Chronic Lung Allograft Dysfunction: A Systematic Review of Mechanisms : Transplantation

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Chronic Lung Allograft Dysfunction

A Systematic Review of Mechanisms

Royer, Pierre-Joseph PhD; Olivera-Botello, Gustavo PhD; Koutsokera, Angela MD; Aubert, John-David MD; Bernasconi, Eric PhD; Tissot, Adrien MD; Pison, Christophe MD, PhD; Nicod, Laurent MD; Boissel, Jean-Pierre MD, PhD; Magnan, Antoine MD on behalf of the SysCLAD consortium

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Transplantation 100(9):p 1803-1814, September 2016. | DOI: 10.1097/TP.0000000000001215
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The 2014 report of the International Society for Heart and Lung Transplantation registry accounts for 47 647 adult lung transplantations and for 3772 adult heart-lung transplantations performed up to June 2013.1 This reflects an average 8% annual increase in the number of adult lung transplantations reported between the years 2001 and 2011. Progresses in surgical techniques and perioperative management have dramatically increased the short-term survival. Yet, long-term survival remains disappointing with a dismal 27% survival rate at 10 years that makes lung transplantation the intervention with the poorest long-term outcome when compared with other solid-organ transplantation such as kidney (58%), liver (70%), heart (56%), pancreas (77%) or intestine (44%).2 The development of chronic dysfunction or chronic lung allograft dysfunction (CLAD), affecting 50% of patients at 5 years, partly accounts for these clinical pictures.

For a long time, bronchiolitis obliterans, or its surrogate bronchiolitis obliterans syndrome (BOS), was considered to be the only manifestation of chronic lung dysfunction, hence the terms “chronic rejection” and “BOS” were indistinctively used.3 However, a distinct nosological entity coined under the name of restrictive allograft syndrome (RAS) was characterized in 2011.4 Since then, the term CLAD has been used to refer to all variants of pulmonary chronic dysfunction, in particular BOS and RAS. In Sato's seminal article, the probability of developing CLAD by 5 years was reported to be around 50%; 35% for the BOS phenotype and 15% for the RAS phenotype (after exclusion of recipients who died within the first 3 months post transplantation).4 Despite its smaller incidence, the restrictive phenotype seems to imply a poorer prognosis, with a median survival, after disease onset of less than 2 years (compared with around 4 years for BOS phenotype). The survival at 10 years reported in the same monocentric study was then 16% for the RAS group and 31% for the BOS group, which heavily contrasts with the 72% figure reported for the free-from-CLAD group. Histologically, RAS is characterized by a stair-step progression pattern, with tissue damage and fibrotic lesions occurring in the periphery of the lungs (ie, in the visceral pleura, in the alveolar interstitium and in the interlobular septa)4; whereas in the case of BOS, the fibrotic lesions are more likely to occur in the bronchioles.5 Nonetheless, both types of lesions may coexist6 and overall, risk factors are similar between BOS and RAS,7 suggesting that both syndromes share common physio-pathological mechanisms. However, the specificity of these 2 diseases start to emerge from recent investigations. Diffuse alveolar damage (DAD) for example precedes CLAD,8,9 but time patterns determine the outcome of the pathology: late-onset DAD has been correlated with RAS, whereas early-onset DAD, diagnosed within the first 3 months after transplantation, has been associated with BOS.8

We will present here the mechanisms leading to CLAD after lung transplantation, and we will highlight the specific factors behind BOS or RAS development. The terms “lung transplantation,” “chronic rejection,” “chronic dysfunction,” “CLAD,” “BOS,” “bronchiolitis obliterans,” or “RAS” were used alone and in combination to search in PubMed over the past 25 years 2015. Abstracts from the 2015 American Transplant Congress, International Society for Heart and Lung Transplantation meeting and European Respiratory Society congress were also reviewed. The most relevant and appropriate articles were then hand selected to prepare this review.


The Receptors of Innate Immunity: Recognition of Exogenous and Endogenous Molecules

Lungs are continuously exposed to environment. Innate immunity is then repeatedly stimulated by pathogens, allergens, or pollutants. The innate immune system recognizes pathogen associated molecular patterns through the expression of a wide range of pathogen recognition receptors. Among them, the toll like receptors (TLR) comprise a family of 13 members expressed by hematopoietic or parenchymal cells involved in the recognition of pathogens.10 In humans, an association was suggested between polymorphism of TLR2, TLR4, and TLR9 involved in bacteria or virus recognition, and the probability of developing CLAD.11,12 In mice, activating TLR4 or TLR3 in the lungs via the administration of repetitive doses of aerosolized LPS13 or synthetic double-strand RNA14 results in obliterative bronchiolitis.

The impact of viral, bacterial, or fungal infections in the development on CLAD has been known for a while and undoubtedly increases the risk for chronic rejection.15-18 Things appear more complex regarding graft colonization. Although colonization by aspergillus is associated with an increase of BOS,19,20 de novo but not persistent colonization by pseudomonas has been found as a risk factor for BOS,21 and reestablishment of the pretransplant microbiota can even reduce the risk of chronic rejection.22 Interestingly, CXCL1 and CXCL5 secretion after pseudomonas colonization determines the transition to chronic rejection.23 Further works will have to establish if modulation of pseudomonas virulence factors during long-term colonization24 regulate host immune response and thus susceptibility to CLAD.

Besides pathogens, TLR can be triggered by the endotoxins present in the gastric reflux of lung transplant recipients suffering from gastroesophageal reflux disease.25 Additionally, pollutants are known now to be strong activators of innate immunity,26 and attention has been recently drawn to traffic-related air pollution exposure and the risk of developing CLAD.27,28 Other cytosolic receptors, such as RIG-1 and Mda5, respond to respiratory virus infection by the expression of type I Interferon29 but their role in the development of CLAD after lung transplantation remains to be investigated.

Graft ischemia time and ischemia-reperfusion injury (after blood recirculation in the devitalized tissue) is a well-known determinant of the long-term survival after lung transplantation.30 Moreover, during the surgical process of lung transplantation, the bronchial circulation is not routinely reconnected to the main circulation, and although blood vessels can be restored by angiogenesis, reduced blood circulation accounts for ischemia, hypoxia, sensitivity to infection, or defect in immunosuppressive drug delivery, all observed after lung transplantation.31 Furthermore, transplant arteriosclerosis is common in solid-organ transplantation, and inflammatory cytokines are activators of vascular smooth muscle cells, promoting their proliferation at the intimal level and the abnormal thickening of the microvessel walls.32

These defects in blood supply to the small airways33 or microvascular injuries34 predispose to chronic dysfunction. Injured cells or tissues released various endogenous factors that can be recognized by pathogen recognition receptor,35 a great deal of attention has been focused on the recognition of these damage-associated molecular patterns or alarmins by the innate immune system.36 Innate immunity can be mobilized within the first hours after the transplantation in particular through the release of high-mobility group box 1 (HMGB1). This molecule secreted by necrotic cells after ischemia, signals via TLR or receptor for advanced glycation end products (RAGE). The recognition of HMGB1 by RAGE plays an important role in the development of early pulmonary dysfunction after transplantation, through an IL-17–dependent neutrophil infiltration.37,38 High-mobility group box 1 and other alarmins, such as S100 proteins,39 heat shock proteins,40 the soluble form of RAGE,41 or hyaluronan,42 have been found in the bronchoalveolar lavages (BAL) of CLAD patients and are supposed to contribute to CLAD via activation of innate immunity. Interestingly, alarmin profile and especially S100A8, S100A9, S100A12, S100P, and HMGB1 proteins can discriminate between BOS or RAS subtypes suggesting a specific role for these molecules in the development of these 2 pathologies.39

Exogenous or endogenous molecules trigger inflammation and the release of cytokines or chemokines resulting in the activation of innate immunity. We will then present the players of innate immunity and detailed the tissue-degrading agents and the chemokines they produced involved in deterioration of lung tissues and activation of adaptive immunity.

Activation of Airway Epithelial Cells

Airway epithelial cells (AEC) are the first line of defense against airborne pathogens, particulate matter, pollutants or allergens. AEC express a wide range of TLR,43 nucleotide oligomerization domain-like receptor or retinoic acid-inducible gene-I-like receptor,44 and their localization make them early responders in case of aggression. Their major impact in pulmonary immunity is now well established.45 In the context of solid-organ transplantation, several types of allodependent or alloindependent stimuli may induce the secretion of proinflammatory cytokines, chemokines, and growth factors by AEC.46-48 Among the molecules produced, it is worth mentioning IL-8, associated with the occurrence of alveolar neutrophilia in lung transplant recipients49; IL-1α, produced after pseudomonas infection and responsible for fibroblast activation50; CCL2, a monocyte-specific chemoattractant protein upregulated in CLAD patients51 or the mononuclear cell attractants CXCL9 and CXCL10, produced during acute lung injury and propagating the inflammation within the allograft.9 Combined with the ability to produce matrix metalloproteinases (MMP)52 and to upregulate costimulatory or major histocompatibility molecules (MHC) class II molecule expression,53-55 AEC are endowed with the capacity to attract and activate innate or adaptive immune cells within the graft.

