title: T-cell suppression mediated by mesenchymal stem cells is deficient in patients with severe aplastic anemia.
abstract: OBJECTIVE
  To compare the suppressive effect of mesenchymal stem cells (MSC), derived from normal individuals or severe aplastic anemia patients (SAA), on T-cell activation.
  
  
  METHODS
  We studied bone marrow MSC from 19 healthy donors and 23 SAA patients in different phases of the disease: at diagnosis (n = 3), following immunosuppressive therapy (IS) (n = 16), or after a bone marrow transplant (BMT) (n = 4). MSC were tested for T-cell suppression in the following assays: mixed lymphocyte reaction (MLR), phytohemaglutinin (PHA)-primed cultures, activation surface markers, gamma-IFN production, hematopoietic colony formation (CFC), production of cyclic ADP-ribose (cADPR).
  
  
  RESULTS
  The abnormalities of SAA MSC included: 1) significantly lower suppression of T-cell proliferation induced by alloantigens (p = 0.009) or PHA (p = 0.006); 2) impaired capacity to suppress CD38 expression on PHA-primed T cells (p = 0.001); 3) impaired ability to suppress gamma-IFN production in PHA cultures, resulting in an 11-fold higher gamma-IFN concentration; 4) no preventive effect on T cell-mediated inhibition of CFC; and 5) significantly reduced (p = 0.009) production of cADPR, a universal calcium mobilizer. MSC-mediated suppression of PHA-induced T-cell proliferation was restored to control levels in 3 of 4 patients post-BMT.
  
  
  CONCLUSIONS
  The ability of MSC to downregulate T-cell priming, proliferation, and cytokine release is deficient in patients with SAA, persists indefinitely after immunosuppressive therapy, but seems to be restored after BMT. Whether these abnormalities are relevant to the pathogenesis of aplastic anemia remains to be determined.
authors.affiliation: Divisione Ematologia Ospedale San Martino, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Bacigalupo
authors.forename: Marisa
authors.initials: M
authors.lastname: Valle
authors.forename: Marina
authors.initials: M
authors.lastname: Podestà
authors.forename: Anna
authors.initials: A
authors.lastname: Pitto
authors.forename: Elena
authors.initials: E
authors.lastname: Zocchi
authors.forename: Antonio
authors.initials: A
authors.lastname: De Flora
authors.forename: Sara
authors.initials: S
authors.lastname: Pozzi
authors.forename: Silvia
authors.initials: S
authors.lastname: Luchetti
authors.forename: Francesco
authors.initials: F
authors.lastname: Frassoni
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Van Lint
authors.forename: Giovanna
authors.initials: G
authors.lastname: Piaggio
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000741:Anemia, Aplastic / Q000276:immunology* / Q000473:pathology*; D001854:Bone Marrow Cells / Q000166:cytology / Q000473:pathology; D016026:Bone Marrow Transplantation / Q000276:immunology; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D008648:Mesoderm / Q000502:physiology*; D008875:Middle Aged; D010835:Phytohemagglutinins; D012016:Reference Values; D013234:Stem Cells / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D010835:Phytohemagglutinins