John Girdlestone1, Jeffrey Pido-Lopez2, Saket Srivastava3, Jianguo Chai4, Neil Leaver5, Antonio Galleu6, Giovanna Lombardi4, Cristina V Navarrete3. 1. 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. 2. Histocompatibility and Immunogenetics Research Group, NHS Blood and Transplant, Colindale, London, United Kingdom. 3. Histocompatibility and Immunogenetics Research Group, NHS Blood and Transplant, Colindale, London, United Kingdom; Division of Infection & Immunity, University College, London, United Kingdom. 4. MRC Centre for Transplantation, King's College, London, United Kingdom. 5. UK National Monitoring Service for Sirolimus, Royal Brompton & Harefield NHS Foundation Trust, Harefield, United Kingdom. 6. Regenerative and Haematological Medicine, Rayne Institute, King's College, London, United Kingdom.
Abstract
BACKGROUND AIMS: 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.
BACKGROUND AIMS: 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.
Authors: Teresa L Ramos; Luis Ignacio Sánchez-Abarca; Alba Redondo; Ángel Hernández-Hernández; Antonio M Almeida; Noemí Puig; Concepción Rodríguez; Rebeca Ortega; Silvia Preciado; Ana Rico; Sandra Muntión; José Ramón González Porras; Consuelo Del Cañizo; Fermín Sánchez-Guijo Journal: Oncotarget Date: 2017-04-25