The Role of Neutrophils

Several independent studies have reported abnormally elevated counts of neutrophils, in BAL,49,56-58 induced sputum59 and biopsies60 from lung transplant recipients suffering from CLAD. Regarding the triggers, IL-8 remains the main mediator for neutrophil recruitment and activation after lung transplantation.46,49 Some of the factors that may induce an upregulation of IL-8 in lung transplant recipients include the presence of bile acids due to concomitant gastroesophageal reflux disease61 as well as the presence of particulate matter due to exposure to a polluted environment62 or infections.48 Neutrophils act through mediators, such as reactive oxygen species63 or MMP,64 and other proteases, such as neutrophil elastase. The local persistence of these substances is thought to induce the epithelial damages that precede the excessive scar formation that characterizes CLAD, making alveolar neutrophilia a predictive biomarker for CLAD.56,65,66

Although neutrophils have been historically associated with the development of CLAD, the therapeutic use of azithromycin has changed the paradigm. Azithromycin is a macrolide antibiotic able to reverse the decline of lung function in a subset of lung recipients.67,68 It remains unclear so far whether azithromycin improves lung function due to its antimicrobial or anti-inflammatory properties. Its use defines a new dysfunction phenotype called azithromycin-responsive allograft dysfunction or neutrophilic reversible allograft dysfunction since this phenotype is often (but not always) characterized by BAL neutrophilia (≥15%).67-72 However, this phenotype is by definition reversible and hence does not fulfill the strict criteria of CLAD.73

The Role of NK Cells

Unlike many other components of the immune system, NK cells remain barely affected by the immunosuppressive therapies used in regular clinical practice.74 That is one of the reasons why they have recently been under the spotlight of the solid-organ transplantation community. NK cells have been associated to both acute75 and chronic75,76 rejections after lung transplantation. NK cells use their membrane receptors (CD16, CD32, and CD56) to identify IgG-coated cells via the Fc region of the antibodies.77 Activation of NK cell may be also antibody-independent. For example, activated endothelial cells express on their surface the chemokine CX3CL1 or fractalkine,78 which interact with the chemokine receptor CX3CR1 present on NK cells.79

In addition, the human MHC class I chain-related proteins MICA and MICB, expressed by epithelial cells under conditions of stress, are known to be ligands for the activating receptor NKG2D on NK cells.80-82 Once activated, NK cells release a series of cytolytic proteins, such as granzymes A and B, perforin, FasL, TNF-related apoptosis-inducing ligand, and chemotactic cytokines, such as TNF-α and IFN-γ.83,84 Because of their cytotoxic arsenal and their propensity to migrate in the lungs of patients with chronic rejection,85 NK cells are ideal culprit for graft destruction. However, recent works have shown their ability to promote graft tolerance through dendritic cells editing.86,87 In a mouse lung transplantation model, killing of allogeneic dendritic cells by NK induces graft tolerance.88 Interestingly, in human, lack of activating killer immunoglobulin-like receptor expression by NK cells is associated with the development of BOS,89 suggesting that NK activity preserves long-term graft function.


The role of macrophages in the development of CLAD is suggested by their accumulation in human or animal models and by the reduction of allograft dysfunction after blockade of their infiltration.90-92 In human, temporal variations in macrophage activation profile, either classical (M1) or alternative (M2), in association with alterations of the lung microbiota, have been reported posttransplantation.93 Whether these variations correlates with the development of CLAD, as suggested in mouse94 remains to be assessed.

Recent works have shown an association between eosinophilia and allograft dysfunction.7,95 Eosinophils may promote CLAD through the release of reactive oxygen species, promoting graft destruction, or transforming growth factor-β supporting aberrant remodeling. Interestingly, BAL eosinophilia seems to be correlated with the restrictive phenotype. Further confirmation of this link would provide a potential mechanism leading to this particular CLAD subtype.

Activation of innate immunity and degradation of allograft support the development of adaptive immunity. As we will see, induction of autoimmune reactions along with dysfunction of regulatory mechanisms will then feed a positive feedback loop, responsible for the perpetuation and amplification of the immune response, driving the transition from acute events to a chronic process.


Th1 Immunity

The role of adaptive cellular immunity in the development of CLAD is highlighted by the association between acute cellular rejection or lymphocytic bronchiolitis and the occurrence of CLAD7,96,97 or by the incidence of BOS after bone marrow transplantation.98 The development of cellular immune response against alloantigens (and autoantigens) generally relies on the migration of antigen presenting cells in the secondary lymphoid organs, where they encounter and activate T cells. Additionally, T cell activation within the lung may take place through the formation of de novo lymphoid tissue, such as bronchus-associated lymphoid tissues (BALT).99,100 Whereas lymphoid neogenesis has been observed in BOS,101 evidences for organized BALT contribution in CLAD remain scarce.102 The role of Th1 immunity in the process of CLAD is suggested by an increase in Th1 cells or cytokines and granzyme B levels in blood or lung lavages of BOS recipients.76,103-106 Furthermore, inhibition of cytotoxic T cells by HLA-G molecules has been suggested in stable patients.107 The molecular bases of this allorecognition involve mainly an indirect presentation of donor MHC class I and II molecules.108-111 However, mouse models have also shown the contribution of minor histocompatibility antigens presentation in the development of obliterative lesions.112,113

Th17 Immunity

There is a growing body of evidence that autoimmunity plays an important part in the development of CLAD.114 Tissue injuries caused by ischemia, primary graft dysfunction (PGD), infections, or alloimmune reactions alter the accessibility of protein antigenic domains. Epitopes normally masked within the protein organization can then be exposed to the immune system, leading to autoimmune responses. In a murine model of lung transplantation, Col(V)-specific T cells found in the lung allograft mediates allograft rejection.115 This has been confirmed in human, where the Col(V)-specific T cell response intensity correlates with the incidence and the severity of BOS. This Col(V) autoimmune response was found to be dependent of IL-17. Interestingly, adoptive transfer of Col(V)-reactive T cells was sufficient to induce an OB in the absence of alloreactivity.116 Association between Th17 immunity and the development of CLAD has then been reported by several groups in human117 or mouse models118,119 and genetic variation in IL-17 receptor is associated with CLAD.120 Furthermore, Th17 immunity is linked to both chronic inflammation and neutrophilia in the lungs.121 In the case of lung transplantation, Th17 immunity may thus favor chronic dysfunction through airway fibrosis, induction of BALT, neutrophil chemotaxis, or expansion of autoantibodies.114

Regulatory Cells

Regulatory T (Treg) cells encompass a wide diversity of immunosuppressive populations characterized by specific ontogeny or mechanisms of action.122 In human, presence of Treg cell in lung allograft or in the blood is correlated with an absence of chronic dysfunction.65,123-125 More specifically, the Th17/Treg cell balance could determine the fate of lung allograft. Indeed, mouse models have shown a downregulation of Th17 immunity after adoptive transfer of Treg cell.126,127 On the other hand, plasticity is a feature of Treg cell and inflammatory environment can favor their differentiation into Th17 cells128 and IL-6, a pivotal factor in the equilibrium of the Th17/Treg cell balance, is a well-known marker of chronic dysfunction.51 Various experimental approaches have thus been proposed to stimulate the activity of Treg cell and modulate the Th17/Treg cell balance. Independent studies for instance have reported a decrease in the rate of pulmonary function loss in CLAD patients as a result of extracorporeal photopheresis therapy.130-133 Mechanistically, the mode of action of extracorporeal photopheresis is not fully understood but probably rely on the induction of a regulatory CD4+CD25+ T cell population.134-136 By contrast, immunosuppressive drugs are thought to impair Treg cell populations and to affect Th17/Treg cell balance, favoring the development of chronic dysfunction.137,138

In addition to Treg cell, regulatory B cell, producing IL-10 or TGF-β have been characterized. Regulatory B cells are involved in the control of airway diseases and can inhibit the development of bronchiolitis obliterans in a mouse model of heterotopic tracheal transplantation.139 A great challenge in the future will be to decipher the impact of these regulatory cell populations on the development of CLAD and to develop immunosuppressive therapies able to maintain or expand these populations, either in vivo or ex vivo.140

Humoral Immunity

The association between humoral immunity and the development of CLAD is well documented. Accumulation of B cells is observed in lung tissues of patients with CLAD.141 The presence of donor-specific HLA antibodies (DSA) is correlated with the development of BOS,142-148 and DSA targeting therapies lower the incidence of chronic dysfunction.149,150 The role of antibodies against MICA molecules has been reported as well.151 Although HLA or MICA/B polymorphism is an evident molecular basis for humoral immunity, recent works have highlighted the role of self-antigen recognition in the humoral immunity associated with BOS. Antibodies directed against col(V) or K-α1 tubulin proteins have been associated with the process of BOS,115,152 and clearance of these antibodies reduced the risk of BOS, independently of the clearance of DSA.153

The direct link between alloimmunity and autoimmunity has been suggested in a mouse model where injection of anti-MHC class I antibody induced the production of anti-Col(V) and anti-K-α1 tubulin antibodies. Noteworthy, this production was IL-17–dependent and resulted in an obliterative disease.154,155 In lung transplant recipients, a retrospective analysis showed a correlation between DSA and self-antigen antibody appearance, with DSA preceding the development of self-antigen antibodies.156 Yet, self-reactive antibodies can be found in the absence of DSA, suggesting a DSA-independent mechanism for their development.153 In addition, such self-reactive antibodies may already be present by the time of the transplantation.157 In fact, several types of stimuli (eg, ischemia reperfusion injury, PGD) may increase the expression of these self-proteins and activate the interstitial remodeling machinery, promoting the exposure of the cryptic antigens.158

Graft-reactive antibodies induce the activation of the complement system and the degradation of lung tissues. Polymorphism in the complement regulatory protein CD59 has then been associated with the development of BOS,159 suggesting that harnessing complement activation may control CLAD development. Complement activation has been largely investigated as a potential marker for humoral rejection, via the immunostaining of the complement component 4 (C4d). Although positive results have been reported for kidney,160 liver,161 and heart162 transplantation, it is much debated for lung transplantation.163

Continuous immune reaction will cause tissue destruction and dysregulation of epithelium repair. This mechanism is hardly controllable by immunosuppression, and aberrant remodeling process will take place, leading ultimately to loss of graft function (Figure 1).

