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Bronchiolitis obliterans in lung transplantation: the good, the bad, and the future

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Lung transplantation remains the hope for many incurable pulmonary diseases, such as cystic fibrosis, pulmonary fibrosis, and chronic obstructive pulmonary disease. Remarkable progress has been made in improving outcomes, although the incidence of acute rejection remains more than 50% in the 1st year, and the 5-year graft survival is still less than 50% primarily because of the development of chronic rejection and graft dysfunction. Chronic rejection is characterized by the development of obliterative bronchiolitis in allografts and manifests as bronchiolitis obliterans syndrome in humans with no effective treatment. Previous studies support a role for alloreactive T cells in the development of bronchiolitis obliterans syndrome, but the specific mechanisms are unknown. One major stumbling block to research in the field of lung transplantation has been the lack of physiologic models to study the disease in the laboratory. We will review the current understanding of the immunology of the pathogenesis of obliterative bronchiolitis and will discuss exciting new advances from the laboratory as well as the implications for future research in lung transplantation.

Section snippets

Current Models

An understanding of the current knowledge in lung transplant research requires a brief introduction to the models used to study OB. In the early 1980s, Marck et al24, 25, 26 demonstrated that lung transplantation in rats was technically feasible and used imaging modalities to assess allograft function. Despite its early successes, the rat model has subsequently yielded mixed results. Yasufuku et al27 have successfully used the rat model to study the pathogenesis of OB and have recently

Alloimmunity

The primary basis for rejection of solid organs is host recognition of non-self-donor antigens or the alloimmune response. The immune response to alloantigens is primarily initiated by a T-cell response, which may then promote a B-cell response that leads to alloantibody production. After transplantation, the T-cell receptor (TCR) on host T cells recognizes its cognate peptide major histocompatibility complex (MHC) present on donor cells. Why humans have evolved to have alloreactive T and B

Innate Immunity: Toll-Like Receptor (TLR) Ligands

A challenge for improving lung transplantation outcomes is to dissect the unique mechanisms by which the lung, unlike other solid organs, may respond to stressors, such as I/R injury, infection, and environmental insults. The normal lung has dendritic cells, macrophages, epithelium, and endothelium, which all contribute to its defense against the environment and mediate the innate immune response. How these cells respond to stimuli impacts the adaptive immune response of T and B cells. The

Innate Immunity: Dendritic Cells

The major APC type that links the innate immune response in the lung to activation of the alloimmune response is the dendritic cell (DC).62, 63 DCs after transplantation migrate from the donor to the recipient's lymph nodes and directly induce the alloimmune response (Fig 1). Studies have found that depletion of DCs significantly abrogates acute allograft rejection in both animal models and human kidney transplant patients.63 Because the mucosal surface of the lung is estimated to have a

Innate Immunity: Macrophages and Other Innate Cells

Although DCs are the likely APCs responsible for initiating the alloimmune response, other innate cell types in the lung clearly modify the adaptive immune response. Macrophages, neutrophils, mast cells, and natural killer (NK) cells have been implicated in transplantation. Macrophages play a role in lung homeostasis and pathogen defense and have been shown to be a source of growth factors thought to mediate the fibroproliferation characteristic of OB in humans.71 Depletion of macrophages in a

Adaptive Immune Response

Studies in humans with BOS have consistently implicated persistent alloimmunity in the pathogenesis of OB. Although the association of MHC class II expression with the development of OB has long been recognized,47 more recently, direct evidence of persistent alloimmune humoral and cellular responses has been found. Humans with antidonor HLA antibodies have been found to be more likely to develop BOS79, 80; as discussed above, anti–donor-specific indirect T-cell responses have also been

Structural Cells

Epithelium. Although the alloimmune response clearly plays a role in the pathogenesis leading to OB, the epithelium has long been thought to contribute to the fibrotic response in the lung. Numerous studies have implicated epithelial cells as both a major target of the immune response and as a causative agent in the creation of OB.93, 94, 95 It is hypothesized that severe damage to bronchiolar epithelium may lead to excessive proliferation of granulation tissue and destructive fibrous scarring

Future Directions

New models are constantly being developed to determine the mechanisms of OB more accurately. The ideal model for studying lung alloreactivity would be one that is not technically prohibitive and that closely resembles both the natural pulmonary physiology, as well as the pathophysiology of lung transplantation rejection both acute and chronic. Currently, none of the available models fulfill these criteria. The limitations of the current models have provided an incentive to investigators to

Summary

The lung is a complex organ involved in mucosal defense and gas exchange in which the immune system has evolved to protect both barriers. The response to chronic alloimmune mediated and acute I/R injury including PGD, infectious, and environmental insults and their effects on the adaptive immune response are only beginning to be defined (Fig 2). The future of lung transplantation depends on dissecting the deleterious immune response to these insults and on determining the mechanisms promoting a

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    Supported by Grant K08 AI 059105 from the National Institute of Health and the Louis Block Fund.

    Rebecca A. Shilling, MD, is Assistant Professor in the Department of Medicine, Section of Pulmonary and Critical at the University of Chicago. Her article is based on a presentation given at the Combined Annual Meeting of the Central Society for Clinical Research and Midwestern Section American Federation for Medical Research held in Chicago, Ill, April 2008.

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