title: Amotosalen-treated donor T cells have polyclonal antigen-specific long-term function without graft-versus-host disease after allogeneic bone marrow transplantation.
abstract: We have previously shown that amotosalen HCl (S-59 psoralen)-treated donor splenocytes, which have limited proliferative capacity in vitro, can protect major histocompatibility complex-mismatched bone marrow transplant (BMT) recipients from lethal murine cytomegalovirus infection without causing graft-versus-host disease. In this study, we further investigated the effects of amotosalen-treated donor T cells on immune reconstitution after allogeneic BMT. We were surprised to find that amotosalen-treated donor T cells persisted long-term in vivo, comprising 6% to 10% on average of the T-cell compartment of transplant recipients at 4 months after transplantation. Donor T cells derived from amotosalen-treated splenocytes were predominantly polyclonal CD44 hi/int CD8 + memory T cells and were functionally active, synthesizing interferon gamma in response to stimulation with murine cytomegalovirus antigen. Amotosalen-treated donor T cells, reisolated from BMT recipients' spleens >/=4 months after transplantation, proliferated in vitro, thus indicating repair of amotosalen-mediated DNA cross-links. Compared with infusion of untreated donor splenocytes, amotosalen-treated cells enhanced thymopoiesis by bone marrow-derived stem cells in BMT recipients. However, amotosalen treatment abrogated the thymopoietic activity of lymphoid progenitor cells among the donor splenocytes. Thus, infusion of amotosalen-treated donor T cells produced rapid immune reconstitution after major histocompatibility complex-mismatched BMT by transferring long-lived polyclonal memory T cells with antiviral activity and also by enhancing bone marrow-derived thymopoiesis. This is a novel approach to adoptive immunotherapy in allogeneic BMT.
authors.affiliation: Department of Hematology and Oncology, Division of Stem Cell and Bone Marrow Transplantation, Winship Cancer Institute, Emory Universiy School of Medicine, Atlanta, Georgia, USA.
authors.forename: Mohammad Sohrab
authors.initials: MS
authors.lastname: Hossain
authors.forename: John D
authors.initials: JD
authors.lastname: Roback
authors.forename: Levan
authors.initials: L
authors.lastname: Lezhava
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 / Q000379:methods*; D016827:CD8 Antigens; D049109:Cell Proliferation; D011564:Furocoumarins / Q000494:pharmacology / Q000627:therapeutic use; D006086:Graft vs Host Disease / Q000517:prevention & control*; D018960:Hyaluronan Receptors; D007107:Immune System / Q000187:drug effects / Q000502:physiology; D007156:Immunologic Memory; D038041:Lymphopoiesis; D051379:Mice; D008815:Mice, Inbred Strains; D012038:Regeneration / Q000187:drug effects; D037182:T-Cell Antigen Receptor Specificity; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000637:transplantation; D013950:Thymus Gland / Q000166:cytology / Q000502:physiology; D014184:Transplantation, Homologous
chemical_list: D016827:CD8 Antigens; D011564:Furocoumarins; D018960:Hyaluronan Receptors; C118577:amotosalen