Bone marrow transplantation is a valuable treatment option for patients with underlying hematological disorders. Unfortunately, complications associated with this course of treatment, such as graft versus host disease and graft failure, results in significant morbidity and mortality. Current clinical methodology relies mainly on the use of corticosteroids and pan-T-cell depletion to restrain these complications, however, their global immunosuppressive attributes, toxicity and increased relapse rate of certain cancers has prompted the search for improved therapies. The research described herein investigates novel cell-based methods that may be used in place of current therapies. More specifically, we investigate the use of mutipotent adult progenitor cells (MAPCs) and myeloid-derived suppressor cells (MDSC) for ameliorating acute graft versus host disease (aGVHD) and the use of mesenchymal stem cells (MSCs) for enhancing bone marrow engraftment. For GVHD, we find that both MAPCs and MDSCs have the capacity to inhibit allo-T-cell reactions in vitro using two distinct mechanisms. However, we find that when these cells are applied to a murine model of aGVHD, only MDSC express the appropriate homing molecules that allows them to traffic to sites of allogeneic T-cell recognition and activation, and therefore, only MDSC decrease GVHD-related mortality when administered i.v. Another major concern following BMT is BM engraftment failure. Currently, MSCs are employed in the clinic as means to promote or enhance BM engraftment, however, there is no definitive mechanism of action identified to be responsible for this effect. We find that MSCs secrete copious amounts of a molecule known to have a positive influence on hematopoietic stem cell (HSC) survival and proliferation, prostaglandin E2 (PGE2). We show that the secretion of PGE2 by MSCs increases the number and differentiation capacity of HSCs and also show that inhibiting the production of PGE2 from MSCs by using COX inhibitors reverses these effects. These data are the first to define a mechanism of action that MSCs use to promote BM engraftment. In conclusion, the cutting edge preclinical research described here has advanced the field of cell therapies following BMT and will hopefully be used to design clinical regimes aimed at improving the lives of patients in need.
University of Minnesota Ph.D. dissertation. June 2010. Major: Microbiology, Immunology and Cancer Biology. Advisor: Bruce R. Blazar, M.D. 1 computer file (PDF); x, 165 pages. Ill. (some col.)
Highfill, Steven Lorenz.
Advancing novel cell-based therapies for the prevention of graft versus host disease (GVHD) and improvement of engraftment following bone marrow transplantation..
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