T cells were effective at preventing MCMV lethality over a wide range of concentrations. Thus, amotosalen treatment rapidly eliminates the GVHD activity of polyclonal T cells, while preserving long-term antiviral and graft facilitation effects, and may be clinically useful for routine adoptive immunotherapy.
authors.affiliation: Department of Pathology and Laboratory Medicine, Transfusion Medicine Program, Emory University School of Medicine, Atlanta, GA 30322, USA. jroback@emory.edu
authors.forename: John D
authors.initials: JD
authors.lastname: Roback
authors.forename: Mohammad S
authors.initials: MS
authors.lastname: Hossain
authors.forename: Levan
authors.initials: L
authors.lastname: Lezhava
authors.forename: John W
authors.initials: JW
authors.lastname: Gorechlad
authors.forename: Sabina A
authors.initials: SA
authors.lastname: Alexander
authors.forename: David L
authors.initials: DL
authors.lastname: Jaye
authors.forename: Stephen
authors.initials: S
authors.lastname: Mittelstaedt
authors.forename: Sohel
authors.initials: S
authors.lastname: Talib
authors.forename: John E
authors.initials: JE
authors.lastname: Hearst
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Hillyer
authors.forename: Edmund K
authors.initials: EK
authors.lastname: Waller
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects / Q000276:immunology* / Q000401:mortality; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D004306:Dose-Response Relationship, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage / Q000276:immunology; D011564:Furocoumarins / Q000627:therapeutic use*; D006086:Graft vs Host Disease / Q000276:immunology / Q000401:mortality / Q000517:prevention & control*; D006566:Herpesviridae Infections / Q000276:immunology* / Q000401:mortality / Q000517:prevention & control* / Q000821:virology; D006650:Histocompatibility Testing; D016219:Immunotherapy, Adoptive / Q000379:methods; D007371:Interferon-gamma / Q000096:biosynthesis; D007519:Isoantigens / Q000008:administration & dosage / Q000276:immunology; D051379:Mice; D020297:Mice, Congenic; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018146:Muromegalovirus / Q000187:drug effects / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000637:transplantation; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000637:transplantation*; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology; D019562:Viral Load; D014779:Virus Replication / Q000187:drug effects / Q000276:immunology
chemical_list: D018984:Epitopes, T-Lymphocyte; D011564:Furocoumarins; D007519:Isoantigens; D007371:Interferon-gamma; C118577:amotosalen