Anti-HLA antibody binding to HLA class I molecules induces proliferation of airway epithelial cells: A potential mechanism for bronchiolitis obliterans syndrome

Reznik, Scott I.; Jaramillo, Andrés; Zhang, Leiying; Patterson, G. Alexander; Cooper, Joel D.; Mohanakumar, T.

doi:10.1016/s0022-5223(00)70215-7

Cited by 68 publications

(42 citation statements)

References 24 publications

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“…A number of studies have suggested possible mechanistic effects of HLA-specific antibodies in the development of obstructive airway disease. [37][38][39][40][41] The majority of these studies utilized W6/32, a monoclonal antibody directed against a monomorphic determinant on HLA Class I molecules. Ligation of W6/32 to epithelial cells has been shown to cause cell proliferation, production of growth factors and chemotactic factors, as well as cell death through apoptosis.…”

Section: Discussionmentioning

confidence: 99%

De novo donor HLA-specific antibodies predict development of bronchiolitis obliterans syndrome after lung transplantation

Safavi

Robinson

Soresi

et al. 2014

The Journal of Heart and Lung Transplantation

115

104

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(2014) De novo donor HLA-specific antibodies predict development of bronchiolitis obliterans syndrome after lung transplantation. The Journal of Heart and Lung Transplantation, 33 (12). pp. 1273 -1281 . ISSN 1053 -2498 This version is available from Sussex Research Online: http://sro.sussex.ac.uk/56766/ This document is made available in accordance with publisher policies and may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher's version. Please see the URL above for details on accessing the published version. Copyright and reuse:Sussex Research Online is a digital repository of the research output of the University.Copyright and all moral rights to the version of the paper presented here belong to the individual author(s) and/or other copyright owners. To the extent reasonable and practicable, the material made available in SRO has been checked for eligibility before being made available.Copies of full text items generally can be reproduced, displayed or performed and given to third parties in any format or medium for personal research or study, educational, or not-for-profit purposes without prior permission or charge, provided that the authors, title and full bibliographic details are credited, a hyperlink and/or URL is given for the original metadata page and the content is not changed in any way. There was a significant reduction in patient survival associated with de novo DSA (HR ¼ 1.886, p ¼ 0.047). In multivariable analyses, de novo DSA was an independent predictor for development of all stages of BOS as well as an independent predictor of poor patient survival. CONCLUSIONS: De novo DSA is a major risk factor for progression to BOS and shorter patient survival. Treatments to remove antibodies or limit antibody-mediated damage could be considered when DSA are first detected. However, a randomized, controlled trial of treatment options would enable a clearer understanding of the benefits, if any, of antibody-removal therapies.

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Section: Discussionmentioning

confidence: 99%

De novo donor HLA-specific antibodies predict development of bronchiolitis obliterans syndrome after lung transplantation

Safavi

Robinson

Soresi

et al. 2014

The Journal of Heart and Lung Transplantation

115

104

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“…In lung allografts, immune responses targeted against the epithelial cells have been thought to play a crucial role in chronic rejection of the transplanted lungs (3)(4)(5)(6). Using primary airway epithelial cell as targets, we analyzed the presence of antiepithelial Abs in a subset of lung transplant recipients with no detectable anti-HLA Abs by both complement-dependent assays as well as solid-phase assays (ELISA and flow cytometry) for the detection of Abs against HLA.…”

Section: Discussionmentioning

confidence: 99%

“…T he development of bronchiolitis obliterans syndrome (BOS) 4 remains the Achilles heel of human lung transplantation. BOS occurs in nearly all allografts by 10 years after transplant and is the main cause of morbidity and mortality following lung transplantation.…”

mentioning

confidence: 99%

“…Several studies have shown that the airway epithelial cells (AECs) are the main target for the immunologic insult during the pathogenesis of allograft rejection (3)(4)(5)(6). In vitro studies from our laboratory (7) and others (8) have demonstrated that activation of epithelial cells results in the production of growth factors including TGF-␤, epidermal growth factor, basic fibroblast growth factor, and endothelin-1.…”

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confidence: 99%

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De Novo Production of K-α1 Tubulin-Specific Antibodies: Role in Chronic Lung Allograft Rejection

