title: Multipotent adult progenitor cells can suppress graft-versus-host disease via prostaglandin E2 synthesis and only if localized to sites of allopriming.
abstract: Multipotent adult progenitor cells (MAPCs) are nonhematopoietic stem cells capable of giving rise to a broad range of tissue cells. As such, MAPCs hold promise for tissue injury repair after transplant. In vitro, MAPCs potently suppressed allogeneic T-cell activation and proliferation in a dose-dependent, cell contact-independent, and T-regulatory cell-independent manner. Suppression occurred primarily through prostaglandin E(2) synthesis in MAPCs, which resulted in decreased proinflammatory cytokine production. When given systemically, MAPCs did not home to sites of allopriming and did not suppress graft-versus-host disease (GVHD). To ensure that MAPCs would colocalize with donor T cells, MAPCs were injected directly into the spleen at bone marrow transplantation. MAPCs limited donor T-cell proliferation and GVHD-induced injury via prostaglandin E(2) synthesis in vivo. Moreover, MAPCs altered the balance away from positive and toward inhibitory costimulatory pathway expression in splenic T cells and antigen-presenting cells. These findings are the first to describe the immunosuppressive capacity and mechanism of MAPC-induced suppression of T-cell alloresponses and illustrate the requirement for MAPC colocalization to sites of initial donor T-cell activation for GVHD inhibition. Such data have implications for the use of allogeneic MAPCs and possibly other immunomodulatory nonhematopoietic stem cells for preventing GVHD in the clinic.
authors.affiliation: University of Minnesota Masonic Cancer Center and Department of Pediatrics, Division of Bone Marrow Transplantation, 420 Delaware Street SE, Minneapolis, MN 55455, USA.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Highfill
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Kelly
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: O'Shaughnessy
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhou
authors.forename: Lily
authors.initials: L
authors.lastname: Xia
authors.forename: Angela
authors.initials: A
authors.lastname: Panoskaltsis-Mortari
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Taylor
authors.forename: Jakub
authors.initials: J
authors.lastname: Tolar
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
mesh_terms: D053687:Adult Stem Cells / Q000276:immunology / Q000637:transplantation; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D016026:Bone Marrow Transplantation / Q000379:methods; D002465:Cell Movement; D015232:Dinoprostone / Q000096:biosynthesis*; D006086:Graft vs Host Disease / Q000517:prevention & control* / Q000628:therapy; D008213:Lymphocyte Activation; D051379:Mice; D039902:Multipotent Stem Cells / Q000276:immunology* / Q000637:transplantation; D013154:Spleen
chemical_list: D015232:Dinoprostone