Physiopathological mechanisms of CLAD. Endogenous (MHC mismatch, graft injuries, self-antigen exposure) or exogenous (infections, pollutants, allergens) risk factors leading to activation of innate and adaptive immunity after lung transplantation. Continuous exposure to environment and development of autoimmunity promote the persistance of inflammation and tissue injuries. Graft destruction and wound/healing processes promote the remodeling of the lung allograft and the development of CLAD. The specific mechanisms skewing the chronic dysfunction toward BOS or RAS phenotypes are poorly characterized. AR, acute rejection; GERD, gastroesophageal reflux disease; HA, hyaluronan; HSP, heat shock protein; IR, ischemia reperfusion; LB, lymphocytic bronchiolitis.


It is now recognized that the recurrent injuries of the lung allograft, either immune or nonimmune related, result in an excessive scarring and an aberrant healing process responsible for CLAD. Specific features of the respiratory system, and in particular, its continuous exposure to environment, probably favor the perpetuation of acute events into chronic injury. Toll like receptors activation for instance may disrupt Treg cell activity and favor a Th1-oriented phenotype.164 The presence of CXCR3 ligands9 or inflammatory cytokines and de novo anti-MHC class II DSA165 may be responsible for the persistence of allograft injury after DAD or PGD, respectively. Overall, this generates and propagates an inflammatory environment and the recruitment of immune cells within the allograft leading to further fibrotic damages. This may explain how very early events, such as PGD or ischemia reperfusion injuries, can be translated several months or years later into chronic dysfunction.

The persistence of local inflammation results in the emergence of a fibroproliferative phenotype with the secretion of growth factors and dysregulation in the extracellular matrix regeneration process (Figure 1). The binding of anti-HLA class I antibodies on AEC may lead to their death through apoptosis and induces the release profibrotic growth factors, such as platelet-derived growth factor, Insulin-like growth factor-1, and TGF-β.47 Their upregulation results in the accumulation of fibroblasts and myofibroblasts, the aberrant deposition of collagen fibers (mainly of type I), and the loss of homeostasis in the regeneration of the extracellular matrix. AEC from BOS patients demonstrated an upregulation of mesenchymal markers (S100A4, fibronectin, MMP) along with a drop in epithelial cell marker expression. The epithelial to mesenchymal transition (EMT) has thus been proposed as a general mechanism leading to airway obstruction after lung transplantation.54,166 TGF-β is the foremost inducer of EMT167 and has long been associated with the development of BOS after transplantation.46,104,129,168 Its impact in the EMT triggering has also been shown in vivo in a rat model of airway obliteration where blocking the binding of TGF-β to its receptor reduced intraluminal airway matrix deposition.169 In human, TGF-β could be the biological link between PGD and BOS,170 and recent evidence has shown a dysregulation of TGF-β signaling by microRNA-144 in BOS patients.171 The antifibrotic drug pirfenidone,172 which acts mainly by suppressing the expression of TGF-β, has thus been proposed as a treatment for BOS173 or RAS.174

Although TGF-β is the main orchestrator of the airway remodeling process after lung transplantation, its effect can be largely modified by an inflammatory environment and cytokines like TNFα or IL-1β.175,176 Besides, pollutants177 or immunossupressive drugs178 have also been described as EMT inducers. Moreover, release of reactive oxygen species by macrophages or neutrophils after lung transplantation179 associated with a decrease in the counterbalancing factors, such as ascorbic acid, urate, glutathione57 or Clara Cell Secretory Protein 16,180 promotes the upregulation of the vascular endothelial growth factor, which may further stimulate fibrosis.181,182 In an allograft model in rats, the simultaneous blockade of both platelet-derived growth factor and vascular endothelial growth factor could then reduce the severity of CLAD.183 The respective roles played by these actors during the remodelling process of chronic dysfunction, however, remain to be defined. Moreover, although the role of EMT during the process of BOS development is well established, its relevance to RAS is not described yet, although airway obstruction is observed in this pathology as well. Furthermore, the exact contribution of EMT with regard to other mechanisms, such as the recruitment of circulating fibroblast within the fibrotic lesions,184 remains poorly documented. Answering these questions will help to develop new strategies for the prevention of CLAD.


Although BOS was first considered as the unique manifestation of chronic dysfunction, the identification of RAS phenotype has transformed our perception of this pathology. Why was RAS characterized more than 15 years after the first description of BOS? Was it “under the radar” and has its identification been overlooked for years, or is RAS the result of new immunosuppressive drug regimens? Current works focusing on the specific features of these 2 syndromes will probably answer these questions.

As presented here, BOS or RAS phenotypes can be delineated by infiltrating cells, alarmins or cytokines present within the allograft (Table 1). An article from the Leuven Group shows a specific IL-6, CXCL10 and CXCL11 release in BAL of RAS patients, suggesting a role for B lymphocytes or NK in this pathology.185 Moreover, the underlying diagnosis and immunosuppression regimens have been recently described as specific risk factors for RAS.186 Further works will be needed to confirm these data and precisely define the specificities and similarities between the 2 diseases. Noteworthy, some evidences presented in this review have been collected before the description of RAS, that is, on chronic rejection groups where BOS and RAS patients were presumably pooled. Reinvestigating these data in light of our current knowledge will be probably useful to refine the perimeter of both diseases.

Innate and adaptive immunity and the development chronic lung allograft dysfunction

Chronic lung allograft dysfunction is irreversible. Therefore, the identification of harbingers of CLAD would allow proactive and targeted strategies to harness the progression of the disease, before degradation of the allograft. Several studies have been carried out to identify predictors. Lung biopsy profiling,187 BAL composition, neutrophilia,66,188,189 level of Treg cell,123,124 cytokines, chemokines,189 or MMP190 or blood levels of endothelin-1,191CCL17,192 or KL-6193 have been proposed as early indicators of CLAD. Interestingly, pretransplant factors may also determine the outcome of the graft.194,195 Prediction of CLAD is thus presumably achievable. Yet, none of these attempts have demonstrated enough robustness to achieve clinical acceptance. Indeed, CLAD is driven by the additive effect of repeated insults to the graft. The diversity of these insults as well as the donor and recipient genetic burden assign each patient a unique clinical history. Hence, large-scale gene expression profiling187,196-199 or the powerful systems biology approach,200-203 which integrates data sets of different nature, represents promising tools to decipher the complex network of factors involved in the development of CLAD.

Lung transplantation appears today as an ideal demonstrator of P4 Systems Medicine (participation, personalization, prediction, and prevention), because all recipients are followed up in well-characterized cohorts for several years, before the occurrence of the disease. Chronic lung allograft dysfunction displays fibrotic processes or alveolar degradation similarly observed in other respiratory diseases such as idiopathic pulmonary fibrosis or chronic obstructive pulmonary disease.204 Investigating CLAD is thus a mighty lever to better understand other chronic inflammatory lower airway diseases.


The authors are indebted to the “Programme Hospitalier de Recherche Clinique 2008” and to “Vaincre la Mucoviscidose” for supporting this project from its beginning, when 11 French lung transplantation centers gave rise to the Cohort in Lung Transplantation (COLT), “Programme Transplantation 2008”, PRTP-13, Identifier: NCT00980967.

