{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T19:43:31Z","timestamp":1790711011569,"version":"4.1.0"},"reference-count":73,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2009,12,1]],"date-time":"2009-12-01T00:00:00Z","timestamp":1259625600000},"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":[[2009,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Chronic allograft rejection (CR) is the leading cause of late graft failure following organ transplantation. CR is a progressive disease, characterized by deteriorating graft function, interstitial fibrosis, cardiac hypertrophy, and occlusive neointima development. TGF\u03b2, known for its immunosuppressive qualities, plays a beneficial role in the transplant setting by maintaining alloreactive T cells in a hyporesponsive state, but has also been implicated in promoting graft fibrosis and CR. In the mouse vascularized cardiac allograft model, transient depletion of CD4+ cells promotes graft survival but leads to CR, which is associated with intragraft TGF\u03b2 expression. Decorin, an extracellular matrix protein, inhibits both TGF\u03b2 bioactivity and gene expression. In this study, gene transfer of decorin into cardiac allografts was used to assess the impact of intragraft TGF\u03b2 neutralization on CR, systemic donor-reactive T cell responses, and allograft acceptance. Decorin gene transfer and neutralization of TGF\u03b2 in cardiac allografts significantly attenuated interstitial fibrosis, cardiac hypertrophy, and improved graft function, but did not result in systemic donor-reactive T cell responses. Thus, donor-reactive T and B cells remained in a hyporesponsive state. These findings indicate that neutralizing intragraft TGF\u03b2 inhibits the cytokine\u2019s fibrotic activities, but does not reverse its beneficial systemic immunosuppressive qualities.<\/jats:p>","DOI":"10.4049\/jimmunol.0902736","type":"journal-article","created":{"date-parts":[[2009,11,16]],"date-time":"2009-11-16T21:55:14Z","timestamp":1258408514000},"page":"7307-7313","source":"Crossref","is-referenced-by-count":21,"title":["TGF\u03b2 Neutralization within Cardiac Allografts by Decorin Gene Transfer Attenuates Chronic Rejection"],"prefix":"10.1093","volume":"183","author":[{"given":"Susan M","family":"Faust","sequence":"first","affiliation":[{"name":"Department of Surgery"},{"name":"Graduate Program in Cellular and Molecular Biology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guanyi","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Surgery"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sherri C","family":"Wood","sequence":"additional","affiliation":[{"name":"Department of Surgery"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D Keith","family":"Bishop","sequence":"additional","affiliation":[{"name":"Department of Surgery"},{"name":"Graduate Program in Cellular and Molecular Biology"},{"name":"Graduate Program in Immunology, University of Michigan School of Medicine , Ann Arbor, MI 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2009,12,1]]},"reference":[{"key":"2026012811272687000_R1","first-page":"455","article-title":"New directions in cardiac transplantation.","volume-title":"Annu. Rev. Med.","year":"2006"},{"key":"2026012811272687000_R2","first-page":"33","article-title":"Chronic allograft rejection.","volume-title":"Immunol. Rev.","year":"1993"},{"key":"2026012811272687000_R3","first-page":"1773","article-title":"Critical role for IL-6 in hypertrophy and fibrosis in chronic cardiac allograft rejection.","volume-title":"Am. J. Transplant.","year":"2009"},{"key":"2026012811272687000_R4","first-page":"387","article-title":"Chronic rejection.","volume-title":"Immunity","year":"2001"},{"key":"2026012811272687000_R5","first-page":"676","article-title":"Chronic remodeling pathology in grafts.","volume-title":"Curr. Opin. Immunol.","year":"1997"},{"key":"2026012811272687000_R6","first-page":"2069","article-title":"Cardiac allograft vasculopathy: a review.","volume-title":"Circulation","year":"1997"},{"key":"2026012811272687000_R7","first-page":"99","article-title":"Transforming growth factor-\u03b2 regulation of immune responses.","volume-title":"Annu. Rev. Immunol.","year":"2006"},{"key":"2026012811272687000_R8","first-page":"693","article-title":"Targeted