{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T01:05:24Z","timestamp":1789607124696,"version":"build-2803163510"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2013,12,1]],"date-time":"2013-12-01T00:00:00Z","timestamp":1385856000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2013,12,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Multipotent mesenchymal stromal cells (MSCs) possess reparative and immunoregulatory properties, making them attractive candidates for cellular therapy. However, the majority of MSCs administered i.v. encounter a pulmonary impasse and soon disappear from the lungs, raising the question of how they induce such durable immunosuppressive effects. Using a mouse model of allergic asthma, we show that administration of MSCs isolated from human bone marrow, umbilical cord, or adipose tissue provoked a pronounced increase in alveolar macrophages and inhibited hallmark features of asthma, including airway hyperresponsiveness, eosinophilic accumulation, and Th2 cytokine production. Importantly, selective depletion of this macrophage compartment reversed the therapeutic benefit of MSC treatment on airway hyperresponsiveness. Our data demonstrate that human MSCs exert cross-species immunosuppressive activity, which is mediated by alveolar macrophages in allergic asthma. As alveolar macrophages are the predominant immune effector cells at the air\u2013tissue interface in the lungs, this study provides a compelling mechanism for durable MSC effects in the absence of sustained engraftment.<\/jats:p>","DOI":"10.4049\/jimmunol.1300667","type":"journal-article","created":{"date-parts":[[2013,11,19]],"date-time":"2013-11-19T04:49:09Z","timestamp":1384836549000},"page":"5914-5924","source":"Crossref","is-referenced-by-count":84,"title":["Alveolar Macrophages Are Critical for the Inhibition of Allergic Asthma by Mesenchymal Stromal Cells"],"prefix":"10.1093","volume":"191","author":[{"given":"Louisa J","family":"Mathias","sequence":"first","affiliation":[{"name":"Department of Anatomy and Developmental Biology, Monash University , Clayton, Victoria 3800,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sacha M L","family":"Khong","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Developmental Biology, Monash University , Clayton, Victoria 3800,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Spyroglou","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Developmental Biology, Monash University , Clayton, Victoria 3800,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie L","family":"Payne","sequence":"additional","affiliation":[{"name":"Australian Regenerative Medicine Institute, Monash University , Clayton, Victoria 3800,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Siatskas","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Developmental Biology, Monash University , Clayton, Victoria 3800,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison N","family":"Thorburn","sequence":"additional","affiliation":[{"name":"Department of Immunology, Monash University , Clayton, Victoria 3800,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard L","family":"Boyd","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Developmental Biology, Monash University , Clayton, Victoria 3800,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tracy S P","family":"Heng","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Developmental Biology, Monash University , Clayton, Victoria 3800,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2013,12,15]]},"reference":[{"key":"2025032406071767600_r1","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1097\/00007890-197404000-00001","article-title":"Stromal cells responsible for transferring the microenvironment of the hemopoietic tissues. Cloning in vitro and retransplantation in vivo","volume":"17","author":"Friedenstein","year":"1974","journal-title":"Transplantation"},{"key":"2025032406071767600_r2","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1126\/science.284.5411.143","article-title":"Multilineage potential of adult human mesenchymal stem cells","volume":"284","author":"Pittenger","year":"1999","journal-title":"Science"},{"key":"2025032406071767600_r3","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1038\/nri2395","article-title":"Mesenchymal stem cells in health and disease","volume":"8","author":"Uccelli","year":"2008","journal-title":"Nat. Rev. Immunol."