Goers¹,

Ramachandran²,

Aloush

et al. 2008

The Journal of Immunology

181

197

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Lung transplantation is the treatment option for a variety of end-stage pulmonary diseases. Posttransplant development of Abs against donor HLA and non-HLA Ags have been associated with acute and chronic rejection of transplanted organs. Development of bronchiolitis obliterans syndrome (BOS) following lung transplantation has been correlated with de novo production of anti-donor-HLA Abs. However, only a portion of the patients with BOS demonstrate detectable anti-donor-HLA Abs. Airway epithelium is considered as a major target for lung allograft rejection. In this study we demonstrate that many BOS+ patients (12 of 36) develop Abs reactive to epithelial cell Ag that are distinct from HLA. Furthermore, de novo production of antiepithelial cell Ab precedes clinical onset of BOS. N-terminal sequencing and blastx analysis as well as blocking with K-α1 tubulin-specific Ab identified the epithelial Ag as K-α1 tubulin. Binding of the de novo-produced anti-K-α1 tubulin Abs to the airway epithelial cells resulted in the increased expression of transcription factors (TCF5 and c-Myc), leading to increased expression of fibrogenic growth factors, activation of cell cycle signaling, and fibroproliferation, the central events in immunopathogenesis of BOS following human lung transplantation.

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“…During acute cellular rejection, there is an increased ratio of IgG2/IgG1 within the lung allograft, suggesting local upregulation of Th1 activity (93). Although non-complementfixing antibodies can activate bronchial epithelial cells by crosslinking antigens (94), recent studies in transplants other than the lung implicate complement activation in the pathogenesis of rejection. For example, systemic activation of complement by cobra venom in rats causes pulmonary vascular leakage that can be prevented by blocking C5a (95).…”

Section: Humoral Immunitymentioning

confidence: 99%

Lung Transplantation: Opportunities for Research and Clinical Advancement

Wilkes¹

2006

Am J Respir Crit Care Med

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Lung transplantation is the only definitive therapy for many forms of end-stage lung diseases. However, the success of lung transplantation is limited by many factors: (1 ) Too few lungs available for transplantation due to limited donors or injury to the donor lung; (2 ) current methods of preservation of excised lungs do not allow extended periods of time between procurement and implantation; (3 ) acute graft failure is more common with lungs than other solid organs, thus contributing to poorer short-term survival after lung transplant compared with that for recipients of other organs; (4 ) lung transplant recipients are particularly vulnerable to pulmonary infections; and (5 ) chronic allograft dysfunction, manifest by bronchiolitis obliterans syndrome, is frequent and limits long-term survival. Scientific advances may provide significant improvements in the outcome of lung transplantation. The National Heart, Lung, and Blood Institute convened a working group of investigators on June 14-15, 2004, in Bethesda, Maryland, to identify opportunities for scientific advancement in lung transplantation, including basic and clinical research. This workshop provides a framework to identify critical issues related to clinical lung transplantation, and to delineate important areas for productive scientific investigation. Keywords: allograft dysfunction; infection; ischemia-reperfusion injury; lung transplantation; obliterative bronchiolitis; rejectionThe transplantation of organs offers the promise of life-saving and life-enhancing therapy for a variety of ailments. Lung transplantation (LTx) has become an acceptable therapy to palliate patients with a variety of end-stage lung diseases. However, lung transplantation has not turned out to be a panacea for chronic lung disease because of significant limitations in the entire transplant process (Figure 1). First, there are not nearly enough suitable donor lungs to meet the needs of all patients with end-stage lung disease. As a result, more patients die waiting for transplants than from mortality associated with a lung transplant. Second, early graft survival after LTx is worse than for other types of organs transplanted (1). Finally, late survival after successful LTx is hampered by the development of chronic allograft dysfunction and by the life-limiting complications associated with conventional immunosuppressive medications. Two factors impede progress to address these problems: (1 ) lung transplant centers lack the infrastructure to facilitate prospective, multicenter clinical studies of sufficient power to address clinical questions and (2 ) there are too few investigators studying the biology of lung transplantation.The NHLBI convened a workshop on June 14-15, 2004, to better understand these complex problems and to identify strategies to address these and prioritize them. The topics addressed by participants were wide-ranging. They included the following: lung use rates from conventional brain-dead organ donors; safe limits for donor lung function; consideration o...

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Anti-HLA antibody binding to HLA class I molecules induces proliferation of airway epithelial cells: A potential mechanism for bronchiolitis obliterans syndrome

Cited by 68 publications

References 24 publications

De novo donor HLA-specific antibodies predict development of bronchiolitis obliterans syndrome after lung transplantation

De novo donor HLA-specific antibodies predict development of bronchiolitis obliterans syndrome after lung transplantation

De Novo Production of K-α1 Tubulin-Specific Antibodies: Role in Chronic Lung Allograft Rejection

Lung Transplantation: Opportunities for Research and Clinical Advancement

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