title: Interaction of human mesenchymal stem cells with cells involved in alloantigen-specific immune response favors the differentiation of CD4+ T-cell subsets expressing a regulatory/suppressive phenotype.
abstract: OBJECTIVE
  Experimental evidence and preliminary clinical studies have demonstrated that human mesenchymal stem cells (MSC) have an important immune modulatory function in the setting of allogeneic hematopoietic stem cell (HSC) transplantation. We extended the evaluation of mechanisms responsible for the immune regulatory effect derived from the interaction of human MSC with cells involved in alloantigen-specific immune response in mixed lymphocyte culture (MLC).
  
  
  METHODS
  Dendritic cell (DC) differentiation, T- and natural killer (NK)-lymphocyte expansion, alloantigen-specific cytotoxic activity and differentiation of CD4+ T-cell subsets co-expressing CD25 and/or CTLA4 molecules were assessed, comparing the effect observed using third-party MSC with that obtained employing MSC autologous to the MLC responder.
  
  
  RESULTS
  We found that human MSC strongly inhibit alloantigen-induced DC1 differentiation, down-regulate alloantigen-induced lymphocyte expansion, especially that of CD8+ T cells and of NK lymphocytes, decrease alloantigen-specific cytotoxic capacity mediated by either cytotoxic T lymphocytes or NK cells and favor the differentiation of CD4+ T-cell subsets co-expressing CD25 and/or CTLA4. More effective suppressive activity on MLC-induced T-cell activation was observed when MSC were third-party, rather than autologous, with respect to MLC-responder cells.
  
  
  CONCLUSIONS
  Our results strongly suggest that MSC-mediated inhibition of alloantigen-induced DC1 differentiation and preferential activation of CD4+ CD25+ T-cell subsets with presumed regulatory activity represent important mechanisms contributing to the immunosuppressive activity of MSC. Collectively, these data provide immunological support for the use of MSC to prevent immune complications related to both HSC and solid organ transplantation and to the theory that MSC are universal suppressors of immune reactivity.
authors.affiliation: Laboratorio di Immunologia dei Trapianti, Oncoematologia Pediatrica, IRCCS Policlinico San Matteo, P.le Golgi 19, 27100 Pavia, Italy. r.maccario@smatteo.pv.it
authors.forename: Rita
authors.initials: R
authors.lastname: Maccario
authors.forename: Marina
authors.initials: M
authors.lastname: Podestà
authors.forename: Antonia
authors.initials: A
authors.lastname: Moretta
authors.forename: Angela
authors.initials: A
authors.lastname: Cometa
authors.forename: Patrizia
authors.initials: P
authors.lastname: Comoli
authors.forename: Daniela
authors.initials: D
authors.lastname: Montagna
authors.forename: Liane
authors.initials: L
authors.lastname: Daudt
authors.forename: Adalberto
authors.initials: A
authors.lastname: Ibatici
authors.forename: Giovanna
authors.initials: G
authors.lastname: Piaggio
authors.forename: Sarah
authors.initials: S
authors.lastname: Pozzi
authors.forename: Francesco
authors.initials: F
authors.lastname: Frassoni
authors.forename: Franco
authors.initials: F
authors.lastname: Locatelli
mesh_terms: D000917:Antibody Formation; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology*; D002450:Cell Communication; D002454:Cell Differentiation; D000939:Epitopes; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000235:genetics; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D007165:Immunosuppression Therapy; D007519:Isoantigens / Q000276:immunology*; D007959:Lymphocyte Culture Test, Mixed; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000276:immunology; D010641:Phenotype; D016176:T-Lymphocyte Subsets / Q000166:cytology*
chemical_list: D000939:Epitopes; D007519:Isoantigens