Consortium, SysCLAD consortium

Cohort Of Lung Transplantation-COLT (associating surgeons; anaesthetists-intensivists; physicians, research staff) Bordeaux: J. Jougon, J.-F. Velly; H. Rozé; E. Blanchard, C. Dromer; Bruxelles: M. Antoine, M. Cappello, R. Souilamas, M. Ruiz, Y. Sokolow, F. Vanden Eynden, G. Van Nooten; L. Barvais, J. Berré, S. Brimioulle, D. De Backer, J. Créteur, E. Engelman, I. Huybrechts, B. Ickx, T. J.C. Preiser, T. Tuna, L. Van Obberghe, N. Vancutsem, J.-L. Vincent; P. De Vuyst, I. Etienne, F. Féry, F. Jacobs, C. Knoop, J.L. Vachiéry, P. Van den Borne, I. Wellemans; G. Amand, L. Collignon, M. Giroux; Grenoble V. Bach, P.-Y. Brichon, P. Chaffanjon, O. Chavanon, S. Guigard, A. Pirvu, P. Porcu, R. Hacini; P. Albaladejo, C. Allègre, A. Bataillard, D. Bedague, E. Briot, M. Casez-Brasseur, D. Colas, G. Dessertaine, M. Durand, G. Francony, A. Hebrard, M.R Marino, B. Oummahan, D. Protar, D. Rehm, S. Robin, M. Rossi-Blancher; P. Bedouch, A. Boignard, H. Bouvaist, A. Briault, B. Camara, S. Chanoine, M. Dubuc, S. Quêtant, J. Maurizi, P. Pavèse, C. Pison, C. Saint-Raymond, N. Wion; C. Chérion; Lyon R. Grima, O. Jegaden, J.-M. Maury, F. Tronc; C. Flamens, S. Paulus; J.-F. Mornex, F. Philit, A. Senechal, J.-C. Glérant, S. Turquier; D. Gamondes; L. Chalabresse, F. Thivolet-Bejui; C Barnel, C. Dubois, A. Tiberghien; Paris, Hôpital Européen Georges Pompidou F. Le Pimpec-Barthes, A. Bel, P. Mordant, P. Achouh; V. Boussaud; R. Guillemain, D. Méléard, M.O. Bricourt, B. Cholley; V. Pezella; Marseille: G. Brioude, X.B. D’Journo, C. Doddoli. P. Thomas, D. Trousse; S. Dizier, M. Leone, L. Papazian; F. Bregeon, B. Coltey, N. Dufeu, H. Dutau, S. Garcia, JY. Gaubert, C. Gomez, S. Laroumagne, A. Nieves, L, C. Picard, F. Rey, M. Reynaud-Gaubert, JM. Rolain, E. Sampol, V. Secq; I. Bouvin; Nantes O. Baron, P. Lacoste, C. Perigaud, J.C. Roussel; I. Danner, A Haloun A. Magnan, A Tissot; T. Lepoivre, M. Treilhaud; K. Botturi-Cavaillès, S. Brouard, R. Danger, J. Loy, M. Morisset, M. Pain, S. Pares, D. Reboulleau, P.-J. Royer; Le Plessis Robinson, Hôpital Marie Lannelongue Ph. Dartevelle, D. Fabre, E. Fadel, O. Mercier, S. Mussot; F. Stephan, P. Viard; J. Cerrina, P. Dorfmuller, S. Feuillet M. Ghigna, Ph. Hervén F. Le Roy Ladurie, J. Le Pavec, V. Thomas de Montpreville; L. Lamrani; Paris, Hôpital Bichat Y. Castier, P. Cerceau, F. Francis, G. Lesèche; N. Allou, P. Augustin, S. Boudinet, M. Desmard, G. Dufour, P. Montravers; O. Brugière, G. Dauriat, G. Jébrak, H. Mal, A. Marceau, A.-C. Métivier, G. Thabut; B. Ait Ilalne; Strasbourg P. Falcoz, G. Massard, N. Santelmo; G. Ajob, O. Collange O. Helms, J. Hentz, A. Roche; B. Bakouboula, T. Degot, A. Dory, S. Hirschi, S. Ohlmann-Caillard, L. Kessler, R. Kessler, A. Schuller; K. Bennedif, S. Vargas; Suresnes P. Bonnette, A. Chapelier, P. Puyo, E. Sage; J. Bresson, V. Caille, C. Cerf, J. Devaquet, V. Dumans-Nizard, ML. Felten, M. Fischler, AG. Si Larbi, M. Leguen, L. Ley, N. Liu, G. Trebbia; S. De Miranda, B. Douvry, F. Gonin, D. Grenet, A.M. Hamid, H. Neveu, F. Parquin, C. Picard, A. Roux, M. Stern; F. Bouillioud, P. Cahen, M. Colombat, C. Dautricourt, M. Delahousse, B. D’Urso, J. Gravisse, A. Guth, S. Hillaire, P. Honderlick, M. Lequintrec, E. Longchampt, F. Mellot, A. Scherrer, L. Temagoult, L. Tricot; M. Vasse, C. Veyrie, L. Zemoura; Toulouse J. Berjaud, L. Brouchet, M. Dahan; F. Le Balle, O. Mathe; H. Benahoua, A. Didier, A.L. Goin, M. Murris; L. Crognier, O. Fourcade.

Swiss Transplant Cohort Study-STCS Genève-Lausanne T. Krueger, H.B. Ris, M. Gonzalez; J.-D. Aubert, L.P. Nicod, B.J. Marsland, T.C. Berutto, T. Rochat, P. Soccal, Ph. Jolliet, A. Koutsokera, C. Marcucci, O. Manuel; E. Bernasconi, M. Chollet, F. Gronchi C Courbon; Zurich S. Hillinger, I. Inci, P. Kestenholz, W. Weder; R. Schuepbach, M. Zalunardo; C. Benden, U. Buergi, L.C. Huber; B. Isenring, M.M. Schuurmans; A. Gaspert, D. Holzmann, N. Müller, C. Schmid, B. Vrugt, T. Rechsteiner.

SME and Platforms Biomax, Germany A. Fritz, D. Maier; Finovatis, Lyon, France K. Desplanche, D. Koubi; GATC, Germany F. Ernst, T. Paprotka, M. Schmitt, B. Wahl; Novasdicovery, Lyon, France J.-P. Boissel, G. Olivera-Botello; Prométhée Proteomics Platform, Grenoble, France C. Trocmé, B. Toussaint, S. Bourgoin-Voillard, M. Séve; Inserm U823, Université Joseph Fourier, Grenoble, France M. Benmerad, V. Siroux, R. Slama; European Institute for Systems Biology & Medicine, Lyon, France C. Auffray, D. Charron, J. Pellet, C. Pison.