},{"key":"2025032406071767600_r4","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1097\/01.TP.0000045055.63901.A9","article-title":"Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation","volume":"75","author":"Tse","year":"2003","journal-title":"Transplantation"},{"key":"2025032406071767600_r5","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1182\/blood-2007-03-078774","article-title":"Immunogenicity of umbilical cord tissue derived cells","volume":"111","author":"Cho","year":"2008","journal-title":"Blood"},{"key":"2025032406071767600_r6","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1089\/scd.2008.0253","article-title":"Pulmonary passage is a major obstacle for intravenous stem cell delivery: the pulmonary first-pass effect","volume":"18","author":"Fischer","year":"2009","journal-title":"Stem Cells Dev."},{"key":"2025032406071767600_r7","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.stem.2009.05.003","article-title":"Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6","volume":"5","author":"Lee","year":"2009","journal-title":"Cell Stem Cell"},{"key":"2025032406071767600_r8","doi-asserted-by":"crossref","first-page":"8407","DOI":"10.1073\/pnas.1432929100","article-title":"Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects","volume":"100","author":"Ortiz","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032406071767600_r9","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1165\/rcmb.2004-0330OC","article-title":"Bone marrow-derived mesenchymal stem cells in repair of the injured lung","volume":"33","author":"Rojas","year":"2005","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"2025032406071767600_r10","doi-asserted-by":"crossref","first-page":"303","DOI":"10.2353\/ajpath.2009.080629","article-title":"Human umbilical cord mesenchymal stem cells reduce fibrosis of bleomycin-induced lung injury","volume":"175","author":"Moodley","year":"2009","journal-title":"Am. J. Pathol."},{"key":"2025032406071767600_r11","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1111\/j.1365-2222.2008.02971.x","article-title":"Pathogenesis of asthma","volume":"38","author":"Holgate","year":"2008","journal-title":"Clin. Exp. Allergy"},{"key":"2025032406071767600_r12","doi-asserted-by":"crossref","first-page":"5652","DOI":"10.1073\/pnas.0910720107","article-title":"Bone marrow stromal cells use TGF-beta to suppress allergic responses in a mouse model of ragweed-induced asthma","volume":"107","author":"Nemeth","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032406071767600_r13","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1111\/j.1398-9995.2010.02509.x","article-title":"Allogeneic mesenchymal stem cells prevent allergic airway inflammation by inducing murine regulatory T cells","volume":"66","author":"Kavanagh","year":"2011","journal-title":"Allergy"},{"key":"2025032406071767600_r14","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1002\/stem.656","article-title":"Bone marrow-derived mesenchymal stromal cells inhibit Th2-mediated allergic airways inflammation in mice","volume":"29","author":"Goodwin","year":"2011","journal-title":"Stem Cells"},{"key":"2025032406071767600_r15","doi-asserted-by":"crossref","first-page":"1811","DOI":"10.1089\/scd.2009.0513","article-title":"Adipose-derived stromal cells inhibit allergic airway inflammation in mice","volume":"19","author":"Park","year":"2010","journal-title":"Stem Cells Dev."},{"key":"2025032406071767600_r16","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1186\/1476-9255-7-51","article-title":"Defining human mesenchymal stem cell efficacy in vivo","volume":"7","author":"Bonfield","year":"2010","journal-title":"J. Inflamm. (Lond.)"},{"key":"2025032406071767600_r17","doi-asserted-by":"crossref","first-page":"L760","DOI":"10.1152\/ajplung.00182.2009","article-title":"Human mesenchymal stem cells suppress chronic airway inflammation in the murine ovalbumin asthma model","volume":"299","author":"Bonfield","year":"2010","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"2025032406071767600_r18","doi-asserted-by":"crossref","first-page":"1954","DOI":"10.1002\/stem.118","article-title":"Species variation in the mechanisms of mesenchymal stem cell-mediated immunosuppression","volume":"27","author":"Ren","year":"2009","journal-title":"Stem Cells"},{"key":"2025032406071767600_r19","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1089\/ten.2006.0313","article-title":"Dose-dependent immunomodulatory effect of human stem cells from amniotic membrane: a comparison with human mesenchymal stem cells from adipose tissue","volume":"13","author":"Wolbank","year":"2007","journal-title":"Tissue Eng."