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      Mesenchymal Stromal Cell Therapy for Chronic Lung Allograft Dysfunction: Results of a First‐in‐Man Study

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          Abstract

          Chronic lung transplant rejection (termed chronic lung allograft dysfunction [CLAD]) is the main impediment to long‐term survival after lung transplantation. Bone marrow‐derived mesenchymal stromal cells (MSCs) represent an attractive cell therapy in inflammatory diseases, including organ rejection, given their relative immune privilege and immunosuppressive and tolerogenic properties. Preclinical studies in models of obliterative bronchiolitis and human trials in graft versus host disease and renal transplantation suggest potential efficacy in CLAD. The purpose of this phase 1, single‐arm study was to explore the feasibility and safety of intravenous delivery of allogeneic MSCs to patients with advanced CLAD. MSCs from unrelated donors were isolated from bone marrow, expanded and cryopreserved in a GMP‐compliant facility. Patients had deteriorating CLAD and were bronchiolitis obliterans (BOS) grade ≥ 2 or grade 1 with risk factors for rapid progression. MSCs (2 x 10 6 cells per kilogram patient weight) were infused via a peripheral vein twice weekly for 2 weeks, with 52 weeks follow‐up. Ten Patients (5 male, 8 bilateral, median [interquartile range] age 40 [30–59] years, 3 BOS2, 7 BOS3) participated. MSC treatment was well tolerated with all patients receiving the full dosing schedule without any procedure‐related serious adverse events. The rate of decline in forced expiratory volume in one second slowed after the MSC infusions (120 ml/month preinfusion vs. 30 ml/month postinfusion, p = .08). Two patients died at 152 and 270 days post‐MSC treatment, both from progressive CLAD. In conclusion, infusion of allogeneic bone marrow‐derived MSCs is feasible and safe even in patients with advanced CLAD. S tem C ells T ranslational M edicine 2017;6:1152–1157

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          The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells.

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            The registry of the International Society for Heart and Lung Transplantation: thirty-first adult lung and heart-lung transplant report--2014; focus theme: retransplantation.

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              Mesenchymal stem/stromal cells precondition lung monocytes/macrophages to produce tolerance against allo- and autoimmunity in the eye.

              Intravenously administered mesenchymal stem/stromal cells (MSCs) engraft only transiently in recipients, but confer long-term therapeutic benefits in patients with immune disorders. This suggests that MSCs induce immune tolerance by long-lasting effects on the recipient immune regulatory system. Here, we demonstrate that i.v. infusion of MSCs preconditioned lung monocytes/macrophages toward an immune regulatory phenotype in a TNF-α-stimulated gene/protein (TSG)-6-dependent manner. As a result, mice were protected against subsequent immune challenge in two models of allo- and autoimmune ocular inflammation: corneal allotransplantation and experimental autoimmune uveitis (EAU). The monocytes/macrophages primed by MSCs expressed high levels of MHC class II, B220, CD11b, and IL-10, and exhibited T-cell-suppressive activities independently of FoxP3(+) regulatory T cells. Adoptive transfer of MSC-induced B220(+)CD11b(+) monocytes/macrophages prevented corneal allograft rejection and EAU. Deletion of monocytes/macrophages abrogated the MSC-induced tolerance. However, MSCs with TSG-6 knockdown did not induce MHC II(+)B220(+)CD11b(+) cells, and failed to attenuate EAU. Therefore, the results demonstrate a mechanism of the MSC-mediated immune modulation through induction of innate immune tolerance that involves monocytes/macrophages.
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                Author and article information

                Contributors
                daniel.chambers@health.qld.gov.au
                Journal
                Stem Cells Transl Med
                Stem Cells Transl Med
                10.1002/(ISSN)2157-6580
                SCT3
                Stem Cells Translational Medicine
                John Wiley and Sons Inc. (Hoboken )
                2157-6564
                2157-6580
                01 February 2017
                April 2017
                : 6
                : 4 ( doiID: 10.1002/sct3.2017.6.issue-4 )
                : 1152-1157
                Affiliations
                [ 1 ]School of Medicine, The University of Queensland Brisbane QueenslandAustralia
                [ 2 ]Queensland Lung Transplant Service, The Prince Charles Hospital Brisbane QueenslandAustralia
                [ 3 ]Western Australian Lung Transplant Program, Fiona Stanley Hospital Perth Western AustraliaAustralia
                [ 4 ] Department of Pathology and Laboratory MedicineUniversity of Western Australia Perth Western AustraliaAustralia
                [ 5 ]Cell & Tissue Therapies Western Australia, Royal Perth Hospital Perth Western AustraliaAustralia
                Author notes
                [*] [* ]Correspondence: Daniel C. Chambers, M.B.B.S. (Hons1), M.R.C.P., F.R.A.C.P., M.D., Qld Lung Transplant Service, Level 1 Administration Building, The Prince Charles Hospital, Rode Road, Chermside, Brisbane, Queensland 4032, Australia. Telephone: 61 7 31394000; Fax: 61 7 31395696; e‐mail: daniel.chambers@ 123456health.qld.gov.au
                Article
                SCT312081
                10.1002/sctm.16-0372
                5442848
                28186707
                8b43ce13-b851-4826-8eae-3d4ac2c85885
                © 2017 The Authors S tem C ells T ranslational M edicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 15 August 2016
                : 16 November 2016
                Page count
                Figures: 3, Tables: 1, Pages: 6, Words: 4807
                Categories
                Cell‐Based Drug Development, Screening, and Toxicology
                Translational Research Articles and Reviews
                Cell‐Based Drug Development, Screening, and Toxicology
                Custom metadata
                2.0
                sct312081
                April 2017
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.0.9 mode:remove_FC converted:23.05.2017

                lung transplantation,graft rejection,cell‐ and tissue‐based therapy,mesenchymal stromal cells,clinical trial,phase 1

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