title: Mesenchymal stem cells together with mycophenolate mofetil inhibit antigen presenting cell and T cell infiltration into allogeneic heart grafts.
abstract: Donor-derived mesenchymal stem cells (MSC) can induce long-term acceptance in a rat heart transplantation model when injected prior to transplantation in combination with mycophenolate mofetil (MMF). In contrast, MSC alone cause accelerated graft rejection. To better understand these conflicting data we studied the effects of MSC and MMF on lymphocyte populations in heart allografts and secondary lymphatic organs. Allogeneic MSC injected prior to transplantation are immunogenic in this model because activated CD4+ and CD8+ cells emerged earlier in secondary lymphatic organs of MSC- and MSC/MMF-treated animals, compared to animals not treated with MSC. Consequently T cells infiltrated the grafts of MSC-only treated animals promptly causing accelerated graft rejection. However, few T cells or antigen-presenting cells (APC) infiltrated the grafts of animals treated with MSC and MMF. Consistent with this finding, intercellular adhesion molecule 1 (ICAM-1) and E-selectin was down-regulated exclusively in MSC/MMF-treated grafts, indicating that MSC together with MMF interfere with endothelial activation. Additionally, the presence of interferon-gamma (IFN-γ) enhanced MSC capabilities to suppress T cell proliferation in vitro. Interestingly, MMF did not influence serum IFN-γ levels in vivo. Together, our data indicate that MSC pre-activate T cells, but co-treatment with MMF eliminates these T cells, decreases intragraft APC and T cell trafficking by inhibiting endothelial activation, and allows IFN-γ stimulation of suppressive MSC.
authors.affiliation: Department of Surgery, University Medical Center Regensburg, Franz Josef Strauss Allee 11, 93053 Regensburg, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Eggenhofer
authors.forename: J F
authors.initials: JF
authors.lastname: Steinmann
authors.forename: P
authors.initials: P
authors.lastname: Renner
authors.forename: P
authors.initials: P
authors.lastname: Slowik
authors.forename: P
authors.initials: P
authors.lastname: Piso
authors.forename: E K
authors.initials: EK
authors.lastname: Geissler
authors.forename: H J
authors.initials: HJ
authors.lastname: Schlitt
authors.forename: M H
authors.initials: MH
authors.lastname: Dahlke
authors.forename: F C
authors.initials: FC
authors.lastname: Popp
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D019040:E-Selectin / Q000276:immunology / Q000378:metabolism*; D004729:Endothelium, Lymphatic / Q000187:drug effects / Q000378:metabolism; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D016027:Heart Transplantation / Q000276:immunology*; D007165:Immunosuppression Therapy / Q000379:methods; D007166:Immunosuppressive Agents / Q000276:immunology / Q000494:pharmacology; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology / Q000378:metabolism*; D007371:Interferon-gamma / Q000097:blood / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000276:immunology; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000276:immunology / Q000494:pharmacology; D051381:Rats; D011912:Rats, Inbred ACI; D011917:Rats, Inbred Lew
chemical_list: D019040:E-Selectin; D007166:Immunosuppressive Agents; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma; D009173:Mycophenolic Acid