Human mesenchymal stem cell-derived microvesicles modulate T cell response to islet antigen glutamic acid decarboxylase in patients with type 1 diabetes.
OBJECTIVE
Mesenchymal stem cells (MSCs) have been shown to abrogate in vitro the proinflammatory response in type 1 diabetes. The mechanism involves paracrine factors, which may include microvesicles (MVs). We evaluated whether MVs derived from heterologous bone-marrow MSCs exert an immunomodulatory effect on T cell responses against GAD (glutamic acid decarboxylase) antigen in type 1 diabetes.


METHODS
MVs were purified from heterologous human MSCs by differential centrifugation. Peripheral blood mononuclear cells (PBMCs) were obtained from patients with type 1 diabetes at disease onset, and responses to GAD65 stimulation were assessed by IFN-γ enzyme-linked immunosorbent spot analysis. Levels of cytokines and prostaglandin E2 (PGE2) were measured in the supernatant fraction, and T helper 17 (Th17) and regulatory T cell analysis was performed.


RESULTS
MVs were internalised by PBMCs, as assessed by confocal microscopy and flow cytometry analyses. MVs significantly decreased IFN-γ spots and levels in GAD65-stimulated PBMCs, and significantly increased transforming growth factor-β (TGF-β), IL-10, IL-6 and PGE2 levels. Furthermore, MVs decreased the number of Th17 cells and the levels of IL-17, and increased FoxP3(+) regulatory T cells in GAD65-stimulated PBMCs.


CONCLUSIONS
These results provide evidence that MSC-derived MVs can inhibit in vitro a proinflammatory response to an islet antigenic stimulus in type 1 diabetes. The action of MVs involves PGE2 and TGF-β signalling pathways and IL-10 secretion, suggesting a switch to an anti-inflammatory response of T cells.
Department of Medical Sciences, University of Turin, Corso Dogliotti 14, 10126, Turin, Italy.
Enrica
E
Favaro
Andrea
A
Carpanetto
Sara
S
Lamorte
Alberto
A
Fusco
Cristiana
C
Caorsi
Maria C
MC
Deregibus
Stefania
S
Bruno
Antonio
A
Amoroso
Mirella
M
Giovarelli
Massimo
M
Porta
Paolo Cavallo
PC
Perin
Ciro
C
Tetta
Giovanni
G
Camussi
Maria M
MM
Zanone
D000328:Adult; D016207:Cytokines / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D005260:Female; D005968:Glutamate Decarboxylase / Q000276:immunology*; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D055815:Young Adult
D016207:Cytokines; D005968:Glutamate Decarboxylase; D015232:Dinoprostone