Immunomodulation of the T-helper 17 Cell Lineage by Mesenchymal Stem Cells
Duffy, Michelle M.
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T-helper 17 (Th17) cells play a pathogenic role in multiple sclerosis, inflammatory bowel disease, psoriasis, acute kidney injury, glomerulonephritis and transplant rejection. Mesenchymal stem cells (MSCs) are immunosuppressive with potential to treat inflammatory and autoimmune disease. Natural and synthetic vitamin D receptor (VDR) agonists also have direct and indirect suppressive effects on T-helper differentiation pathways including Th17. The aim of this thesis was to investigate the effects of MSCs and the VDR agonist paricalcitol alone and in combination on Th17- mediated responses in vitro and in a mouse model of obstructive nephropathy, characterized by maladaptive Th17 responses - unilateral ureteral obstruction (UUO). MSCs potently suppressed naïve-phenotype responders undergoing primary Th17 differentiation but were less inhibitory towards memory-phenotype responders and had the potential to enhance IL-17A production by fully differentiated Th17 cells in the presence of IL-1 and IL-23. MSC-induced primary Th17 inhibition was mediated via induction of cyclooxygenase (COX)2 and subsequent prostaglandin E2 (PGE2)/EP4 signaling. This was associated with reduced expression of multiple key intracellular transcription factors including ROR gamma t, IRF4 and Runx1. Paricalcitolmediated suppression of Th17 differentiation occurred independently of antigen presenting cells and was associated with upregulation of the VDR. In UUO, MSCs and paricalcitol, alone and in combination suppressed Th17 responses in terms of IL-17A expression and neutrophil recruitment. This was associated with evidence of an alteration in the balance between pro- and anti-inflammatory macrophages in addition to reduced interstitial fibrosis and tubular atrophy. My results indicate the potential for MSCs to ameliorate tissue damage associated with maladaptive acute or chronic Th17 activation and suggest that adjunctive therapy with VDR agonists may represent a strategy for enhancing the immunosuppressive properties of MSCs.