A functional role for soluble HLA-G antigens in immune modulation mediated by mesenchymal stromal cells.
BACKGROUND
It has been suggested that soluble factors produced by bone marrow (BM) mesenchymal stromal cells (MSC) play a fundamental role in mediating immune modulation. HLA-G antigens (Ag) are major histocompatibility complex (MHC) class Ib molecules characterized by a limited polymorphism and a splicing mechanism that regulates the production of membrane-bound and soluble isoforms. Interleukin-10 (IL-10) cytokine is one of the main up-modulators of soluble HLA-G Ag (sHLA-G) production by CD14+ peripheral blood monocyte cells and increased IL-10 levels are reported to be associated with MSC immune modulation.


METHODS
We investigated, by specific enzyme-linked immunosorbent assay (ELISA), the possible role of sHLA-G molecules in the inhibition of the peripheral blood mononuclear cell (PBMC) response to phytohemagglutinin (PHA) mediated by MSC from different sources.


RESULTS
There was a significant correlation between the presence of increased levels of sHLA-G and IL-10 in the MSC/PBMC/PHA culture supernatants and lymphoproliferative inhibition. Neutralizing experiments performed with monoclonal Ab directed against HLA-G and IL-10 molecules confirmed the inhibitory ability of sHLA-G Ag. Furthermore, exogenous IL-10 induced sHLA-G molecule secretion by MSC alone in a polymorphic way, while a longitudinal analysis confirmed the loss of MSC inhibitory functions in relation to in vitro MSC aging.


CONCLUSIONS
Overall the results obtained suggest a functional role for sHLA-G molecules in inhibiting the PBMC response mediated by MSC. Moreover, the ability of IL-10 to induce sHLA-G Ag production by MSC alone could be proposed as a marker of MSC functional ability.
Rizzo
R
R
Department of Experimental and Diagnostic Medicine, Laboratory of Immunogenetics, Section of Medical Genetics, University of Ferrara, Ferrara, Italy.
Campioni
D
D
Stignani
M
M
Melchiorri
L
L
Bagnara
G P
GP
Bonsi
L
L
Alviano
F
F
Lanzoni
G
G
Moretti
S
S
Cuneo
A
A
Lanza
F
F
Baricordi
O R
OR
D000328:Adult; D000818:Animals; D000906:Antibodies / Q000276:immunology; D015703:Antigens, CD / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D005260:Female; D006680:HLA Antigens / Q000276:immunology*; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D007109:Immunity / Q000502:physiology*; D016130:Immunophenotyping; D016753:Interleukin-10 / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology; D008648:Mesoderm / Q000166:cytology*; D008875:Middle Aged; D017154:Stromal Cells / Q000166:cytology / Q000276:immunology*
D000906:Antibodies; D015703:Antigens, CD; D015415:Biomarkers; D006680:HLA Antigens; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I; D016753:Interleukin-10