Title |
Mesenchymal stem cells and a vitamin D receptor agonist additively suppress T helper 17 cells and the related inflammatory response in the kidney
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Published in |
American Journal of Physiology: Renal, Fluid & Electrolyte Physiology, October 2014
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DOI | 10.1152/ajprenal.00024.2014 |
Pubmed ID | |
Authors |
Michelle M Duffy, Bairbre A McNicholas, David A Monaghan, Shirley A Hanley, Jill M McMahon, Jana Pindjakova, Senthilkumar Alagesan, Howard O Fearnhead, Matthew D Griffin |
Abstract |
Mesenchymal stem cells (MSCs) suppress T-helper (Th)-17 cell differentiation and are being pursued clinically for the treatment of conditions associated with aberrant Th17 responses. Whether such immunomodulatory effects are enhanced by co-administration of MSCs with other agents is not well known. In this study, the individual and combined effects of MSCs and the vitamin D receptor (VDR) agonist paricalcitol on Th17 induction were investigated in vitro and in a mouse model of sterile kidney inflammation (unilateral ureteral obstruction). In-vitro, MSCs and paricalcitol additively suppressed Th17 differentiation although only MSCs suppressed expression of Th17-associated transcriptions factors. The combined administration of MSCs and paricalcitol resulted in early (day 3) reduction of intra-renal CD4(+) and CD8(+) T-cells, CD11b(+)/Ly6G(+) neutrophils and inflammatory (Ly6C(hi)) monocytes as well as reduced transcript for IL-17. Later (day 8), obstructed kidneys of MSC and paricalcitol double-treated, but not single-treated, mice had reduced tubular injury and interstitial fibrosis as well as lower numbers of neutrophils and inflammatory monocytes and an increase in the ratio between M2 (CD206(+)) and M1 (CD206(-)) macrophages compared to controls. Adjunctive therapy with VDR agonists may represent a strategy for enhancing the immunosuppressive properties of MSCs in the setting of pathogenic Th17-type immune responses and related inflammatory responses. |
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