1. Yusen RD, Edwards LB, Kucheryavaya AY, et al. The registry of the International Society for Heart and Lung Transplantation: thirty-first adult lung and heart-lung transplant report—2014; focus theme: retransplantation. J Heart Lung Transplant. 2014;33:1009–1024.
2. Wolfe RA, Roys EC, Merion RM. Trends in organ donation and transplantation in the United States, 1999-2008. Am J Transplant. 2010;10:961–972.
3. Sato M. Chronic lung allograft dysfunction after lung transplantation: the moving target. Gen Thorac Cardiovasc Surg. 2013;61:67–78.
4. Sato M, Waddell TK, Wagnetz U, et al. Restrictive allograft syndrome (RAS): a novel form of chronic lung allograft dysfunction. J Heart Lung Transplant. 2011;30:735–742.
5. Martinu T, Howell DN, Davis RD, et al. Pathologic correlates of bronchiolitis obliterans syndrome in pulmonary retransplant recipients. Chest. 2006;129:1016–1023.
6. Ofek E, Sato M, Saito T, et al. Restrictive allograft syndrome post lung transplantation is characterized by pleuroparenchymal fibroelastosis. Mod Pathol. 2013;26:350–356.
7. Verleden SE, Ruttens D, Vandermeulen E, et al. Bronchiolitis obliterans syndrome and restrictive allograft syndrome: do risk factors differ? Transplantation. 2013;95:1167–1172.
8. Sato M, Hwang DM, Ohmori-Matsuda K, et al. Revisiting the pathologic finding of diffuse alveolar damage after lung transplantation. J Heart Lung Transplant. 2012;31:354–363.
9. Shino MY, Weigt SS, Li N, et al. CXCR3 ligands are associated with the continuum of diffuse alveolar damage to chronic lung allograft dysfunction. Am J Respir Crit Care Med. 2013;188:1117–1125.
10. Alegre ML, Leemans J, Le Moine A, et al. The multiple facets of toll-like receptors in transplantation biology. Transplantation. 2008;86:1–9.
11. Palmer SM, Burch LH, Trindade AJ, et al. Innate immunity influences long-term outcomes after human lung transplant. Am J Respir Crit Care Med. 2005;171:780–785.
12. Kastelijn EA, van Moorsel CHM, Rijkers GT, et al. Polymorphisms in innate immunity genes associated with development of bronchiolitis obliterans after lung transplantation. J Heart Lung Transplant. 2010;29:665–671.
13. Garantziotis S, Palmer SM, Snyder LD, et al. Alloimmune lung injury induced by local innate immune activation through inhaled lipopolysaccharide. Transplantation. 2007;84:1012–1019.
14. Miller HL, Shah PD, Orens JB, et al. Prevention of airway allograft tolerance by polyinosinic:polycytidylic acid requires type I interferon responsiveness for mouse airway obliteration. J Heart Lung Transplant. 2013;32:914–924.
15. Witt CA, Meyers BF, Hachem RR. Pulmonary infections following lung transplantation. Thorac Surg Clin. 2012;22:403–412.
16. Solé A, Morant P, Salavert M, et al. Aspergillus infections in lung transplant recipients: risk factors and outcome. Clin Microbiol Infect. 2005;11:359–365.
17. Khalifah AP, Hachem RR, Chakinala MM, et al. Respiratory viral infections are a distinct risk for bronchiolitis obliterans syndrome and death. Am J Respir Crit Care Med. 2004;170:181–187.
18. Fisher CE, Preiksaitis CM, Lease ED, et al. Symptomatic respiratory virus infection and chronic lung allograft dysfunction. Clin Infect Dis. 2016;62:313–319.
19. Weigt SS, Elashoff RM, Huang C, et al. Aspergillus colonization of the lung allograft is a risk factor for bronchiolitis obliterans syndrome. Am J Transplant. 2009;9:1903–1911.
20. Weigt SS, Copeland CAF, Derhovanessian A, et al. Colonization with small conidia Aspergillus species is associated with bronchiolitis obliterans syndrome: a two-center validation study. Am J Transplant. 2013;13:919–927.
21. Botha P, Archer L, Anderson RL, et al. Pseudomonas aeruginosa colonization of the allograft after lung transplantation and the risk of bronchiolitis obliterans syndrome. Transplantation. 2008;85:771–774.
22. Willner DL, Hugenholtz P, Yerkovich ST, et al. Reestablishment of recipient-associated microbiota in the lung allograft is linked to reduced risk of bronchiolitis obliterans syndrome. Am J Respir Crit Care Med. 2013;187:640–647.
23. Gregson AL, Wang X, Weigt SS, et al. Interaction between Pseudomonas and CXC chemokines increases risk of bronchiolitis obliterans syndrome and death in lung transplantation. Am J Respir Crit Care Med. 2013;187:518–526.
24. Cigana C, Curcurù L, Leone MR, et al. Pseudomonas aeruginosa exploits lipid A and muropeptides modification as a strategy to lower innate immunity during cystic fibrosis lung infection. PLoS One. 2009;4:e8439.
25. Mertens V, Blondeau K, Vanaudenaerde B, et al. Gastric juice from patients “on” acid suppressive therapy can still provoke a significant inflammatory reaction by human bronchial epithelial cells. J Clin Gastroenterol. 2010;44:e230–e235.
26. Bauer RN, Diaz-Sanchez D, Jaspers I. Effects of air pollutants on innate immunity: the role of Toll-like receptors and nucleotide-binding oligomerization domain-like receptors. J Allergy Clin Immunol. 2012;129:14–24.
27. Bhinder S, Chen H, Sato M, et al. Air pollution and the development of posttransplant chronic lung allograft dysfunction. Am J Transplant. 2014;14:2749–2757.
28. Nawrot TS, Vos R, Jacobs L, et al. The impact of traffic air pollution on bronchiolitis obliterans syndrome and mortality after lung transplantation. Thorax. 2011;66:748–754.
29. Kimura H, Yoshizumi M, Ishii H, et al. Cytokine production and signaling pathways in respiratory virus infection. Front Microbiol. 2013;4:276.
30. Thabut G, Mal H, Cerrina J, et al. Graft ischemic time and outcome of lung transplantation. Am J Respir Crit Care Med. 2005;171:786–791.
31. Tong MZ, Johnston DR, Pettersson GB. The role of bronchial artery revascularization in lung transplantation. Thorac Surg Clin. 2015;25:77–85.
32. Sato M, Keshavjee S. Bronchiolitis obliterans syndrome: alloimmune-dependent and -independent injury with aberrant tissue remodeling. Semin Thorac Cardiovasc Surg. 2008;20:173–182.
33. Luckraz H, Goddard M, McNeil K, et al. Microvascular changes in small airways predispose to obliterative bronchiolitis after lung transplantation. J Heart Lung Transplant. 2004;23:527–531.
34. Khan MA, Nicolls MR. Complement-mediated microvascular injury leads to chronic rejection. Adv Exp Med Biol. 2013;735:233–246.
35. Kono H, Rock KL. How dying cells alert the immune system to danger. Nat Rev Immunol. 2008;8:279–289.
36. Kreisel D, Goldstein DR. Innate immunity and organ transplantation: focus on lung transplantation. Transpl Int. 2013;26:2–10.
37. Sharma AK, LaPar DJ, Stone ML, et al. Receptor for advanced glycation end products (RAGE) on iNKT cells mediates lung ischemia-reperfusion injury. Am J Transplant. 2013;13:2255–2267.
38. Weber DJ, Gracon ASA, Ripsch MS, et al. The HMGB1-RAGE axis mediates traumatic brain injury-induced pulmonary dysfunction in lung transplantation. Sci Transl Med. 2014;6:252ra124.
39. Saito T, Liu M, Binnie M, et al. Distinct expression patterns of alveolar “alarmins” in subtypes of chronic lung allograft dysfunction. Am J Transplant. 2014;14:1425–1432.
40. Wood KL, Nunley DR, Moffatt-Bruce S, et al. The role of heat shock protein 27 in bronchiolitis obliterans syndrome after lung transplantation. J Heart Lung Transplant. 2010;29:786–791.
41. Shah RJ, Bellamy SL, Lee JC, et al. Early plasma soluble receptor for advanced glycation end-product levels are associated with bronchiolitis obliterans syndrome. Am J Transplant. 2013;13:754–759.
42. Todd JL, Wang X, Sugimoto S, et al. Hyaluronan contributes to bronchiolitis obliterans syndrome and stimulates lung allograft rejection through activation of innate immunity. Am J Respir Crit Care Med. 2014;189:556–566.
43. Ioannidis I, Ye F, McNally B, et al. Toll-like receptor expression and induction of type I and type III interferons in primary airway epithelial cells. J Virol. 2013;87:3261–3270.
44. Lambrecht BN, Hammad H. The airway epithelium in asthma. Nat Med. 2012;18:684–692.
45. Whitsett JA, Alenghat T. Respiratory epithelial cells orchestrate pulmonary innate immunity. Nat Immunol. 2015;16:27–35.
46. Elssner A, Jaumann F, Dobmann S, et al. Elevated levels of interleukin-8 and transforming growth factor-beta in bronchoalveolar lavage fluid from patients with bronchiolitis obliterans syndrome: proinflammatory role of bronchial epithelial cells. Munich Lung Transplant Group. Transplantation. 2000;70:362–367.
47. Jaramillo A, Smith CR, Maruyama T, et al. Anti-HLA class I antibody binding to airway epithelial cells induces production of fibrogenic growth factors and apoptotic cell death: a possible mechanism for bronchiolitis obliterans syndrome. Hum Immunol. 2003;64:521–529.
48. Proud D, Leigh R. Epithelial cells and airway diseases. Immunol Rev. 2011;242:186–204.
49. DiGiovine B, Lynch JP 3rd, Martinez FJ, et al. Bronchoalveolar lavage neutrophilia is associated with obliterative bronchiolitis after lung transplantation: role of IL-8. J Immunol. 1996;157:4194–4202.
50. Borthwick LA, Suwara MI, Carnell SC, et al. Pseudomonas aeruginosa induced airway epithelial injury drives fibroblast activation: a mechanism in chronic lung allograft dysfunction. Am J Transplant.
51. Scholma J, Slebos DJ, Boezen HM, et al. Eosinophilic granulocytes and interleukin-6 level in bronchoalveolar lavage fluid are associated with the development of obliterative bronchiolitis after lung transplantation. Am J Respir Crit Care Med. 2000;162:2221–2225.
52. Banerjee B, Ling K-M, Sutanto EN, et al. The airway epithelium is a direct source of matrix degrading enzymes in bronchiolitis obliterans syndrome. J Heart Lung Transplant. 2011;30:1175–1185.
53. Cunningham AC, Zhang J-G, Moy JV, et al. A comparison of the antigen-presenting capabilities of class II MHC-expressing human lung epithelial and endothelial cells. Immunology. 1997;91:458–463.