disruption of the mouse transforming growth factor-\u03b2 1 gene results in multifocal inflammatory disease.","volume-title":"Nature","year":"1992"},{"key":"2026012811272687000_R9","first-page":"264","article-title":"Transforming growth factor-\u03b2 1 null mice: an animal model for inflammatory disorders.","volume-title":"Am. J. Pathol.","year":"1995"},{"key":"2026012811272687000_R10","first-page":"443","article-title":"TGF\u03b2 signalling in control of T-cell-mediated self-reactivity.","volume-title":"Nat. Rev. Immunol.","year":"2007"},{"key":"2026012811272687000_R11","first-page":"1297","article-title":"The role of TGF-\u03b2 in growth, differentiation, and maturation of B lymphocytes.","volume-title":"Microbes Infect.","year":"1999"},{"key":"2026012811272687000_R12","first-page":"629","article-title":"Cell contact-dependent immunosuppression by CD4+CD25+ regulatory T cells is mediated by cell surface-bound transforming growth factor \u03b2.","volume-title":"J. Exp. Med.","year":"2001"},{"key":"2026012811272687000_R13","first-page":"263","article-title":"The role of IL-10 and TGF-\u03b2 in the differentiation and effector function of T regulatory cells.","volume-title":"Int. Arch. Allergy Immunol.","year":"2002"},{"key":"2026012811272687000_R14","first-page":"1875","article-title":"Conversion of peripheral CD4+CD25\u2212 naive T cells to CD4+CD25+ regulatory T cells by TGF-\u03b2 induction of transcription factor Foxp3.","volume-title":"J. Exp. Med.","year":"2003"},{"key":"2026012811272687000_R15","first-page":"441","article-title":"Cellular mechanisms of fatal early-onset autoimmunity in mice with the T cell-specific targeting of transforming growth factor-\u03b2 receptor.","volume-title":"Immunity","year":"2006"},{"key":"2026012811272687000_R16","first-page":"1349","article-title":"TGF-\u03b2 and fibrosis.","volume-title":"Microbes Infect.","year":"1999"},{"key":"2026012811272687000_R17","first-page":"816","article-title":"TGF-\u03b2 signaling and the fibrotic response.","volume-title":"FASEB J.","year":"2004"},{"key":"2026012811272687000_R18","first-page":"7723","article-title":"Transforming growth factor (TGF)-\u03b21 stimulates pulmonary fibrosis and inflammation via a Bax-dependent, bid-activated pathway that involves matrix metalloproteinase-12.","volume-title":"J. Biol. Chem.","year":"2007"},{"key":"2026012811272687000_R19","first-page":"461","article-title":"Expression of transforming growth factor-\u03b2 isoforms in human glomerular diseases.","volume-title":"Kidney Int.","year":"1996"},{"key":"2026012811272687000_R20","first-page":"505","article-title":"Transforming growth factor-\u03b2 and connective tissue growth factor: key cytokines in scleroderma pathogenesis.","volume-title":"Curr. Opin. Rheumatol.","year":"2001"},{"key":"2026012811272687000_R21","first-page":"959","article-title":"Transforming growth factor \u03b2-induced connective tissue growth factor and chronic allograft rejection.","volume-title":"Am. J. Transplant.","year":"2006"},{"key":"2026012811272687000_R22","first-page":"207","article-title":"TGF\u03b2, cardiac fibroblasts, and the fibrotic response.","volume-title":"Cardiovasc. Res.","year":"2007"},{"key":"2026012811272687000_R23","first-page":"221","article-title":"Transforming growth factor-\u03b2 and p-21: multiple molecular targets of decorin-mediated suppression of neoplastic growth.","volume-title":"Cell Tissue Res.","year":"1999"},{"key":"2026012811272687000_R24","first-page":"281","article-title":"Negative regulation of transforming growth factor-\u03b2 by the proteoglycan decorin.","volume-title":"Nature","year":"1990"},{"key":"2026012811272687000_R25","first-page":"361","article-title":"Natural inhibitor of transforming growth factor-\u03b2 protects against scarring in experimental kidney disease.","volume-title":"Nature","year":"1992"},{"key":"2026012811272687000_R26","first-page":"418","article-title":"Gene therapy by skeletal muscle expression of decorin prevents fibrotic disease in rat kidney.","volume-title":"Nat. Med.","year":"1996"},{"key":"2026012811272687000_R27","first-page":"643","article-title":"Decorin suppresses transforming growth factor-\u03b2-induced