title: Recipient-specific tolerance after HLA-mismatched umbilical cord blood stem cell transplantation.
abstract: BACKGROUND
  Lower incidence and severity of acute graft versus host disease (GVHD) has been observed in leukemia patients receiving HLA-mismatched umbilical cord (UCB) transplants. However, despite the increased use of UCB in stem cell transplantation, the mechanisms underlying these favorable outcomes are not well delineated.
  
  
  METHODS
  We analyzed antigen specific lymphocyte responses after transplant to determine whether the decreased allogeneic responsiveness of UCB lymphocytes is attributable to pan-unresponsiveness, lymphocyte repressive or recipient-specific tolerance.
  
  
  RESULTS
  Circulating lymphocytes collected early (3 months) after UCB transplant demonstrate a less naïve phenotype compared with that in the infused graft. Additionally, after transplant, circulating peripheral blood UCB-derived lymphocytes produced normal levels of interferon-gamma and proliferated normally when stimulated with mitogen or third party alloantigen. In contrast, when stimulated with recipient antigen, circulating lymphocytes emerging posttransplant did not proliferate nor produce interferon-gamma. Moreover, analysis of interleukin-4 production revealed a Th2 response to recipient antigens. These data indicate early induction of immune tolerance of naïve UCB graft lymphocytes with skewing of transplant recipient-specific immune response towards Th2 cytokine profile.
  
  
  CONCLUSIONS
  UCB graft lymphocyte immune naivety and observed early tolerance induction may contribute to the observed favorable GVHD incidence, despite infusion of HLA mismatch grafts in the unrelated allogeneic setting.
authors.affiliation: Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106-7284, USA.
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Kleen
authors.forename: Suzanne
authors.initials: S
authors.lastname: Kadereit
authors.forename: Laura R
authors.initials: LR
authors.lastname: Fanning
authors.forename: Jennifer
authors.initials: J
authors.lastname: Jaroscak
authors.forename: Pingfu
authors.initials: P
authors.lastname: Fu
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Meyerson
authors.forename: Lara
authors.initials: L
authors.lastname: Kulchycki
authors.forename: Laura F
authors.initials: LF
authors.lastname: Slivka
authors.forename: Margaret
authors.initials: M
authors.lastname: Kozik
authors.forename: Magdalena
authors.initials: M
authors.lastname: Tary-Lehmann
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Laughlin
mesh_terms: D000328:Adult; D001782:Blood Donors; D001787:Blood Group Incompatibility / Q000276:immunology*; D005312:Fetal Blood; D006680:HLA Antigens / Q000097:blood; D006801:Humans; D007372:Interferons / Q000096:biosynthesis; D007959:Lymphocyte Culture Test, Mixed; D008214:Lymphocytes / Q000276:immunology; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology; D033581:Stem Cell Transplantation; D023001:Transplantation Tolerance
chemical_list: D006680:HLA Antigens; D007372:Interferons