Abstract
BackgroundNon-obese diabetic (NOD) mice develop Sjögren's-like disease (SS-like) with loss of saliva flow and increased lymphocytic infiltrates in salivary glands (SGs). There are recent reports using multipotent mesenchymal stromal cells (MSCs) as a therapeutic strategy for autoimmune diseases due to their anti-inflammatory and immunomodulatory capabilities. This paper proposed a combined immuno- and cell-based therapy consisting of: A) an injection of complete Freund's adjuvant (CFA) to eradicate autoreactive T lymphocytes, and B) transplantations of MSCs to reselect lymphocytes. The objective of this was to test the effectiveness of CD45−/TER119− cells (MSCs) in re-establishing salivary function and in reducing the number of lymphocytic infiltrates (foci) in SGs. The second objective was to study if the mechanisms underlying a decrease in inflammation (focus score) was due to CFA, MSCs, or CFA+MSCs combined.Methodology/Principal FindingsDonor MSCs were isolated from bones of male transgenic eGFP mice. Eight week-old female NOD mice received one of the following treatments: insulin, CFA, MSC, or CFA+MSC (combined therapy). Mice were followed for 14 weeks post-therapy. CD45−/TER119− cells demonstrated characteristics of MSCs as they were positive for Sca-1, CD106, CD105, CD73, CD29, CD44, negative for CD45, TER119, CD11b, had high number of CFU-F, and differentiated into osteocytes, chondrocytes and adipocytes. Both MSC and MSC+CFA groups prevented loss of saliva flow and reduced lymphocytic infiltrations in SGs. Moreover, the influx of T and B cells decreased in all foci in MSC and MSC+CFA groups, while the frequency of Foxp3+ (Treg) cell was increased. MSC-therapy alone reduced inflammation (TNF-α, TGF-β), but the combination of MSC+CFA reduced inflammation and increased the regenerative potential of SGs (FGF-2, EGF).Conclusions/SignificanceThe combined use of MSC+CFA was effective in both preventing saliva secretion loss and reducing lymphocytic influx in salivary glands.
Highlights
Sjogren’s syndrome (SS) is a chronic autoimmune disease characterized by infiltrates of lymphocytes in the salivary glands [1,2]
The influx of T and B cells decreased in all foci in mesenchymal stromal cells (MSCs) and MSC+complete Freund’s adjuvant (CFA) groups, while the frequency of fork head box p3 (Foxp3)+ (Treg) cell was increased
Combined therapy (MSC+CFA) reduced inflammation and increased the regenerative potential of salivary glands (EGF, FGF2, IGF-IR). 4. Both MSC and combined therapy decreased the number of T and B cells in foci, while increasing regulatory T cells (Treg)
Summary
Sjogren’s syndrome (SS) is a chronic autoimmune disease characterized by infiltrates of lymphocytes in the salivary glands [1,2]. This paper proposed a combined immuno- and cell-based therapy consisting of: A) an injection of complete Freund’s adjuvant (CFA) to eradicate autoreactive T lymphocytes, and B) transplantations of MSCs to reselect lymphocytes. The objective of this was to test the effectiveness of CD452/TER1192 cells (MSCs) in re-establishing salivary function and in reducing the number of lymphocytic infiltrates (foci) in SGs. The second objective was to study if the mechanisms underlying a decrease in inflammation (focus score) was due to CFA, MSCs, or CFA+MSCs combined
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