},{"key":"2025032406071767600_r20","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.jim.2004.03.004","article-title":"A rapid flow cytometric method for determining the cellular composition of bronchoalveolar lavage fluid cells in mouse models of asthma","volume":"288","author":"van Rijt","year":"2004","journal-title":"J. Immunol. Methods"},{"key":"2025032406071767600_r21","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1080\/14653240600855905","article-title":"Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement","volume":"8","author":"Dominici","year":"2006","journal-title":"Cytotherapy"},{"key":"2025032406071767600_r22","doi-asserted-by":"crossref","DOI":"10.1002\/0471142735.im1518s79","article-title":"Animal models of airway sensitization","volume-title":"Curr. Protoc. Immunol. Chapter 15:Unit 15.18","author":"Pichavant","year":"2007"},{"key":"2025032406071767600_r23","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1146\/annurev.immunol.22.012703.104716","article-title":"Asthma: mechanisms of disease persistence and progression","volume":"22","author":"Cohn","year":"2004","journal-title":"Annu. Rev. Immunol."},{"key":"2025032406071767600_r24","doi-asserted-by":"crossref","first-page":"1663","DOI":"10.4049\/jimmunol.0902185","article-title":"Importance of cytokines in murine allergic airway disease and human asthma","volume":"184","author":"Finkelman","year":"2010","journal-title":"J. Immunol."},{"key":"2025032406071767600_r25","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1046\/j.1365-2567.2003.01609.x","article-title":"Dendritic cells recruited to the lung shortly after intranasal delivery of Mycobacterium bovis BCG drive the primary immune response towards a type 1 cytokine production","volume":"108","author":"Lagranderie","year":"2003","journal-title":"Immunology"},{"key":"2025032406071767600_r26","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1084\/jem.170.2.499","article-title":"Alveolar macrophage elimination in vivo is associated with an increase in pulmonary immune response in mice","volume":"170","author":"Thepen","year":"1989","journal-title":"J. Exp. Med."},{"key":"2025032406071767600_r27","doi-asserted-by":"crossref","first-page":"2042","DOI":"10.1002\/stem.1400","article-title":"Two negative feedback loops place mesenchymal stem\/stromal cells (MSCs) at the center of early regulators of inflammation","volume":"31","author":"Prockop","year":"2013","journal-title":"Stem Cells"},{"key":"2025032406071767600_r28","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1186\/scrt68","article-title":"Human multipotent stromal cells attenuate lipopolysaccharide-induced acute lung injury in mice via secretion of tumor necrosis factor-\u03b1-induced protein 6","volume":"2","author":"Danchuk","year":"2011","journal-title":"Stem Cell Res Ther"},{"key":"2025032406071767600_r29","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1172\/JCI59643","article-title":"Macrophage plasticity and polarization: in vivo veritas","volume":"122","author":"Sica","year":"2012","journal-title":"J. Clin. Invest."},{"key":"2025032406071767600_r30","doi-asserted-by":"crossref","first-page":"e9252","DOI":"10.1371\/journal.pone.0009252","article-title":"Mouse bone marrow-derived mesenchymal stromal cells turn activated macrophages into a regulatory-like profile","volume":"5","author":"Maggini","year":"2010","journal-title":"PLoS ONE"},{"key":"2025032406071767600_r31","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1016\/j.exphem.2009.09.004","article-title":"Mesenchymal stem cell-educated macrophages: a novel type of alternatively activated macrophages","volume":"37","author":"Kim","year":"2009","journal-title":"Exp. Hematol."},{"key":"2025032406071767600_r32","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1038\/mt.2011.189","article-title":"Human MSC suppression correlates with cytokine induction of indoleamine 2,3-dioxygenase and bystander M2 macrophage differentiation","volume":"20","author":"Fran\u00e7ois","year":"2012","journal-title":"Mol. Ther."},{"key":"2025032406071767600_r33","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1084\/jem.20121849","article-title":"Lung-resident tissue macrophages generate Foxp3+ regulatory T cells and promote airway tolerance","volume":"210","author":"Soroosh","year":"2013","journal-title":"J. Exp. Med."},{"key":"2025032406071767600_r34","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1038\/nri2711","article-title":"The regulation of IL-10 production by immune cells","volume":"10","author":"Saraiva","year":"2010","journal-title":"Nat. Rev. Immunol."