Treatment Of Experimental Arthritis By Downregulatingthe Level Of Thl7Cell With Human Uc-de Irved Mesenchymal Stem Cells

BackgroundRheumatoid arthritis (RA) is a autoimmune disease caused by loss ofimmunologic self tolerance and characterized by chronic joint inflammation anddestruction.In this course,Th cells play a pivot role in both cellular defence againstpathogens and in cellular self-tolerance.The activation of Th cells is a crucial factor inthe prosess of a immune response.The Th17cells worsen the process of inflammationand joints destruction in RA. It is believe that Th17are very important in the courseof disease with Rheumatoid arthritis.Mesenchymal stem cells(MSCs)are identifiedfirst in bone marrow.Nevertheless,they are able to differentiate into various types ofcells under certain conditions. In addition,MSCs and their progenies are importantsupporting cells in bone marrow microenvironment. They can generate cytokines andcell surface signals during the prosses of modulating the survival, proliferation, anddifferentiation of most hematopietic cells. Adult mesenchymal stem cells (MSCs)have been found to suppress effector T cell responses.They have beneficial effectson the treatment of various immune disorders. Based on the above observation,aneffective therapy for Rheumatoid Arthritis has been discovered. The effect of humanderived MSCs on Th17cells needs further investigation.OBJECTIVEMesenchymal stem cells (MSCs) have been found to suppress effector T cellresponses.They have beneficial effects on the treatment of various immunedisorders. The purpose of this study was to explore a new therapeutic strategy throughdown-regulating the level of Th17for RA based on the administration of humanumbilical cord–derived MSCs (hUC-MSCs).METHODS:1. hUC-MSCs were isolated from human umbilical cord and purified by adherent andcultured in vitro. Morphology,immunophenotype, proliferative property and differentiation of hUC-MSCs were measured and analyzed.2. To explore the potential effect of MSCs derived-human umbilical cord oncollagen-induced arthritis （CIA）.S.D rat with CIA were treated with humanUC-MSCs after disease courses at different dose. The clinical scores were determined.Inflammatory response was determined by measuring the levels of different mediatorsof inflammation in the joints, serum and spleed. The Th17-mediated autoreactiveresponse was evaluated by determining the level of ROR-γt and cytokine profile.3. In vitro co-culture system, UC-MSCs were observed to regulat the level ofROR-γt and cytokine profile in periphery blood mononuclear cell.RESULTS:1.The culture expanded cells from human umbilical cord-derived mesenchymal stemcells presented a typical fibroblast-like morphology.Cells were positive forCD105,CD44and CD29, but negative for CD45.2.Systemic infusion of human UC-MSCs significantly reduced the incidence andseverity of experimental arthritis. This therapeutic effect was mediated by down-regulating Th17deleterious disease components: the Th17-driven autoimmune andinflammatory responses. Human UC-MSCs decreased the production of variousinflammatory cytokines and chemokines, decreased antigen-specific Th17cellexpansion, and induced the production of inflammatory interleukin-17in spleen,serum and joints.3.UC-MSCs significantly inhibited the expression of ROR-γt in vitro and coulddown-regulating the level of IL-17on RA with DAS28>5.1.CONCLUSION: Human UC-MSCs emerge as key regulators of immune tolerance byinducing the generation of Th17cells and are thus attractive candidates for acell-based therapy for RA.