title: Heart grafts tolerized through third-party multipotent adult progenitor cells can be retransplanted to secondary hosts with no immunosuppression.
abstract: Multipotent adult progenitor cells (MAPCs) are an adherent stem cell population that belongs to the mesenchymal-type progenitor cell family. Although MAPCs are emerging as candidate agents for immunomodulation after solid organ transplantation, their value requires further validation in a clinically relevant cell therapy model using an organ donor- and organ recipient-independent, third-party cell product. We report that stable allograft survival can be achieved following third-party MAPC infusion in a rat model of fully allogeneic, heterotopic heart transplantation. Furthermore, long-term accepted heart grafts recovered from MAPC-treated animals can be successfully retransplanted to naïve animals without additional immunosuppression. This prolongation of MAPC-mediated allograft acceptance depends upon a myeloid cell population since depletion of macrophages by clodronate abrogates the tolerogenic MAPC effect. We also show that MAPC-mediated allograft acceptance differs mechanistically from drug-induced tolerance regarding marker gene expression, T regulatory cell induction, retransplantability, and macrophage dependence. MAPC-based immunomodulation represents a promising pathway for clinical immunotherapy that has led us to initiate a phase I clinical trial for testing safety and feasibility of third-party MAPC therapy after liver transplantation.
authors.affiliation: Department of Surgery, University Hospital Regensburg, Regensburg, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Eggenhofer
authors.forename: Felix C
authors.initials: FC
authors.lastname: Popp
authors.forename: Michael
authors.initials: M
authors.lastname: Mendicino
authors.forename: Paula
authors.initials: P
authors.lastname: Silber
authors.forename: Wouter
authors.initials: W
authors.lastname: Van't Hof
authors.forename: Philipp
authors.initials: P
authors.lastname: Renner
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Hoogduijn
authors.forename: Jef
authors.initials: J
authors.lastname: Pinxteren
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.forename: Edward K
authors.initials: EK
authors.lastname: Geissler
authors.forename: Robert
authors.initials: R
authors.lastname: Deans
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Schlitt
authors.forename: Marc H
authors.initials: MH
authors.lastname: Dahlke
mesh_terms: D053687:Adult Stem Cells / Q000166:cytology* / Q000187:drug effects; D000818:Animals; D048429:Cell Size / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology*; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology*; D007165:Immunosuppression Therapy; D008285:Major Histocompatibility Complex / Q000276:immunology; D039902:Multipotent Stem Cells / Q000166:cytology* / Q000187:drug effects; D022423:Myeloid Cells / Q000166:cytology / Q000187:drug effects; D010641:Phenotype; D051381:Rats; D011917:Rats, Inbred Lew; D033581:Stem Cell Transplantation; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects; D014184:Transplantation, Homologous / Q000276:immunology
chemical_list: D016572:Cyclosporine
keywords: Immunosuppression; Mesenchymal stem cells; T cells; Transplantation