},{"key":"2025032406071767600_r35","doi-asserted-by":"crossref","first-page":"1314","DOI":"10.1111\/j.1365-2222.2009.03301.x","article-title":"Regulatory T cells and asthma","volume":"39","author":"Robinson","year":"2009","journal-title":"Clin. Exp. Allergy"},{"key":"2025032406071767600_r36","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1084\/jem.20051166","article-title":"Resolution of airway inflammation and hyperreactivity after in vivo transfer of CD4+CD25+ regulatory T cells is interleukin 10 dependent","volume":"202","author":"Kearley","year":"2005","journal-title":"J. Exp. Med."},{"key":"2025032406071767600_r37","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1165\/rcmb.f279","article-title":"The alveolar macrophage: the forgotten cell in asthma","volume":"31","author":"Peters-Golden","year":"2004","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"2025032406071767600_r38","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1084\/jem.177.2.397","article-title":"Downregulation of the antigen presenting cell function(s) of pulmonary dendritic cells in vivo by resident alveolar macrophages","volume":"177","author":"Holt","year":"1993","journal-title":"J. Exp. Med."},{"key":"2025032406071767600_r39","doi-asserted-by":"crossref","first-page":"2845","DOI":"10.1002\/eji.1830211128","article-title":"Regulation of immune response to inhaled antigen by alveolar macrophages: differential effects of in vivo alveolar macrophage elimination on the induction of tolerance vs. immunity","volume":"21","author":"Thepen","year":"1991","journal-title":"Eur. J. Immunol."},{"key":"2025032406071767600_r40","doi-asserted-by":"crossref","first-page":"1471","DOI":"10.4049\/jimmunol.166.3.1471","article-title":"Th type 1-stimulating activity of lung macrophages inhibits Th2-mediated allergic airway inflammation by an IFN-gamma-dependent mechanism","volume":"166","author":"Tang","year":"2001","journal-title":"J. Immunol."},{"key":"2025032406071767600_r41","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1089\/jir.2011.0027","article-title":"Macrophages in allergic asthma: fine-tuning their pro- and anti-inflammatory actions for disease resolution","volume":"31","author":"Moreira","year":"2011","journal-title":"J. Interferon Cytokine Res."},{"key":"2025032406071767600_r42","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1038\/nri3073","article-title":"Protective and pathogenic functions of macrophage subsets","volume":"11","author":"Murray","year":"2011","journal-title":"Nat. Rev. Immunol."},{"key":"2025032406071767600_r43","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1038\/nm.1905","article-title":"Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production","volume":"15","author":"N\u00e9meth","year":"2009","journal-title":"Nat. Med."},{"key":"2025032406071767600_r44","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.1007\/s00395-011-0221-9","article-title":"Mesenchymal stromal cells mediate a switch to alternatively activated monocytes\/macrophages after acute myocardial infarction","volume":"106","author":"Dayan","year":"2011","journal-title":"Basic Res. Cardiol."},{"key":"2025032406071767600_r45","doi-asserted-by":"crossref","first-page":"1855","DOI":"10.4049\/jimmunol.179.3.1855","article-title":"Intrapulmonary delivery of bone marrow-derived mesenchymal stem cells improves survival and attenuates endotoxin-induced acute lung injury in mice","volume":"179","author":"Gupta","year":"2007","journal-title":"J. Immunol."},{"key":"2025032406071767600_r46","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1038\/nri1589","article-title":"Potential role of interleukin-10-secreting regulatory T cells in allergy and asthma","volume":"5","author":"Hawrylowicz","year":"2005","journal-title":"Nat. Rev. Immunol."},{"key":"2025032406071767600_r47","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1038\/nri3209","article-title":"Multipotent mesenchymal stromal cells and the innate immune system","volume":"12","author":"Le Blanc","year":"2012","journal-title":"Nat. Rev. Immunol."}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/191\/12\/5914\/61537368\/1300667.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/191\/12\/5914\/61537368\/1300667.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,25]],"date-time":"2025-03-25T18:52:41Z","timestamp":1742928761000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/191\/12\/5914\/7966650"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,12]]},"references-count":47,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2013,12,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1300667","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2013,12]]},"published":{"date-parts":[[2013,12]]}}}