Abstract
IntroductionThe immunological and homing properties of mesenchymal stem cells (MSCs) provide a potentially attractive treatment for arthritis. The objective of this study was to determine effects of genetic disparity on the immunosuppressive potential of MSCs in vitro and in vivo within collagen induced arthritis (CIA).MethodsThe ability of DBA/1, FVB and BALB/c MSC preparations to impact the cytokine release profile of CD3/CD28 stimulated DBA/1 T cells was assessed in vitro. The effect of systemically delivered MSCs on the progression of CIA and cytokine production was assessed in vivo.ResultsAll MSC preparations suppressed the release of TNFα and augmented the secretion of IL-4 and IL-10 by stimulated DBA/1 T-cells. However, assessment of the ratio of IFNγ to IL-4 production indicated that the more genetically distant BALB/c MSCs had significantly less immunosuppressive capacity. Systemic delivery of BALB/c MSC resulted in an exacerbation of CIA disease score in vivo and a higher erosive disease burden. This was not seen after treatment with syngeneic or partially mismatched MSCs. An increase in serum levels of IL-1β was observed up to 20 days post treatment with allogeneic MSCs. An initial elevation of IL-17 in these treatment groups persisted in those treated with fully mismatched BALB/c MSCs. Over the course of the study, there was a significant suppression of serum IL-17 levels in groups treated with syngeneic MSCs.ConclusionsThese data demonstrate a significant difference in the immunosuppressive properties of syngeneic and allogeneic MSCs in vitro and in vivo, which needs to be appreciated when developing MSC based therapies for inflammatory arthritis.
Highlights
The immunological and homing properties of mesenchymal stem cells (MSCs) provide a potentially attractive treatment for arthritis
IL-1b has been implicated in both Rheumatoid Arthritis (RA) and collagen induced arthritis (CIA); it is known to have a pro-inflammatory role in CIA which is independent of IL-17 and inhibition with an IL1 receptor antagonist results in amelioration of arthritis [15,16]
All three MSCs preparations were over 95% positive for CD29 and CD44
Summary
The immunological and homing properties of mesenchymal stem cells (MSCs) provide a potentially attractive treatment for arthritis. The inflamed synovium is populated with CD4+ T lymphocytes, B cells, macrophages and synovial like fibroblasts which elaborate pathophysiologically important cytokines including TNFa, IL-1, IL-4, IL-10 and IL-17 [1,2,3]. While TNFa produced by macrophages is at the center of a complex cytokine network in inflammatory arthritis, it is well established that CD4+ T cells play an important role in orchestrating and maintaining this immune response. IL-17 is produced by a subset of memory CD4+ T lymphocytes termed Th17 cells and plays a critical role in CIA, having a synergistic effect with TNFa in promoting poor disease outcome [12,13,14]. The role of anti-inflammatory cytokines in CIA is less clear; IL-4 can inhibit production of TNFa and reduce T cell proliferation [2]
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