Donor antigen-presenting cells regulate T-cell expansion and antitumor activity after allogeneic bone marrow transplantation.
Delayed immunologic recovery after allogeneic bone marrow transplantation (BMT) represents a major cause of morbidity and mortality that limits the overall success of the transplantation procedure. Recent clinical data suggest that a subset of donor dendritic cells may inhibit the graft-versus-tumor activity of donor T cells. We studied the immunoregulatory activity of donor dendritic cells in allogeneic BMT between major histocompatibility complex-disparate strains of mice. Bone marrow grafts enriched or depleted of CD11b- and CD11b+ dendritic cell subsets by immunomagnetic cell sorting were combined with small numbers of congenic splenic T cells. Recipients of CD11b-depleted bone marrow had significant posttransplantation expansion of donor spleen-derived CD4+ memory T cells compared with recipients of unmanipulated bone marrow. CD11b depletion enhanced the antitumor activity of the splenic donor T cells without producing significant graft-versus-host disease and resulted in long-term survival after a supralethal dose of T-cell leukemia administered after BMT. Expansion of donor spleen-derived T cells was proportional to the number of CD11b- dendritic cells in the bone marrow graft and was associated with increased levels of serum interferon-gamma. Thus, manipulating the content of donor antigen-presenting cells in allogeneic BMT is a novel strategy to activate donor memory T cells and enhance allogeneic graft-versus-leukemia effects with minimal graft-versus-host disease.
Division of Hematology and Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Jian-Ming
JM
Li
Edmund K
EK
Waller
D000818:Animals; D000938:Antigen-Presenting Cells / Q000737:chemistry / Q000166:cytology / Q000276:immunology*; D015703:Antigens, CD / Q000032:analysis; D001773:Blood Cells / Q000166:cytology / Q000276:immunology; D001854:Bone Marrow Cells / Q000737:chemistry / Q000166:cytology; D016026:Bone Marrow Transplantation / Q000276:immunology*; D039481:CD11b Antigen / Q000032:analysis; D016516:CD4-CD8 Ratio; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D002469:Cell Separation; D003713:Dendritic Cells / Q000737:chemistry / Q000166:cytology / Q000276:immunology; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000276:immunology / Q000401:mortality / Q000473:pathology; D020544:Graft vs Leukemia Effect / Q000276:immunology*; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000097:blood / Q000378:metabolism; D007938:Leukemia / Q000276:immunology / Q000473:pathology / Q000628:therapy; D008099:Liver / Q000276:immunology / Q000473:pathology; D018655:Lymphocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000166:cytology; D015996:Survival Rate; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000637:transplantation; D014181:Transplantation Immunology / Q000276:immunology; D014184:Transplantation, Homologous
D015703:Antigens, CD; D039481:CD11b Antigen; D007371:Interferon-gamma