54. Hodge S, Holmes M, Banerjee B, et al. Posttransplant bronchiolitis obliterans syndrome is associated with bronchial epithelial to mesenchymal transition. Am J Transplant. 2009;9:727–733.
55. Heinecke L, Proud D, Sanders S, et al. Induction of B7-H1 and B7-DC expression on airway epithelial cells by the Toll-like receptor 3 agonist double-stranded RNA and human rhinovirus infection: In vivo and in vitro studies. J Allergy Clin Immunol. 2008;121:1155–1160.
56. Devouassoux G, Drouet C, Pin I, et al. Alveolar neutrophilia is a predictor for the bronchiolitis obliterans syndrome, and increases with degree of severity. Transpl Immunol. 2002;10:303–310.
57. Riise GC, Williams A, Kjellström C, et al. Bronchiolitis obliterans syndrome in lung transplant recipients is associated with increased neutrophil activity and decreased antioxidant status in the lung. Eur Respir J. 1998;12:82–88.
58. Suwara MI, Vanaudenaerde BM, Verleden SE, et al. Mechanistic differences between phenotypes of chronic lung allograft dysfunction after lung transplantation. Transpl Int. 2014;27:857–867.
59. Beeh KM, Kornmann O, Lill J, et al. Induced sputum cell profiles in lung transplant recipients with or without chronic rejection: correlation with lung function. Thorax. 2001;56:557–560.
60. Devouassoux G, Pison C, Drouet C, et al. Early lung leukocyte infiltration, HLA and adhesion molecule expression predict chronic rejection. Transplant Immunol. 2001;8:229–236.
61. D’Ovidio F, Mura M, Tsang M, et al. Bile acid aspiration and the development of bronchiolitis obliterans after lung transplantation. J Thorac Cardiovasc Surg. 2005;129:1144–1152.
62. Verleden SE, Scheers H, Nawrot TS, et al. Lymphocytic bronchiolitis after lung transplantation is associated with daily changes in air pollution. Am J Transplant. 2012;12:1831–1838.
63. Behr J, Maier K, Braun B, et al. Evidence for oxidative stress in bronchiolitis obliterans syndrome after lung and heart-lung transplantation. The Munich Lung Transplant Group. Transplantation. 2000;69:1856–1860.
64. Zheng L, Lam WK, Tipoe GL, et al. Overexpression of matrix metalloproteinase-8 and -9 in bronchiectatic airways in vivo. Eur Respir J. 2002;20:170–176.
65. Mamessier E, Lorec A-M, Thomas P, et al. T regulatory cells in stable posttransplant bronchiolitis obliterans syndrome. Transplantation. 2007;84:908–916.
66. Neurohr C, Huppmann P, Samweber B, et al. Prognostic value of bronchoalveolar lavage neutrophilia in stable lung transplant recipients. J Heart Lung Transplant. 2009;28:468–474.
67. Gerhardt SG, McDyer JF, Girgis RE, et al. Maintenance azithromycin therapy for bronchiolitis obliterans syndrome: results of a pilot study. Am J Respir Crit Care Med. 2003;168:121–125.
68. Yates B, Murphy DM, Forrest IA, et al. Azithromycin reverses airflow obstruction in established bronchiolitis obliterans syndrome. Am J Respir Crit Care Med. 2005;172:772–775.
69. Corris PA, Ryan VA, Small T, et al. A randomised controlled trial of azithromycin therapy in bronchiolitis obliterans syndrome (BOS) post lung transplantation. Thorax. 2015;70:442–450.
70. Vanaudenaerde BM, Meyts I, Vos R, et al. A dichotomy in bronchiolitis obliterans syndrome after lung transplantation revealed by azithromycin therapy. Eur Respir J. 2008;32:832–843.
71. Gottlieb J, Szangolies J, Koehnlein T, et al. Long-term azithromycin for bronchiolitis obliterans syndrome after lung transplantation. Transplantation. 2008;85:36–41.
72. Verleden GM, Vanaudenaerde BM, Dupont LJ, et al. Azithromycin reduces airway neutrophilia and interleukin-8 in patients with bronchiolitis obliterans syndrome. Am J Respir Crit Care Med. 2006;174:566–570.
73. Verleden GM, Raghu G, Meyer KC, et al. A new classification system for chronic lung allograft dysfunction. J Heart Lung Transplant. 2014;33:127–133.
74. Kitchens WH, Uehara S, Chase CM, et al. The changing role of natural killer cells in solid organ rejection and tolerance. Transplantation. 2006;81:811–817.
75. Fildes JE, Yonan N, Leonard CT. Natural killer cells and lung transplantation, roles in rejection, infection, and tolerance. Transpl Immunol. 2008;19:1–11.
76. Hodge G, Hodge S, Holmes-Liew C-L, et al. Bronchiolitis obliterans syndrome is associated with increased peripheral blood natural killer and natural killer T-like granzymes, perforin, and T-helper-type 1 pro-inflammatory cytokines. J Heart Lung Transplant. 2012;31:888–895.
77. Colvin RB, Smith RN. Antibody-mediated organ-allograft rejection. Nat Rev Immunol. 2005;5:807–817.
78. Cao G, Lu Y, Gao R, et al. Expression of fractalkine, CX3CR1, and vascular endothelial growth factor in human chronic renal allograft rejection. Transplant Proc. 2006;38:1998–2000.
79. Sechler JM, Barlic J, Grivel JC, et al. IL-15 alters expression and function of the chemokine receptor CX3CR1 in human NK cells. Cell Immunol. 2004;230:99–108.
80. Borchers MT, Harris NL, Wesselkamper SC, et al. NKG2D ligands are expressed on stressed human airway epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2006;291:L222–L231.
81. Raulet DH. Roles of the NKG2D immunoreceptor and its ligands. Nat Rev Immunol. 2003;3:781–790.
82. Zdrenghea MT, Telcian AG, Laza-Stanca V, et al. RSV infection modulates IL-15 production and MICA levels in respiratory epithelial cells. Eur Respir J. 2012;39:712–720.
83. Biron CA, Nguyen KB, Pien GC, et al. Natural killer cells in antiviral defense: function and regulation by innate cytokines. Annu Rev Immunol. 1999;17:189–220.
84. Trapani JA, Smyth MJ. Functional significance of the perforin/granzyme cell death pathway. Nat Rev Immunol. 2002;2:735–747.
85. Fildes JE, Yonan N, Tunstall K, et al. Natural killer cells in peripheral blood and lung tissue are associated with chronic rejection after lung transplantation. J Heart Lung Transplant. 2008;27:203–207.
86. Beilke JN, Kuhl NR, Van Kaer L, et al. NK cells promote islet allograft tolerance via a perforin-dependent mechanism. Nat Med. 2005;11:1059–1065.
87. Yu G, Xu X, Vu MD, et al. NK cells promote transplant tolerance by killing donor antigen-presenting cells. J Exp Med. 2006;203:1851–1858.
88. Jungraithmayr W, Codarri L, Bouchaud G, et al. Cytokine complex-expanded natural killer cells improve allogeneic lung transplant function via depletion of donor dendritic cells. Am J Respir Crit Care Med. 2013;187:1349–1359.
89. Kwakkel-van Erp JM, van de Graaf EA, Paantjens AWM, et al. The killer immunoglobulin-like receptor (KIR) group A haplotype is associated with bronchiolitis obliterans syndrome after lung transplantation. J Heart Lung Transplant. 2008;27:995–1001.
90. Belperio JA, Keane MP, Burdick MD, et al. Critical role for the chemokine MCP-1/CCR2 in the pathogenesis of bronchiolitis obliterans syndrome. J Clin Invest. 2001;108:547–556.
91. Mikols CL, Yan L, Norris JY, et al. IL-12 p80 is an innate epithelial cell effector that mediates chronic allograft dysfunction. Am J Respir Crit Care Med. 2006;174:461–470.
92. Oyaizu T, Okada Y, Shoji W, et al. Reduction of recipient macrophages by gadolinium chloride prevents development of obliterative airway disease in a rat model of heterotopic tracheal transplantation. Transplantation. 2003;76:1214–1220.
93. Bernasconi E, Koutsokera A, Pattaroni C, et al. Alveolar macrophages and pulmonary microbiota are interconnected indicators of lung ecology post-transplantation. Eur Respir J. 2015;46:OA3269.
94. Liu J, Zhou X, Zhan Z, et al. IL-25 regulates the polarization of macrophages and attenuates obliterative bronchiolitis in murine trachea transplantation models. Int Immunopharmacol. 2015;25:383–392.
95. Verleden SE, Ruttens D, Vandermeulen E, et al. Elevated bronchoalveolar lavage eosinophilia correlates with poor outcome after lung transplantation. Transplantation. 2014;97:83.
96. Meyer KC, Raghu G, Verleden GM, et al. An international ISHLT/ATS/ERS clinical practice guideline: diagnosis and management of bronchiolitis obliterans syndrome. Eur Respir J. 2014;44:1479–1503.
97. Hopkins PM, Aboyoun CL, Chhajed PN, et al. Association of minimal rejection in lung transplant recipients with obliterative bronchiolitis. Am J Respir Crit Care Med. 2004;170:1022–1026.
98. Chien JW, Duncan S, Williams KM, et al. Bronchiolitis obliterans syndrome after allogeneic hematopoietic stem cell transplantation-an increasingly recognized manifestation of chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2010;16:S106–S114.
99. Gelman AE, Li W, Richardson SB, et al. Cutting edge: acute lung allograft rejection is independent of secondary lymphoid organs. J Immunol. 2009;182:3969–3973.
100. Moyron-Quiroz JE, Rangel-Moreno J, Kusser K, et al. Role of inducible bronchus associated lymphoid tissue (iBALT) in respiratory immunity. Nat Med. 2004;10:927–934.
101. Sato M, Hirayama S, Hwang DM, et al. The role of intrapulmonary de novo lymphoid tissue in obliterative bronchiolitis after lung transplantation. J Immunol. 2009;182:7307–7316.
102. Shenoy KV, Solomides C, Cordova F, et al. Low CD4/CD8 ratio in bronchus-associated lymphoid tissue is associated with lung allograft rejection. J Transplant. 2012;2012:928081.
103. Hodge G, Hodge S, Chambers D, et al. Bronchiolitis obliterans syndrome is associated with absence of suppression of peripheral blood Th1 proinflammatory cytokines. Transplantation. 2009;88:211–218.
104. Kennedy VE, Todd JL, Palmer SM. Bronchoalveolar lavage as a tool to predict, diagnose and understand bronchiolitis obliterans syndrome. Am J Transplant. 2013;13:552–561.
105. Bharat A, Narayanan K, Street T, et al. Early posttransplant inflammation promotes the development of alloimmunity and chronic human lung allograft rejection. Transplantation. 2007;83:150–158.
106. Hodge S, Hodge G, Ahern J, et al. Increased levels of T cell granzyme b in bronchiolitis obliterans syndrome are not suppressed adequately by current immunosuppressive regimens. Clin Exp Immunol. 2009;158:230–236.
