title: Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation.
abstract: BACKGROUND
  Marrow stromal cells (MSC) can differentiate into multiple mesenchymal tissues. To assess the feasibility of human MSC transplantation, we evaluated the in vitro immunogenicity of MSC and their ability to function as alloantigen presenting cells (APC).
  
  
  METHODS
  Human MSC were derived and used in mixed cell cultures with allogeneic peripheral blood mononuclear cells (PBMC). Expression of immunoregulatory molecules on MSC was analyzed by flow cytometry. An MSC-associated suppressive activity was analyzed using cell-proliferation assays and enzyme-linked immunoassays.
  
  
  RESULTS
  MSC failed to elicit a proliferative response when cocultured with allogeneic PBMC, despite provision of a costimulatory signal delivered by an anti-CD28 antibody and pretreatment of MSC with gamma-interferon. MSC express major histocompatibility complex (MHC) class I and lymphocyte function-associated antigen (LFA)-3 antigens constitutively and MHC class II and intercellular adhesion molecule (ICAM)-1 antigens upon gamma-interferon treatment but do not express CD80, CD86, or CD40 costimulatory molecules. MSC actively suppressed proliferation of responder PBMC stimulated by third-party allogeneic PBMC as well as T cells stimulated by anti-CD3 and anti-CD28 antibodies. Separation of MSC and PBMC by a semipermeable membrane did not abrogate the suppression. The suppressive activity could not be accounted for by MSC production of interleukin-10, transforming growth factor-beta1, or prostaglandin E2, nor by tryptophan depletion of the culture medium.
  
  
  CONCLUSIONS
  Human MSC fail to stimulate allogeneic PBMC or T-cell proliferation in mixed cell cultures. Unlike other nonprofessional APC, this failure of function is not reversed by provision of CD28-mediated costimulation nor gamma-interferon pretreatment. Rather, MSC actively inhibit T-cell proliferation, suggesting that allogeneic MSC transplantation might be accomplished without the need for significant host immunosuppression.
authors.affiliation: Division of Hematology/Oncology, Children's Hospital, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. william.tse@tch.harvard.edu.
authors.forename: William T
authors.initials: WT
authors.lastname: Tse
authors.forename: John D
authors.initials: JD
authors.lastname: Pendleton
authors.forename: Wendy M
authors.initials: WM
authors.lastname: Beyer
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Egalka
authors.forename: Eva C
authors.initials: EC
authors.lastname: Guinan
mesh_terms: D017209:Apoptosis / Q000276:immunology; D001854:Bone Marrow Cells / Q000166:cytology*; D016026:Bone Marrow Transplantation; D018106:CD28 Antigens / Q000276:immunology; D002450:Cell Communication / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D015232:Dinoprostone / Q000276:immunology; D006801:Humans; D007165:Immunosuppression Therapy; D016753:Interleukin-10 / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D017154:Stromal Cells / Q000166:cytology* / Q000637:transplantation*; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000276:immunology; D053773:Transforming Growth Factor beta1
chemical_list: D018106:CD28 Antigens; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D016753:Interleukin-10; D015232:Dinoprostone