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Allogeneic T Cells Treated with Amotosalen Prevent Lethal Cytomegalovirus Disease without Producing Graft-versus-Host Disease Following Bone Marrow Transplantation ¹

John D. Roback^2,*,, Mohammad S. Hossain, Levan Lezhava^*, John W. Gorechlad, Sabina A. Alexander^*, David L. Jaye^*, Stephen Mittelstaedt, Sohel Talib, John E. Hearst, Christopher D. Hillyer^*,, and Edmund K. Waller

^* Department of Pathology and Laboratory Medicine, Transfusion Medicine Program, and Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322; and Cerus, Concord, CA 94520

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 10⁶ 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- production by MCMV-primed CD8⁺ T cells. In vivo, pretreated lymphocytes reduced hepatic MCMV load by 4-log₁₀ 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- 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.

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