Submitted March 30, 2009
Accepted May 17, 2009
Multipotent adult progenitor cells (MAPC) can suppress graft-versus-host disease via prostaglandin E2 synthesis and only if localized to sites of allopriming
Steven L. Highfill, Ryan M. Kelly, Matthew J. O'Shaughnessy, Qing Zhou, Lily Xia, Angela Panoskaltsis-Mortari, Patricia A. Taylor, Jakub Tolar, and Bruce R. Blazar*
University of Minnesota Masonic Cancer Center and Department of Pediatrics, Division of Bone Marrow Transplantation, Minneapolis, MN, United States
* Corresponding author; email: blaza001{at}umn.edu.
Multipotent adult progenitor cells (MAPCs) are non-hematopoietic stem cells capable of giving rise to a broad range of tissue cells. As such, MAPCs hold promise for tissue injury repair post-transplant. In vitro, MAPCs potently suppressed allogeneic T-cell activation and proliferation in a dose-dependent, cell contact-independent and Tregulatory cell independent manner. Suppression occurred primarily through prostaglandin E2 (PGE2) 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 GVHD. To ensure that MAPCs would co-localize with donor T-cells, MAPCs were injected directly into the spleen at BMT. MAPCs limited donor T-cell proliferation and GVHD-induced injury via PGE2 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 (APCs). 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 co-localization to site of initial donor T-cell activation for GVHD inhibition. Such data have implications for the use of allogeneic MAPCs and possibly other immunomodulatory non-hematopoietic stem cells for preventing GVHD in the clinic.