107. Brugière O, Thabut G, Krawice-Radanne I, et al. Role of HLA-G as a predictive marker of low risk of chronic rejection in lung transplant recipients: a clinical prospective study. Am J Transplant. 2015;15:461–471.
108. Chalermskulrat W, Neuringer IP, Schmitz JL, et al. Human leukocyte antigen mismatches predispose to the severity of bronchiolitis obliterans syndrome after lung transplantation. Chest. 2003;123:1825–1831.
109. Reznik SI, Jaramillo A, SivaSai KS, et al. Indirect allorecognition of mismatched donor HLA class II peptides in lung transplant recipients with bronchiolitis obliterans syndrome. Am J Transplant. 2001;1:228–235.
110. SivaSai KS, Smith MA, Poindexter NJ, et al. Indirect recognition of donor HLA class I peptides in lung transplant recipients with bronchiolitis obliterans syndrome. Transplantation. 1999;67:1094–1098.
111. Stanford RE, Ahmed S, Hodson M, et al. A role for indirect allorecognition in lung transplant recipients with obliterative bronchiolitis. Am J Transplant. 2003;3:736–742.
112. Higuchi T, Maruyama T, Jaramillo A, et al. Induction of obliterative airway disease in murine tracheal allografts by CD8+ CTLs recognizing a single minor histocompatibility antigen. J Immunol. 2005;174:1871–1878.
113. Richards DM, Dalheimer SL, Ehst BD, et al. Indirect minor histocompatibility antigen presentation by allograft recipient cells in the draining lymph node leads to the activation and clonal expansion of CD4+ T cells that cause obliterative airways disease. J Immunol. 2004;172:3469–3479.
114. Weber DJ, Wilkes DS. The role of autoimmunity in obliterative bronchiolitis after lung transplantation. Am J Physiol Lung Cell Mol Physiol. 2013;304:L307–L311.
115. Haque MA, Mizobuchi T, Yasufuku K, et al. Evidence for immune responses to a self-antigen in lung transplantation: role of type V collagen-specific T cells in the pathogenesis of lung allograft rejection. J Immunol. 2002;169:1542–1549.
116. Burlingham WJ, Love RB, Jankowska-Gan E, et al. IL-17-dependent cellular immunity to collagen type V predisposes to obliterative bronchiolitis in human lung transplants. J Clin Invest. 2007;117:3498–3506.
117. Vanaudenaerde BM, De Vleeschauwer SI, Vos R, et al. The role of the IL23/IL17 axis in bronchiolitis obliterans syndrome after lung transplantation. Am J Transplant. 2008;8:1911–1920.
118. Fan L, Benson HL, Vittal R, et al. Neutralizing IL-17 prevents obliterative bronchiolitis in murine orthotopic lung transplantation. Am J Transplant. 2011;11:911–922.
119. Nakagiri T, Inoue M, Morii E, et al. Local IL-17 production and a decrease in peripheral blood regulatory T cells in an animal model of bronchiolitis obliterans. Transplantation. 2010;89:1312–1319.
120. Ruttens D, Wauters E, Kiciński M, et al. Genetic variation in interleukin-17 receptor A is functionally associated with chronic rejection after lung transplantation. J Heart Lung Transplant. 2013;32:1233–1240.
121. Halwani R, Al-Muhsen S, Hamid Q. T helper 17 cells in airway diseases: from laboratory bench to bedside. Chest. 2013;143:494–501.
122. Benoist C, Mathis D. Treg cells, life history, and diversity. Cold Spring Harb Perspect Biol. 2012;4:a007021.
123. Bhorade SM, Chen H, Molinero L, et al. Decreased percentage of CD4+FoxP3+ cells in bronchoalveolar lavage from lung transplant recipients correlates with development of bronchiolitis obliterans syndrome. Transplantation. 2010;90:540–546.
124. Gregson AL, Hoji A, Palchevskiy V, et al. Protection against bronchiolitis obliterans syndrome is associated with allograft CCR7+ CD45RA- T regulatory cells. PLoS One. 2010;5:e11354.
125. Meloni FF, Vitulo PP, Bianco AMA, et al. Regulatory CD4+CD25+ T cells in the peripheral blood of lung transplant recipients: correlation with transplant outcome. Transplantation. 2004;77:762–766.
126. Tiriveedhi V, Takenaka M, Ramachandran S, et al. T regulatory cells play a significant role in modulating MHC class I antibody-induced obliterative airway disease. Am J Transplant. 2012;12:2663–2674.
127. Zhou W, Zhou X, Gaowa S, et al. The critical role of induced CD4+ FoxP3+ regulatory cells in suppression of interleukin-17 production and attenuation of mouse orthotopic lung allograft rejection. Transplantation. 2015;99:1356–1364.
128. Kleinewietfeld M, Hafler DA. The plasticity of human Treg and Th17 cells and its role in autoimmunity. Semin Immunol. 2013;25:305–312.
129. Magnan A, Mege JL, Escallier JC, et al. Balance between alveolar macrophage IL-6 and TGF-beta in lung-transplant recipients. Marseille and Montréal Lung Transplantation Group. Am J Respir Crit Care Med. 1996;153:1431–1436.
130. Benden C, Speich R, Hofbauer GF, et al. Extracorporeal photopheresis after lung transplantation: a 10-year single-center experience. Transplantation. 2008;86:1625–1627.
131. Morrell MR, Despotis GJ, Lublin DM, et al. The efficacy of photopheresis for bronchiolitis obliterans syndrome after lung transplantation. J Heart Lung Transplant. 2010;29:424–431.
132. Meloni F, Cascina A, Miserere S, et al. Peripheral CD4(+)CD25(+) TREG cell counts and the response to extracorporeal photopheresis in lung transplant recipients. Transplant Proc. 2007;39:213–217.
133. Del Fante C, Scudeller L, Oggionni T, et al. Long-term off-line extracorporeal photochemotherapy in patients with chronic lung allograft rejection not responsive to conventional treatment: a 10-year single-centre analysis. Respiration. 2015;90:118–128.
134. Lamioni A, Parisi F, Isacchi G, et al. The immunological effects of extracorporeal photopheresis unraveled: induction of tolerogenic dendritic cells in vitro and regulatory T cells in vivo. Transplantation. 2005;79:846–850.
135. Maeda A, Schwarz A, Kernebeck K, et al. Intravenous infusion of syngeneic apoptotic cells by photopheresis induces antigen-specific regulatory T cells. J Immunol. 2005;174:5968–5976.
136. Bruserud Ø, Tvedt THA, Paulsen PQ, et al. Extracorporeal photopheresis (photochemotherapy) in the treatment of acute and chronic graft versus host disease: immunological mechanisms and the results from clinical studies. Cancer Immunol Immunother. 2014;63:757–777.
137. Akimova T, Diamond J, Wilkes D, et al. Comparison of T regulatory (Treg) cell function pre- and post-lung transplantation shows a major negative impact of immunosuppression on Treg function. ATC Abstracts. 2015;15(suppl 3).
138. Lemaitre PH, Vokaer B, Charbonnier LM, et al. Cyclosporine A drives a Th17- and Th2-mediated posttransplant obliterative airway disease. Am J Transplant. 2013;13:611–620.
139. Zhao Y, Gillen JR, Meher AK, et al. Rapamycin prevents bronchiolitis obliterans through increasing infiltration of regulatory B cells in a murine tracheal transplantation model. J Thorac Cardiovasc Surg. 2015;151:487-496.e3.
140. Juvet SC, Whatcott AG, Bushell AR, et al. Harnessing regulatory T cells for clinical use in transplantation: the end of the beginning. Am J Transplant. 2014;14:750–763.
141. Vandermeulen E, Verleden SE, Ruttens D, et al. The role of B-cells in phenotypes of chronic lung allograft dysfunction. J Heart Lung Transplant. 2015;34:S29.
142. Jaramillo A, Smith MA, Phelan D, et al. Development of ELISA-detected anti-HLA antibodies precedes the development of bronchiolitis obliterans syndrome and correlates with progressive decline in pulmonary function after lung transplantation. Transplantation. 1999;67:1155–1161.
143. Sundaresan S, Mohanakumar T, Smith MA, et al. HLA-A locus mismatches and development of antibodies to HLA after lung transplantation correlate with the development of bronchiolitis obliterans syndrome. Transplantation. 1998;65:648–653.
144. Safavi S, Robinson DR, Soresi S, et al. De novo donor HLA-specific antibodies predict development of bronchiolitis obliterans syndrome after lung transplantation. J Heart Lung Transplant. 2014;33:1273–1281.
145. Morrell MR, Pilewski JM, Gries CJ, et al. De novo donor-specific HLA antibodies are associated with early and high-grade bronchiolitis obliterans syndrome and death after lung transplantation. J Heart Lung Transplant. 2014;33:1288–1294.
146. Roux A, Bendib Le Lan I, Holifanjaniaina S, et al. Antibody-mediated rejection in lung transplantation: clinical outcomes and donor-specific antibody characteristics. Am J Transplant. 2016.
147. Snyder LD, Wang Z, Chen D-F, et al. Implications for human leukocyte antigen antibodies after lung transplantation: a 10-year experience in 441 patients. Chest. 2013;144:226–233.
148. Kauke T, Kneidinger N, Martin B, et al. Bronchiolitis obliterans syndrome due to donor-specific HLA-antibodies. Tissue Antigens. 2015;86:178–185.
149. Hachem RR, Yusen RD, Meyers BF, et al. Anti-human leukocyte antigen antibodies and preemptive antibody-directed therapy after lung transplantation. J Heart Lung Transplant. 2010;29:973–980.
150. Baskaran G, Tiriveedhi V, Ramachandran S, et al. Efficacy of extracorporeal photopheresis in clearance of antibodies to donor-specific and lung-specific antigens in lung transplant recipients. J Heart Lung Transplant. 2014;33:950–956.
151. Angaswamy N, Saini D, Ramachandran S, et al. Development of antibodies to human leukocyte antigen precedes development of antibodies to major histocompatibility class I–related chain A and are significantly associated with development of chronic rejection after human lung transplantation. Hum Immunol. 2010;71:560–565.
152. Goers TA, Ramachandran S, Aloush A, et al. De novo production of K-alpha1 tubulin-specific antibodies: role in chronic lung allograft rejection. J Immunol. 2008;180:4487–4494.
153. Hachem RR, Tiriveedhi V, Patterson GA, et al. Antibodies to K-α 1 tubulin and collagen V are associated with chronic rejection after lung transplantation. Am J Transplant. 2012;12:2164–2171.
