T-cell suppression mediated by mesenchymal stem cells is deficient in patients with severe aplastic anemia.
OBJECTIVE
To compare the suppressive effect of mesenchymal stem cells (MSC), derived from normal individuals or severe aplastic anemia patients (SAA), on T-cell activation.


METHODS
We studied bone marrow MSC from 19 healthy donors and 23 SAA patients in different phases of the disease: at diagnosis (n = 3), following immunosuppressive therapy (IS) (n = 16), or after a bone marrow transplant (BMT) (n = 4). MSC were tested for T-cell suppression in the following assays: mixed lymphocyte reaction (MLR), phytohemaglutinin (PHA)-primed cultures, activation surface markers, gamma-IFN production, hematopoietic colony formation (CFC), production of cyclic ADP-ribose (cADPR).


RESULTS
The abnormalities of SAA MSC included: 1) significantly lower suppression of T-cell proliferation induced by alloantigens (p = 0.009) or PHA (p = 0.006); 2) impaired capacity to suppress CD38 expression on PHA-primed T cells (p = 0.001); 3) impaired ability to suppress gamma-IFN production in PHA cultures, resulting in an 11-fold higher gamma-IFN concentration; 4) no preventive effect on T cell-mediated inhibition of CFC; and 5) significantly reduced (p = 0.009) production of cADPR, a universal calcium mobilizer. MSC-mediated suppression of PHA-induced T-cell proliferation was restored to control levels in 3 of 4 patients post-BMT.


CONCLUSIONS
The ability of MSC to downregulate T-cell priming, proliferation, and cytokine release is deficient in patients with SAA, persists indefinitely after immunosuppressive therapy, but seems to be restored after BMT. Whether these abnormalities are relevant to the pathogenesis of aplastic anemia remains to be determined.
Bacigalupo
Andrea
A
Divisione Ematologia Ospedale San Martino, Italy.
Valle
Marisa
M
Podestà
Marina
M
Pitto
Anna
A
Zocchi
Elena
E
De Flora
Antonio
A
Pozzi
Sara
S
Luchetti
Silvia
S
Frassoni
Francesco
F
Van Lint
Maria Teresa
MT
Piaggio
Giovanna
G
D000293:Adolescent; D000328:Adult; D000368:Aged; D000741:Anemia, Aplastic / Q000276:immunology* / Q000473:pathology*; D001854:Bone Marrow Cells / Q000166:cytology / Q000473:pathology; D016026:Bone Marrow Transplantation / Q000276:immunology; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D008648:Mesoderm / Q000502:physiology*; D008875:Middle Aged; D010835:Phytohemagglutinins; D012016:Reference Values; D013234:Stem Cells / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology*
D010835:Phytohemagglutinins