Amotosalen-treated donor T cells have polyclonal antigen-specific long-term function without graft-versus-host disease after allogeneic bone marrow transplantation.
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.
Hossain
Mohammad Sohrab
MS
Department of Hematology and Oncology, Division of Stem Cell and Bone Marrow Transplantation, Winship Cancer Institute, Emory Universiy School of Medicine, Atlanta, Georgia, USA.
Roback
John D
JD
Lezhava
Levan
L
Hillyer
Christopher D
CD
Waller
Edmund K
EK
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
D016827:CD8 Antigens; D011564:Furocoumarins; D018960:Hyaluronan Receptors; C118577:amotosalen