expression of plasminogen activator inhibitor-1 in human mesangial cells through a mechanism that involves Ca2+-dependent phosphorylation of Smad2 at serine-240.","volume-title":"Biochem J.","year":"2002"},{"key":"2026012811272687000_R28","first-page":"L1327","article-title":"Proteoglycans decorin and biglycan differentially modulate TGF-\u03b2-mediated fibrotic responses in the lung.","volume-title":"Am. J. Physiol.","year":"2001"},{"key":"2026012811272687000_R29","first-page":"1920","article-title":"A critical role for transforming growth factor-\u03b2 in donor transfusion-induced allograft tolerance.","volume-title":"J. Clin. Invest.","year":"1998"},{"key":"2026012811272687000_R30","first-page":"3648","article-title":"A key role for TGF-\u03b2 signaling to T cells in the long-term acceptance of allografts.","volume-title":"J. Immunol.","year":"2007"},{"key":"2026012811272687000_R31","first-page":"576","article-title":"Helper T lymphocyte unresponsiveness to cardiac allografts following transient depletion of CD4-positive cells: implications for cellular and humoral responses.","volume-title":"Transplantation","year":"1994"},{"key":"2026012811272687000_R32","first-page":"1548","article-title":"Cytokine regulation of chronic cardiac allograft rejection: evidence against a role for Th1 in the disease process.","volume-title":"Transplantation","year":"1999"},{"key":"2026012811272687000_R33","first-page":"1622","article-title":"The classical complement pathway in transplantation: unanticipated protective effects of C1q and role in inductive antibody therapy.","volume-title":"Am. J. 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Med.","year":"1999"},{"key":"2026012811272687000_R38","first-page":"1292","article-title":"DNA-liposome versus adenoviral mediated gene transfer of transforming growth factor \u03b21 in vascularized cardiac allografts: differential sensitivity of CD4+ and CD8+ T cells to transforming growth factor \u03b21.","volume-title":"Transplantation","year":"2000"},{"key":"2026012811272687000_R39","first-page":"906","article-title":"High-resolution characterization of cytokine-producing alloreactivity in naive and allograft-primed mice.","volume-title":"Transplantation","year":"1998"},{"key":"2026012811272687000_R40","first-page":"S54","article-title":"TGF-\u03b2-induced fibrosis and SMAD signaling: oligo decoys as natural therapeutics for inhibition of tissue fibrosis and scarring.","volume-title":"Wound Repair Regen.","year":"2007"},{"key":"2026012811272687000_R41","first-page":"1398","article-title":"Tregs and transplantation tolerance.","volume-title":"J. Clin. Invest.","year":"2004"},{"key":"2026012811272687000_R42","first-page":"120","article-title":"Role and mechanisms of CD4+CD25+ regulatory T cells in the induction and maintenance of transplantation tolerance.","volume-title":"Transpl. Immunol.","year":"2007"},{"key":"2026012811272687000_R43","first-page":"235","article-title":"Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells.","volume-title":"Nature","year":"2006"},{"key":"2026012811272687000_R44","first-page":"231","article-title":"Transforming growth factor-\u03b2 induces development of the TH17 lineage.","volume-title":"Nature","year":"2006"},{"key":"2026012811272687000_R45","first-page":"236","article-title":"TGF-\u03b2-induced Foxp3 inhibits TH17 cell differentiation by antagonizing ROR\u03b3t function.","volume-title":"Nature","year":"2008"},{"key":"2026012811272687000_R46","first-page":"1518","article-title":"T regulatory cells and migration.","volume-title":"Am. J. Transplant.","year":"2006"},{"key":"2026012811272687000_R47","first-page":"199","article-title":"Genetic determinants of cardiac hypertrophy.","volume-title":"Curr. Opin. Cardiol.","year":"2008"},{"key":"2026012811272687000_R48","first-page":"715","article-title":"Serial killer: angiotensin drives cardiac hypertrophy via TGF-\u03b21.","volume-title":"J. Clin. Invest.","year":"2002"},{"key":"2026012811272687000_R49","first-page":"132","article-title":"Cardiac allograft remodeling after heart transplantation is associated with increased graft vasculopathy and mortality.","volume-title":"Am. J. Transplant.","year":"2009"},{"key":"2026012811272687000_R50","first-page":"7","article-title":"Cardiac allograft hypertrophy: a new target for therapy, a surrogate marker for survival?.","volume-title":"Am. J. Transplant.","year":"2009"},{"key":"2026012811272687000_R51","first-page":"867","article-title":"Therapeutic targets in the treatment of allograft fibrosis.","volume-title":"Am. J. 