Human graft-derived mesenchymal stromal cells potently suppress alloreactive T-cell responses.
After organ transplantation, recipient T cells contribute to graft rejection. Mesenchymal stromal cells from the bone marrow (BM-MSCs) are known to suppress allogeneic T-cell responses, suggesting a possible clinical application of MSCs in organ transplantation. Human liver grafts harbor resident populations of MSCs (L-MSCs). We aimed to determine the immunosuppressive effects of these graft-derived MSCs on allogeneic T-cell responses and to compare these with the effects of BM-MSCs. BM-MSCs were harvested from aspirates and L-MSCs from liver graft perfusates. We cultured them for 21 days and compared their suppressive effects with the effects of BM-MSCs on allogeneic T-cell responses. Proliferation, cytotoxic degranulation, and interferon-gamma production of alloreactive T cells were more potently suppressed by L-MSCs than BM-MSCs. Suppression was mediated by both cell-cell contact and secreted factors. In addition, L-MSCs showed ex vivo a higher expression of PD-L1 than BM-MSCs, which was associated with inhibition of T-cell proliferation and cytotoxic degranulation in vitro. Blocking PD-L1 partly abrogated the inhibition of cytotoxic degranulation by L-MSCs. In addition, blocking indoleamine 2,3-dioxygenase partly abrogated the inhibitive effects of L-MSCs, but not BM-MSCs, on T-cell proliferation. In conclusion, liver graft-derived MSC suppression of allogeneic T-cell responses is stronger than BM-MSCs, which may be related to in situ priming and mobilization from the graft. These graft-derived MSCs may therefore be relevant in transplantation by promoting allohyporesponsiveness.
1Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
Emmy L D
EL
de Mare-Bredemeijer
1Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
Shanta
S
Mancham
2Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
Monique M A
MM
Verstegen
2Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
Petra E
PE
de Ruiter
1Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
Rogier
R
van Gent
3Neostem, Inc., New York, New York.
David
D
O'Neill
2Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
Hugo W
HW
Tilanus
1Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
Herold J
HJ
Metselaar
2Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
Jeroen
J
de Jonge
1Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
Jaap
J
Kwekkeboom
2Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.|4Division of Thoracic Surgery, University Hospital Bern, Bern, Switzerland.
Sean R R
SR
Hall
2Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
Luc J W
LJ
van der Laan
D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D049109:Cell Proliferation / Q000235:genetics; D006084:Graft Rejection / Q000209:etiology / Q000276:immunology* / Q000628:therapy; D006801:Humans; D016130:Immunophenotyping; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D007371:Interferon-gamma / Q000378:metabolism; D016031:Liver Transplantation / Q000009:adverse effects; D008213:Lymphocyte Activation / Q000276:immunology; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology
D060890:B7-H1 Antigen; C423236:CD274 protein, human; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007371:Interferon-gamma