154. Fukami N, Ramachandran S, Saini D, et al. Antibodies to MHC class I induce autoimmunity: role in the pathogenesis of chronic rejection. J Immunol. 2009;182:309–318.
155. Xu Z, Ramachandran S, Gunasekaran M, et al. B cell-activating transcription factor plays a critical role in the pathogenesis of anti-major histocompatibility complex-induced obliterative airway disease. Am J Transplant. 2016.
156. Saini D, Weber J, Ramachandran S, et al. Alloimmunity-induced autoimmunity as a potential mechanism in the pathogenesis of chronic rejection of human lung allografts. J Heart Lung Transplant. 2011;30:624–631.
157. Tiriveedhi V, Gautam B, Sarma NJ, et al. Pre-transplant antibodies to Kα1 tubulin and collagen-V in lung transplantation: clinical correlations. J Heart Lung Transplant. 2013;32:807–814.
158. Iwata T, Chiyo M, Yoshida S, et al. Lung transplant ischemia reperfusion injury: metalloprotease inhibition down-regulates exposure of type V collagen, growth-related oncogene-induced neutrophil chemotaxis, and tumor necrosis factor-alpha expression. Transplantation. 2008;85:417–426.
159. Budding K, van de Graaf EA, Kardol-Hoefnagel T, et al. A promoter polymorphism in the CD59 complement regulatory protein gene in donor lungs correlates with a higher risk for chronic rejection after lung transplantation. Am J Transplant. 2016;16:987–998 2015; doi: 10.1111/ajt.13497.
160. Worthington JE, McEwen A, McWilliam LJ, et al. Association between C4d staining in renal transplant biopsies, production of donor-specific HLA antibodies, and graft outcome. Transplantation. 2007;83:398–403.
161. Sakashita H, Haga H, Ashihara E, et al. Significance of C4d staining in ABO-identical/compatible liver transplantation. Mod Pathol. 2007;20:676–684.
162. Fedrigo M, Gambino A, Tona F, et al. Can C4d immunostaining on endomyocardial biopsies be considered a prognostic biomarker in heart transplant recipients? Transplantation. 2010;90:791–798.
163. Westall GP, Snell GI. Antibody-mediated rejection in lung transplantation: fable, spin, or fact? Transplantation. 2014;98:927–930.
164. Porrett PM, Yuan X, LaRosa DF, et al. Mechanisms underlying blockade of allograft acceptance by TLR ligands. J Immunol. 2008;181:1692–1699.
165. Bharat A, Kuo E, Steward N, et al. Immunological link between primary graft dysfunction and chronic lung allograft rejection. Ann Thorac Surg. 2008;86:189–195.
166. Borthwick LA, Parker SM, Brougham KA, et al. Epithelial to mesenchymal transition (EMT) and airway remodelling after human lung transplantation. Thorax. 2009;64:770–777.
167. Pain M, Bermudez O, Lacoste P, et al. Tissue remodelling in chronic bronchial diseases: from the epithelial to mesenchymal phenotype. Eur Respir Rev. 2014;23:118–130.
168. El-Gamel A, Sim E, Hasleton P, et al. Transforming growth factor beta (TGF-β) and obliterative bronchiolitis following pulmonary transplantation. J Heart Lung Transplant. 1999;18:828–837.
169. Liu M, Suga M, Maclean AA, et al. Soluble transforming growth factor-beta type III receptor gene transfection inhibits fibrous airway obliteration in a rat model of bronchiolitis obliterans. Am J Respir Crit Care Med. 2002;165:419–423.
170. DerHovanessian A, Weigt SS, Palchevskiy V, et al. The role of TGF-β in the association between primary graft dysfunction and bronchiolitis obliterans syndrome. Am J Transplant. 2016;16:640–649.
171. Xu Z, Ramachandran S, Gunasekaran M, et al. MicroRNA-144 dysregulates the transforming growth factor-β signaling cascade and contributes to the development of bronchiolitis obliterans syndrome after human lung transplantation. J Heart Lung Transplant. 2015;34:1154–1162.
172. Noble PW, Albera C, Bradford WZ, et al. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet. 2011;377:1760–1769.
173. Ihle F, von Wulffen W, Neurohr C. Pirfenidone: a potential therapy for progressive lung allograft dysfunction? J Heart Lung Transplant. 2013;32:574–575.
174. Vos R, Verleden SE, Ruttens D, et al. Pirfenidone: a potential new therapy for restrictive allograft syndrome? J Heart Lung Transplant. 2013;13:3035–3040.
175. Borthwick LA, McIlroy EI, Gorowiec MR, et al. Inflammation and epithelial to mesenchymal transition in lung transplant recipients: role in dysregulated epithelial wound repair. Am J Transplant. 2010;10:498–509.
176. Borthwick LA, Corris PA, Mahida R, et al. TNFα from classically activated macrophages accentuates epithelial to mesenchymal transition in obliterative bronchiolitis. Am J Transplant. 2013;13:621–633.
177. Thevenot PT, Saravia J, Jin N, et al. Radical-containing ultrafine particulate matter initiates epithelial-to-mesenchymal transitions in airway epithelial cells. Am J Respir Cell Mol Biol. 2013;48:188–197.
178. Felton VM, Inge LJ, Willis BC, et al. Immunosuppression-induced bronchial epithelial–mesenchymal transition: a potential contributor to obliterative bronchiolitis. J Thorac Cardiovasc Surg. 2011;141:523–530.
179. Gorowiec MR, Borthwick LA, Parker SM, et al. Free radical generation induces epithelial-to-mesenchymal transition in lung epithelium via a TGF-β1-dependent mechanism. Free Radic Biol Med. 2012;52:1024–1032.
180. Mattsson J, Remberger M, Andersson O, et al. Decreased serum levels of clara cell secretory protein (CC16) are associated with bronchiolitis obliterans and may permit early diagnosis in patients after allogeneic stem-cell transplantation. Transplantation. 2005;79:1411–1416.
181. Pilmore HL, Eris JM, Painter DM, et al. Vascular endothelial growth factor expression in human chronic renal allograft rejection. Transplantation. 1999;67:929–933.
182. Schafer G, Cramer T, Suske G, et al. Oxidative stress regulates vascular endothelial growth factor-A gene transcription through Sp1- and Sp3-dependent activation of two proximal GC-rich promoter elements. J Biol Chem. 2003;278:8190–8198.
183. Tikkanen JM, Hollmen M, Nykanen AI, et al. Role of platelet-derived growth factor and vascular endothelial growth factor in obliterative airway disease. Am J Respir Crit Care Med. 2006;174:1145–1152.
184. Brocker V, Langer F, Fellous TG, et al. Fibroblasts of recipient origin contribute to bronchiolitis obliterans in human lung transplants. Am J Respir Crit Care Med. 2006;173:1276–1282.
185. Verleden SE, Ruttens D, Vos R, et al. Differential cytokine, chemokine and growth factor expression in phenotypes of chronic lung allograft dysfunction. Transplantation. 2015;99:86–93.
186. Koutsokera A, Royer P-J, Fritz A, et al. Risk factors for chronic lung allograft dysfunction (CLAD) in the SysCLAD cohort. Eur Respir J. 2015;46:PA1800.
187. Jonigk D, Izykowski N, Rische J, et al. Molecular profiling in lung biopsies of human pulmonary allografts to predict chronic lung allograft dysfunction. Am J Pathol. 2015;185:3178–3188.
188. Henke JA, Golden JA, Yelin EH, et al. Persistent increases of BAL neutrophils as a predictor of mortality following lung transplant. Chest. 1999;115:403–409.
189. Reynaud-Gaubert M, Marin V, Thirion X, et al. Upregulation of chemokines in bronchoalveolar lavage fluid as a predictive marker of post-transplant airway obliteration. J Heart Lung Transplant. 2002;21:721–730.
190. Hübner RH, Meffert S, Mundt U, et al. Matrix metalloproteinase-9 in bronchiolitis obliterans syndrome after lung transplantation. Eur Respir J. 2005;25:494–501.
191. Salama M, Jaksch P, Andrukhova O, et al. Endothelin-1 is a useful biomarker for early detection of bronchiolitis obliterans in lung transplant recipients. J Thorac Cardiovasc Surg. 2010;140:1422–1427.
192. Paantjens AWM, Kwakkel-van Erp JM, Van Ginkel WGJ, et al. Serum thymus and activation regulated chemokine levels post-lung transplantation as a predictor for the bronchiolitis obliterans syndrome. Clin Exp Immunol. 2008;154:202–208.
193. Besa V, Bonella F, Ohshimo S, et al. KL-6 changes in serum can be predictive of chronic lung allograft dysfunction in lung transplant recipients. J Heart Lung Transplant. 2015;34:S46.
194. Jaksch P, Taghavi S, Klepetko W, et al. Pretransplant serum human chitinase-like glycoprotein YKL-40 concentrations independently predict bronchiolitis obliterans development in lung transplant recipients. J Thorac Cardiovasc Surg. 2014;148:273–281.
195. Saito T, Takahashi H, Kaneda H, et al. Impact of cytokine expression in the pre-implanted donor lung on the development of chronic lung allograft dysfunction subtypes. Am J Transplant. 2013;13:3192–3201.
196. Royer P-J, Baron D, Reboulleau D, et al. Blood mRNA and miRNA transcriptome to predict chronic lung allograft dysfunction. Eur Respir J. 2015;46:PA1792.
197. Lande JD, Patil J, Li N, et al. Novel insights into lung transplant rejection by microarray analysis. Proc Am Thorac Soc. 2007;4:44–51.
198. Gregson AL, Hoji A, Injean P, et al. Altered exosomal RNA profiles in bronchoalveolar lavage from lung transplants with acute rejection. Am J Respir Crit Care Med. 2015;192:1490–1503.
199. Xu Z, Nayak D, Yang W, et al. Dysregulated MicroRNA expression and chronic lung allograft rejection in recipients with antibodies to donor HLA. Am J Transplant. 2015;15:1933.
200. Pison C, Magnan A, Botturi K, et al. Prediction of chronic lung allograft dysfunction: a systems medicine challenge. Eur Respir J. 2014;43:689.
201. Nathan SD. The future of lung transplantation. Chest. 2015;147:309.
202. Kirschner M, Bauch A, Agusti A, et al. Implementing systems medicine within healthcare. Genome Med. 2015;7:102.
203. Pellet J, Lefaudeux D, Royer P-J, et al. A multi-omics data integration approach to identify a predictive molecular signature of CLAD. Eur Respir J. 2015;46:OA3271.
204. Fernandez IE, Heinzelmann K, Verleden S, et al. Characteristic patterns in the fibrotic lung. Comparing idiopathic pulmonary fibrosis with chronic lung allograft dysfunction. Ann Am Thorac Soc. 2015;12Suppl 1:S34–S41.
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