title: CD4+CD25+FOXP3+ T regulatory cells reconstitute and accumulate in the bone marrow of patients with multiple myeloma following allogeneic stem cell transplantation.
abstract: BACKGROUND
  Very little is known about the number and function of immunosuppressive CD4(+)CD25(+)FOXP3(+) T regulatory cells (Treg) in the human bone marrow and it is unclear whether bone marrow-residing Treg are capable of regenerating following allogeneic stem cell transplantation. This is particularly surprising since the bone marrow represents a major priming site for T-cell responses and Treg play important roles in the prevention of T-cell-mediated graft-versus-host disease and in promoting tumor escape from T-cell-dependent immunosurveillance.
  
  
  METHODS
  Applying flow cytometry, real-time polymerase chain reaction, and functional assays, we performed the first study on bone marrow and peripheral blood Treg in healthy donors as well as multiple myeloma patients before and after allogeneic stem cell transplantation.
  
  
  RESULTS
  We found that, following the allogeneic transplantation, donor-derived CD4(+)CD25(+)FOXP3(+) Treg expanded faster than conventional CD4(+) T cells, leading to an accumulation of Treg in the bone marrow of transplanted patients who lack relevant thymic function. The reconstituted bone marrow-residing CD4(+)CD25(+)FOXP3(+) Treg of myeloma patients after allogeneic stem cell transplantation consisted preferably of CD45RA(-)CCR7(-) memory T-cells and contained low numbers of T-cell receptor excision cycles, indicating that Treg had indeed expanded outside the thymus. Importantly, bone marrow-residing Treg of newly diagnosed and myeloma patients after allogeneic stem cell transplantation expressed high levels of transforming growth factor beta and cytotoxic T-lymphocyte antigen 4, and showed a strong inhibitory function.
  
  
  CONCLUSIONS
  We suggest that allogeneic stem cell transplantation provides a short but significant window of opportunity for CD8(+) T cells before an exuberant regeneration of immunosuppressive Treg sets in. Later after transplantation, bone marrow-residing Treg probably contribute to suppressing graft-versus-host disease but may also undermine persistent immune control of multiple myeloma.
authors.affiliation: Department of Medicine II, Oncology/Hematology, University Medical Center, Hamburg-Eppendorf Martinistr. 52, 20246 Hamburg, Germany. d.atanackovic@uke.uni-hamburg.de
authors.forename: Djordje
authors.initials: D
authors.lastname: Atanackovic
authors.forename: Yanran
authors.initials: Y
authors.lastname: Cao
authors.forename: Tim
authors.initials: T
authors.lastname: Luetkens
authors.forename: Jens
authors.initials: J
authors.lastname: Panse
authors.forename: Christiane
authors.initials: C
authors.lastname: Faltz
authors.forename: Julia
authors.initials: J
authors.lastname: Arfsten
authors.forename: Katrin
authors.initials: K
authors.lastname: Bartels
authors.forename: Christine
authors.initials: C
authors.lastname: Wolschke
authors.forename: Thomas
authors.initials: T
authors.lastname: Eiermann
authors.forename: Axel R
authors.initials: AR
authors.lastname: Zander
authors.forename: Boris
authors.initials: B
authors.lastname: Fehse
authors.forename: Carsten
authors.initials: C
authors.lastname: Bokemeyer
authors.forename: Nicolaus
authors.initials: N
authors.lastname: Kroger
mesh_terms: D015703:Antigens, CD / Q000096:biosynthesis; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001853:Bone Marrow / Q000276:immunology* / Q000473:pathology; D015704:CD4 Antigens / Q000032:analysis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D060908:CTLA-4 Antigen; D003131:Combined Modality Therapy; D005260:Female; D051858:Forkhead Transcription Factors / Q000032:analysis; D006086:Graft vs Host Disease / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007156:Immunologic Memory; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy / Q000473:pathology* / Q000601:surgery; D016879:Salvage Therapy; D016176:T-Lymphocyte Subsets / Q000737:chemistry / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000737:chemistry / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D014184:Transplantation, Homologous
chemical_list: D015703:Antigens, CD; D015704:CD4 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053645:Interleukin-2 Receptor alpha Subunit; D016212:Transforming Growth Factor beta