Immunobiology of Chronic Lung Allograft Dysfunction: New Insights from the Bench and Beyond

Section of Pulmonary and Critical Care Medicine, Department of Medicine and Committee on Immunology, University of Chicago, Chicago, IL, USA.
American Journal of Transplantation (Impact Factor: 5.68). 07/2009; 9(8):1714-8. DOI: 10.1111/j.1600-6143.2009.02690.x
Source: PubMed


The first successful human lung transplants were performed in the 1980s. Since that time lung transplantation has been a therapeutic modality for end-stage pulmonary diseases. However, chronic rejection, known as obliterative bronchiolitis (OB)/bronchiolitis obliterans syndrome (BOS), is the key reason why the 5-year survival is only 50%, which is significantly worse than most other solid organ transplants. Recent studies have provided exciting advances that are beginning to be translated into findings in humans. This review will highlight the current advances in understanding the mechanisms of OB/BOS in lung transplant recipients.

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Available from: Rebecca Shilling, Jun 27, 2014
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    • "However, long-term allograft survival in lung transplantation is hampered by chronic graft dysfunction. Major improvements in surgical techniques, management with immunosuppressive agents, and control of infections have improved 1-yr survival to 70–80%, but mortality due to OB remains alarmingly high, with only 40–50% survival five years after OB develops [5, 9, 33, 34]. The lung has the highest rate of rejection among all solid organ transplants, probably owing to epithelial immunological vulnerability and injury due to its constant exposure to airborne antigens, pathogens, and pollutants. "
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    ABSTRACT: Obliterative bronchiolitis (OB) remains the most significant cause of death in long-term survival of lung transplantation. Using an established murine heterotopic tracheal allograft model, the effects of different routes of administration of bone marrow-derived multipotent stromal cells (MSCs) on the development of OB were evaluated. Tracheas from BALB/c mice were implanted into the subcutaneous tissue of major histocompatibility complex- (MHC-) disparate C57BL/6 mice. At the time of transplant, bone marrow-derived MSCs were administered either systemically or locally or via a combination of the two routes. The allografts were explanted at various time points after transplantation and were evaluated for epithelial integrity, inflammatory cell infiltration, fibrosis, and luminal obliteration. We found that the most effective route of bone marrow-derived MSC administration is the combination of systemic and local delivery. Treatment of recipient mice with MSCs suppressed neutrophil, macrophage, and T-cell infiltration and reduced fibrosis. These beneficial effects were observed despite lack of significant MSC epithelial engraftment or new epithelial cell generation. Our study suggests that optimal combination of systemic and local delivery of MSCs may ameliorate the development of obliterative airway disease through modulation of immune response.
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    • "A 'semi-direct' pathway has also been recently described which involves recipient APCs that acquire donor MHC through cell-to-cell contact and activate host T cell responses which may contributes to CR [4] [5] [6] [7]. While the direct pathway is more important for acute allograft rejection, the indirect pathway plays a dominant role in CR [8] [9]. Experiments have demonstrated that inhibition of acute rejection by depleting passenger APC significantly delays but does not prevent development of CR [10]. "
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    ABSTRACT: Recent studies strongly suggest an increasing role for immune responses against self-antigens (Ags) which are not encoded by the major histocompatibility complex in the immunopathogenesis of allograft rejection. Although, improved surgical techniques coupled with improved methods to detect and avoid sensitization against donor human leukocyte antigen (HLA) have improved the immediate and short term function of transplanted organs. However, acute and chronic rejection still remains a vexing problem for the long term function of the transplanted organ. Immediately following organ transplantation, several factors both immune and non immune mechanisms lead to the development of local inflammatory milieu which sets the stage for allograft rejection. Traditionally, development of antibodies (Abs) against mismatched donor HLA have been implicated in the development of Ab mediated rejection. However, recent studies from our laboratory and others have demonstrated that development of humoral and cellular immune responses against non-HLA self-Ags may contribute in the pathogenesis of allograft rejection. There are reports demonstrating that immune responses to self-Ags especially Abs to the self-Ags as well as cellular immune responses especially through IL17 has significant pro-fibrotic properties leading to chronic allograft failure. This review summarizes recent studies demonstrating the role for immune responses to self-Ags in allograft immunity leading to rejection as well as present recent evidence suggesting there is interplay between allo- and autoimmunity leading to allograft dysfunction.
    Full-text · Article · Jul 2013 · Human immunology
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