Recently developed cell-based therapies have shown potential for graft-versus-host disease (GvHD) mitigation. Our team previously developed a protocol to generate human monocyte-derived suppressor Cells (HuMoSC), a subpopulation of CD33+ suppressor cells of monocytic origin. CD33+HuMoSC successfully reduced xenoGvHD severity in NOD/SCID/IL-2Rγc-/- (NSG) mice. While CD33+ HuMoSC culture supernatant inhibits T cell activation and proliferation, the recovery of CD33+ HuMoSC immunosuppressive cells and the subsequent production of their supernatant is limited. An attractive solution would be to use both the CD33+ and the large number of CD14+ cells derived from our protocol. Here, we assessed the immunoregulatory properties of the CD14+HuMoSC supernatant and demonstrated that it inhibited both CD4 and CD8 T cell proliferation and decreased CD8 cytotoxicity. In vivo, injection of CD14+HuMoSC supernatant reduced xenoGvHD in NSG mice. Furthermore, CD14+HuMoSC supernatant maintained its immunoregulatory properties in an inflammatory environment. Proteomic and multiplex analyses revealed the presence of immunosuppressive proteins such as GPNMB, galectin-3 and IL-1R(A) Finally, CD14+HuMoSC supernatant can be produced using good manufacturing practices and be used as complement to current immunosuppressive drugs. CD14+HuMoSC supernatant is thus a promising therapy for preventing GvHD. .

Department of Immunology Faculty of Medicine Tbilisi State Medical University Tbilisi Georgia

Department of Internal Medicine Dijon University Hospital Dijon France

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Prague Czechia

UBFC Inserm EFS BFC UMR1098 RIGHT Interactions Greffon Hôte Tumeur Ingénierie Cellulaire et Génique Besançon France

Université Bourgogne Franche Comté Inserm EFS BFC UMR1098 Team « immunoregulation immunopathology » RIGHT Interactions Greffon Hôte Tumeur Ingénierie Cellulaire et Génique Dijon France

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D’Aveni M, Notarantonio AB, Bertrand A, Boulangé L, Pochon C, Rubio MT. Myeloid-Derived Suppressor Cells in the Context of Allogeneic Hematopoietic Stem Cell Transplantation. Front Immunol (2020) 11:989. doi: 10.3389/fimmu.2020.00989 PubMed DOI PMC

Koehn BH, Apostolova P, Haverkamp JM, Miller JS, McCullar V, Tolar J, et al. . GVHD-Associated, Inflammasome-Mediated Loss of Function in Adoptively Transferred Myeloid-Derived Suppressor Cells. Blood (2015) 126:1621–8. doi: 10.1182/blood-2015-03-634691 PubMed DOI PMC

Lv M, Zhao X-S, Hu Y, Chang Y-J, Zhao X-Y, Kong Y, et al. . Monocytic and Promyelocytic Myeloid-Derived Suppressor Cells may Contribute to G-CSF-Induced Immune Tolerance in Haplo-Identical Allogeneic Hematopoietic Stem Cell Transplantation. Am J Hematol (2015) 90:E9–16. doi: 10.1002/ajh.23865 PubMed DOI

Janikashvili N, Trad M, Gautheron A, Samson M, Lamarthée B, Bonnefoy F, et al. . Human Monocyte-Derived Suppressor Cells Control Graft-Versus-Host Disease by Inducing Regulatory Forkhead Box Protein 3–Positive CD8+ T Lymphocytes. J Allergy Clin Immunol (2015) 135:1614–24.e4. doi: 10.1016/j.jaci.2014.12.1868 PubMed DOI

Janikashvili N, Gérard C, Thébault M, Brazdova A, Boibessot C, Cladière C, et al. . Efficiency of Human Monocyte-Derived Suppressor Cell-Based Treatment in Graft-Versus-Host Disease Prevention While Preserving Graft-Versus-Leukemia Effect. Oncoimmunology (2021) 10:1880046. doi: 10.1080/2162402X.2021.1880046 PubMed DOI PMC

Craig R, Beavis RC. TANDEM: Matching Proteins With Tandem Mass Spectra. Bioinformatics (2004) 20:1466–7. doi: 10.1093/bioinformatics/bth092 PubMed DOI

Langella O, Valot B, Balliau T, Blein-Nicolas M, Bonhomme L, Zivy M. X!TandemPipeline: A Tool to Manage Sequence Redundancy for Protein Inference and Phosphosite Identification. J Proteome Res (2017) 16:494–503. doi: 10.1021/acs.jproteome.6b00632 PubMed DOI

Balliau T, Blein-Nicolas M, Zivy M. Evaluation of Optimized Tube-Gel Methods of Sample Preparation for Large-Scale Plant Proteomics. Proteomes (2018) 6:6. doi: 10.3390/proteomes6010006 PubMed DOI PMC

Ferrara JL, Levine JE, Reddy P, Holler E. Graft-Versus-Host Disease. Lancet (2009) 373:1550–61. doi: 10.1016/S0140-6736(09)60237-3 PubMed DOI PMC

Hill GR, Crawford JM, Cooke KR, Brinson YS, Pan L, Ferrara JL. Total Body Irradiation and Acute Graft-Versus-Host Disease: The Role of Gastrointestinal Damage and Inflammatory Cytokines. Blood (1997) 90:3204–13. doi: 10.1182/blood.V90.8.3204 PubMed DOI

