Enhancement of the immunoregulatory potency of mesenchymal stromal cells by treatment with immunosuppressive drugs.
OBJECTIVE
Multipotent mesenchymal stromal cells (MSCs) are distinguished by their ability to differentiate into a number of stromal derivatives of interest for regenerative medicine, but they also have immunoregulatory properties that are being tested in a number of clinical settings.


METHODS
We show that brief incubations with rapamycin, everolimus, FK506 or cyclosporine A increase the immunosuppressive potency of MSCs and other cell types.


RESULTS
The treated MSCs are up to 5-fold more potent at inhibiting the induced proliferation of T lymphocytes in vitro. We show that this effect probably is due to adsorption of the drug by the MSCs during pre-treatment, with subsequent diffusion into co-cultures at concentrations sufficient to inhibit T-cell proliferation. MSCs contain measurable amounts of rapamycin after a 15-min exposure, and the potentiating effect is blocked by a neutralizing antibody to the drug. With the use of a pre-clinical model of acute graft-versus-host disease, we demonstrate that a low dose of rapamycin-treated but not untreated umbilical cord-derived MSCs significantly inhibit the onset of disease.


CONCLUSIONS
The use of treated MSCs may achieve clinical end points not reached with untreated MSCs and allow for infusion of fewer cells to reduce costs and minimize potential side effects.
Histocompatibility and Immunogenetics Research Group, NHS Blood and Transplant, Colindale, London, United Kingdom; Division of Infection & Immunity, University College, London, United Kingdom. Electronic address: john.girdlestone@nhsbt.nhs.uk.
John
J
Girdlestone
Histocompatibility and Immunogenetics Research Group, NHS Blood and Transplant, Colindale, London, United Kingdom.
Jeffrey
J
Pido-Lopez
Histocompatibility and Immunogenetics Research Group, NHS Blood and Transplant, Colindale, London, United Kingdom; Division of Infection & Immunity, University College, London, United Kingdom.
Saket
S
Srivastava
MRC Centre for Transplantation, King's College, London, United Kingdom.
Jianguo
J
Chai
UK National Monitoring Service for Sirolimus, Royal Brompton & Harefield NHS Foundation Trust, Harefield, United Kingdom.
Neil
N
Leaver
Regenerative and Haematological Medicine, Rayne Institute, King's College, London, United Kingdom.
Antonio
A
Galleu
MRC Centre for Transplantation, King's College, London, United Kingdom.
Giovanna
G
Lombardi
Histocompatibility and Immunogenetics Research Group, NHS Blood and Transplant, Colindale, London, United Kingdom; Division of Infection & Immunity, University College, London, United Kingdom.
Cristina V
CV
Navarrete
D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D018920:Coculture Techniques; D016572:Cyclosporine / Q000494:pharmacology; D004195:Disease Models, Animal; D000068338:Everolimus / Q000494:pharmacology; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control*; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects*; D007165:Immunosuppression Therapy / Q000379:methods; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D020123:Sirolimus / Q000276:immunology / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000276:immunology; D016559:Tacrolimus / Q000494:pharmacology; D014470:Umbilical Cord / Q000166:cytology
D057134:Antibodies, Neutralizing; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D000068338:Everolimus; D020123:Sirolimus; D016559:Tacrolimus
immunoregulation; immunosuppression; mesenchymal stromal cells; rapamycin; sirolimus