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Immunol.","year":"2007"},{"key":"2026012811272687000_R56","first-page":"1037","article-title":"Recruitment of Foxp3+ T regulatory cells mediating allograft tolerance depends on the CCR4 chemokine receptor.","volume-title":"J. Exp. Med.","year":"2005"},{"key":"2026012811272687000_R57","first-page":"616","article-title":"Control of regulatory T cell lineage commitment and maintenance.","volume-title":"Immunity","year":"2009"},{"key":"2026012811272687000_R58","first-page":"176","article-title":"Thymic development and peripheral homeostasis of regulatory T cells.","volume-title":"Curr. Opin. Immunol.","year":"2007"},{"key":"2026012811272687000_R59","first-page":"458","article-title":"Regulatory T cells sequentially migrate from inflamed tissues to draining lymph nodes to suppress the alloimmune response.","volume-title":"Immunity","year":"2009"},{"key":"2026012811272687000_R60","first-page":"258","article-title":"Stimulation of collagen production by transforming growth factor-\u03b21 during differentiation of cardiac fibroblasts to myofibroblasts.","volume-title":"Hypertension","year":"2002"},{"key":"2026012811272687000_R61","first-page":"75","article-title":"Pathologic hypertrophy with fibrosis: the structural basis for myocardial failure.","volume-title":"Blood","year":"1992"},{"key":"2026012811272687000_R62","first-page":"34","article-title":"Decorin-mediated transforming growth factor-\u03b2 inhibition ameliorates adverse cardiac remodeling.","volume-title":"J. Heart Lung Transplant.","year":"2007"},{"key":"2026012811272687000_R63","first-page":"1051","article-title":"Induction and effector functions of TH17 cells.","volume-title":"Nature","year":"2008"},{"key":"2026012811272687000_R64","first-page":"454","article-title":"The biological functions of T helper 17 cell effector cytokines in inflammation.","volume-title":"Immunity","year":"2008"},{"key":"2026012811272687000_R65","first-page":"H3356","article-title":"IL-17 stimulates MMP-1 expression in primary human cardiac fibroblasts via p38 MAPK- and ERK1\/2-dependent C\/EBP-\u03b2, NF-\u03baB, and AP-1 activation.","volume-title":"Am. J. Physiol.","year":"2007"},{"key":"2026012811272687000_R66","first-page":"H2078","article-title":"Resveratrol inhibits high glucose-induced PI3K\/Akt\/ERK-dependent interleukin-17 expression in primary mouse cardiac fibroblasts.","volume-title":"Am. J. Physiol.","year":"2008"},{"key":"2026012811272687000_R67","first-page":"3498","article-title":"IL-17-dependent cellular immunity to collagen type V predisposes to obliterative bronchiolitis in human lung transplants.","volume-title":"J. Clin. Invest.","year":"2007"},{"key":"2026012811272687000_R68","first-page":"430","article-title":"IL-17 is increased in asthmatic airways and induces human bronchial fibroblasts to produce cytokines.","volume-title":"J. Allergy Clin. Immunol.","year":"2001"},{"key":"2026012811272687000_R69","first-page":"221","article-title":"Is cystic fibrosis a TH17 disease?.","volume-title":"Inflamm. Res.","year":"2007"},{"key":"2026012811272687000_R70","first-page":"657","article-title":"Th17-polarized immune response in a murine model of hypersensitivity pneumonitis and lung fibrosis.","volume-title":"J. Immunol.","year":"2009"},{"key":"2026012811272687000_R71","first-page":"4715","article-title":"Interactions of the extracellular matrix proteoglycans decorin and biglycan with C1q and collectins.","volume-title":"J. Immunol.","year":"2005"},{"key":"2026012811272687000_R72","first-page":"191","article-title":"Antibody and complement in transplant vasculopathy.","volume-title":"Circ. Res.","year":"2007"},{"key":"2026012811272687000_R73","first-page":"7297","article-title":"Role of T cell TGF\u03b2 signaling and IL-17 in allograft acceptance and fibrosis associated with chronic rejection.","volume-title":"J. 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