Cooke KR, Hill GR, Crawford JM, Bungard D, Brinson YS, Delmonte J, et al. . Tumor Necrosis Factor- Alpha Production to Lipopolysaccharide Stimulation by Donor Cells Predicts the Severity of Experimental Acute Graft-Versus-Host Disease. J Clin Invest (1998) 102:1882–91. doi: 10.1172/JCI4285 PubMed DOI PMC

Antin JH, Ferrara JL. Cytokine Dysregulation and Acute Graft-Versus-Host Disease. Blood (1992) 80:2964–8. doi: 10.1182/blood.V80.12.2964.2964 PubMed DOI

Mohty M, Blaise D, Faucher C, Vey N, Bouabdallah R, Stoppa A-M, et al. . Inflammatory Cytokines and Acute Graft-Versus-Host Disease After Reduced-Intensity Conditioning Allogeneic Stem Cell Transplantation. Blood (2005) 106:4407–11. doi: 10.1182/blood-2005-07-2919 PubMed DOI

Blazar BR, Murphy WJ, Abedi M. Advances in Graft-Versus-Host Disease Biology and Therapy. Nat Rev Immunol (2012) 12:443–58. doi: 10.1038/nri3212 PubMed DOI PMC

Sioud. Mesenchymal Stem Cell-Mediated T Cell Suppression Occurs Through Secreted Galectins. Int J Oncol (2011) 38:385–90. doi: 10.3892/ijo.2010.869 PubMed DOI

Sioud M, Mobergslien A, Boudabous A, Fløisand Y. Evidence for the Involvement of Galectin-3 in Mesenchymal Stem Cell Suppression of Allogeneic T-Cell Proliferation. Scand J Immunol (2010) 71:267–74. doi: 10.1111/j.1365-3083.2010.02378.x PubMed DOI

Gilson RC, Gunasinghe SD, Johannes L, Gaus K. Galectin-3 Modulation of T-Cell Activation: Mechanisms of Membrane Remodelling. Prog Lipid Res (2019) 76:101010. doi: 10.1016/j.plipres.2019.101010 PubMed DOI

Demetriou M, Granovsky M, Quaggin S, Dennis JW. Negative Regulation of T-Cell Activation and Autoimmunity by Mgat5 N-Glycosylation. Nature (2001) 409:733–9. doi: 10.1038/35055582 PubMed DOI

Zuberi RI, Hsu DK, Kalayci O, Chen H-Y, Sheldon HK, Yu L, et al. . Critical Role for Galectin-3 in Airway Inflammation and Bronchial Hyperresponsiveness in a Murine Model of Asthma. Am J Pathol (2004) 165:2045–53. doi: 10.1016/S0002-9440(10)63255-5 PubMed DOI PMC

Guo Y, Shen R, Yu L, Zheng X, Cui R, Song Y, et al. . Roles of Galectin−3 in the Tumor Microenvironment and Tumor Metabolism (Review). Oncol Rep (2020) 44:1799–809. doi: 10.3892/or.2020.7777 PubMed DOI

Chung L-Y, Tang S-J, Wu Y-C, Sun G-H, Liu H-Y, Sun K-H. Galectin-3 Augments Tumor Initiating Property and Tumorigenicity of Lung Cancer Through Interaction With β-Catenin. Oncotarget (2015) 6:4936–52. doi: 10.18632/oncotarget.3210 PubMed DOI PMC

Heine A, Held SAE, Schulte-Schrepping J, Wolff JFA, Klee K, Ulas T, et al. . Generation and Functional Characterization of MDSC-Like Cells. Oncoimmunology (2017) 6:e1295203. doi: 10.1080/2162402X.2017.1295203 PubMed DOI PMC

Colombo MP. Is GPNMB the Achilles’ Heel of Mo-MDSC While Marking Their Suppressive Activity? Clin Cancer Res (2019) 25:453–4. doi: 10.1158/1078-0432.CCR-18-2334 PubMed DOI

Ripoll VM, Irvine KM, Ravasi T, Sweet MJ, Hume DA. Gpnmb Is Induced in Macrophages by IFN-γ and Lipopolysaccharide and Acts as a Feedback Regulator of Proinflammatory Responses. J Immunol (2007) 178:6557–66. doi: 10.4049/jimmunol.178.10.6557 PubMed DOI

Gabay C, Lamacchia C, Palmer G. IL-1 Pathways in Inflammation and Human Diseases. Nat Rev Rheumatol (2010) 6:232–41. doi: 10.1038/nrrheum.2010.4 PubMed DOI

So A, De Smedt T, Revaz S, Tschopp J. A Pilot Study of IL-1 Inhibition by Anakinra in Acute Gout. Arthritis Res Ther (2007) 9:R28. doi: 10.1186/ar2143 PubMed DOI PMC

Gattorno M, Pelagatti MA, Meini A, Obici L, Barcellona R, Federici S, et al. . Persistent Efficacy of Anakinra in Patients With Tumor Necrosis Factor Receptor–Associated Periodic Syndrome. Arthritis Rheum (2008) 58:1516–20. doi: 10.1002/art.23475 PubMed DOI

Roldan R, Ruiz AM, Miranda MD, Collantes E. Anakinra: New Therapeutic Approach in Children With Familial Mediterranean Fever Resistant to Colchicine. Jt Bone Spine (2008) 75:504–5. doi: 10.1016/j.jbspin.2008.04.001 PubMed DOI

Zobrazit více v PubMed

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10.6084/m9.figshare.17128733.v1