Nona Janikashvili1, Malika Trad2, Alexandrine Gautheron2, Maxime Samson3, Baptiste Lamarthée2, Francis Bonnefoy2, Stéphanie Lemaire-Ewing4, Marion Ciudad2, Khatuna Rekhviashvili2, Famky Seaphanh2, Béatrice Gaugler2, Sylvain Perruche2, Andrew Bateman5, Laurent Martin6, Sylvain Audia3, Philippe Saas7, Nicolas Larmonier8, Bernard Bonnotte3. 1. INSERM UMR1098, University of Bourgogne Franche-Comté, EFS Bourgogne Franche-Comté, LabEX LipSTIC, ANR-11-LABX-0021, Besançon, France. Electronic address: Nona.Janikashvili@u-bourgogne.fr. 2. INSERM UMR1098, University of Bourgogne Franche-Comté, EFS Bourgogne Franche-Comté, LabEX LipSTIC, ANR-11-LABX-0021, Besançon, France. 3. INSERM UMR1098, University of Bourgogne Franche-Comté, EFS Bourgogne Franche-Comté, LabEX LipSTIC, ANR-11-LABX-0021, Besançon, France; Department of Internal Medicine, University Hospital, Dijon, France. 4. INSERM UMR866, University of Bourgogne, Dijon, France. 5. Cancer Sciences, University of Southampton, Southampton, United Kingdom. 6. INSERM UMR1098, University of Bourgogne Franche-Comté, EFS Bourgogne Franche-Comté, LabEX LipSTIC, ANR-11-LABX-0021, Besançon, France; Department of Pathology and Cytology, University Hospital, Dijon, France. 7. INSERM UMR1098, University of Bourgogne Franche-Comté, EFS Bourgogne Franche-Comté, LabEX LipSTIC, ANR-11-LABX-0021, Besançon, France; CHU Besançon, CIC-BT506, FHU INCREASE, Besançon, France. 8. Department of Pediatrics, Steele Children's Research Center, Department of Immunobiology, BIO5 Institute and Arizona Cancer Center, University of Arizona, Tucson, Ariz.
Abstract
BACKGROUND: Adoptive transfer of immunosuppressive cells has emerged as a promising strategy for the treatment of immune-mediated disorders. However, only a limited number of such cells can be isolated from in vivo specimens. Therefore efficient ex vivo differentiation and expansion procedures are critically needed to produce a clinically relevant amount of these suppressive cells. OBJECTIVE: We sought to develop a novel, clinically relevant, and feasible approach to generate ex vivo a subpopulation of human suppressor cells of monocytic origin, referred to as human monocyte-derived suppressive cells (HuMoSCs), which can be used as an efficient therapeutic tool to treat inflammatory disorders. METHODS: HuMoSCs were generated from human monocytes cultured for 7 days with GM-CSF and IL-6. The immune-regulatory properties of HuMoSCs were investigated in vitro and in vivo. The therapeutic efficacy of HuMoSCs was evaluated by using a graft-versus-host disease (GvHD) model of humanized mice (NOD/SCID/IL-2Rγc(-/-) [NSG] mice). RESULTS: CD33+ HuMoSCs are highly potent at inhibiting the proliferation and activation of autologous and allogeneic effector T lymphocytes in vitro and in vivo. The suppressive activity of these cells depends on signal transducer and activator of transcription 3 activation. Of therapeutic relevance, HuMoSCs induce long-lasting memory forkhead box protein 3-positive CD8+ regulatory T lymphocytes and significantly reduce GvHD induced with human PBMCs in NSG mice. CONCLUSION: Ex vivo-generated HuMoSCs inhibit effector T lymphocytes, promote the expansion of immunosuppressive forkhead box protein 3-positive CD8+ regulatory T cells, and can be used as an efficient therapeutic tool to prevent GvHD.
BACKGROUND: Adoptive transfer of immunosuppressive cells has emerged as a promising strategy for the treatment of immune-mediated disorders. However, only a limited number of such cells can be isolated from in vivo specimens. Therefore efficient ex vivo differentiation and expansion procedures are critically needed to produce a clinically relevant amount of these suppressive cells. OBJECTIVE: We sought to develop a novel, clinically relevant, and feasible approach to generate ex vivo a subpopulation of human suppressor cells of monocytic origin, referred to as human monocyte-derived suppressive cells (HuMoSCs), which can be used as an efficient therapeutic tool to treat inflammatory disorders. METHODS: HuMoSCs were generated from human monocytes cultured for 7 days with GM-CSF and IL-6. The immune-regulatory properties of HuMoSCs were investigated in vitro and in vivo. The therapeutic efficacy of HuMoSCs was evaluated by using a graft-versus-host disease (GvHD) model of humanized mice (NOD/SCID/IL-2Rγc(-/-) [NSG] mice). RESULTS: CD33+ HuMoSCs are highly potent at inhibiting the proliferation and activation of autologous and allogeneic effector T lymphocytes in vitro and in vivo. The suppressive activity of these cells depends on signal transducer and activator of transcription 3 activation. Of therapeutic relevance, HuMoSCs induce long-lasting memory forkhead box protein 3-positive CD8+ regulatory T lymphocytes and significantly reduce GvHD induced with human PBMCs in NSG mice. CONCLUSION: Ex vivo-generated HuMoSCs inhibit effector T lymphocytes, promote the expansion of immunosuppressive forkhead box protein 3-positive CD8+ regulatory T cells, and can be used as an efficient therapeutic tool to prevent GvHD.
Keywords:
Human monocyte-derived suppressor cells; T lymphocytes; graft-versus-host disease; inflammation; regulatory T cells; signal transducer and activator of transcription 3
Authors: Maud D'Aveni; Anne B Notarantonio; Allan Bertrand; Laura Boulangé; Cécile Pochon; Marie T Rubio Journal: Front Immunol Date: 2020-05-22 Impact factor: 7.561