Transcript Signatures of Lymphocytic Bronchitis in Lung Allograft Biopsy Specimens

Xu, Xin; Golden, Jeffrey A.; Dolganov, Gregory; Jones, Kirk D.; Donnelly, Samantha; Weaver, T.; Caughey, George H.

doi:10.1016/j.healun.2004.06.016

Cited by 17 publications

(11 citation statements)

References 37 publications

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“…This epithelial response was unique to viral infection (in mice) and transplant bronchitis (in humans) but was absent in other conditions such as acute rejection and CMV infection. These results, along with a study that identified different gene transcript profiles between subjects with transplant bronchitis and acute rejection (53), support the concept that distinct pathophysiologic mechanisms (and mediators) are likely responsible for mediating these various conditions.…”

Section: Discussionsupporting

confidence: 71%

IL-12 p80 Is an Innate Epithelial Cell Effector That Mediates Chronic Allograft Dysfunction

Mikols

Yan

Norris

et al. 2006

Am J Respir Crit Care Med

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Rationale: Bronchiolitis obliterans syndrome is the leading cause of chronic lung allograft dysfunction. We have demonstrated that respiratory viral infection is a bronchiolitis obliterans syndrome risk factor and virus-dependent injury induces expression of innate airway epithelial genes belonging to the interleukin (IL)-12 family. Thus, we hypothesized that epithelial cell IL-12 family members could mediate lung allograft dysfunction. Objectives: We used mouse and human allograft specimens to evaluate the role of epithelial cell IL-12 family members in allograft dysfunction associated with and without viral infection. Methods: Murine and human IL-12 family members were characterized and manipulated in allografts and then correlated with epithelial cell injury, immune cell accumulation, and collagen deposition. Results: In a mouse model of lung transplantation, concurrent viral infection and allogeneic transplantation increased epithelial injury and this was followed by exaggerated accumulation of macrophages and collagen deposition. This virus-driven allograft dysfunction was associated with an epithelial innate response manifested by a synergistic increase in the production of the macrophage chemoattractant IL-12 p80 (p80), but not IL-12 or IL-23. Blockade or overexpression of donor epithelial p80 resulted in a corresponding abrogation or enhancement of macrophage accumulation and allograft dysfunction. We extended these findings to human recipients with viral infection and transplant bronchitis and again observed excessive epithelial p80 expression that correlated with increased macrophage accumulation. Conclusions: These experiments support a role for an enhanced epithelial innate response as a central process in allograft dysfunction and identify the macrophage chemoattractant p80 as an innate epithelial effector of disease progression.

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Section: Discussionsupporting

confidence: 71%

IL-12 p80 Is an Innate Epithelial Cell Effector That Mediates Chronic Allograft Dysfunction

Mikols

Yan

Norris

et al. 2006

Am J Respir Crit Care Med

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“…This lymphocytosis is predominantly CD4 1 and CD45 1 (10). Work from the present laboratory showed differential expression of gene transcripts in patients with large-airway, but not small-airway, lymphocytic bronchitis (11). However, the ability of pathologic changes in large airways to predict future development of BOS has been less clear (12).…”

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confidence: 58%

Association of Large-Airway Lymphocytic Bronchitis with Bronchiolitis Obliterans Syndrome

Greenland

Jones²,

Hays³

et al. 2013

Am J Respir Crit Care Med

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Rationale: Lung transplantation offers great promise for otherwise terminal lung diseases, but the development of bronchiolitis obliterans syndrome (BOS) continues to limit survival. Although acute rejection and lymphocytic bronchiolitis have been identified as risk factors for the development of BOS, it is unclear whether largeairway lymphocytic inflammation conveys the same risk. Objectives: We evaluated lymphocytic bronchitis on endobronchial biopsies as a risk factor for BOS and mortality. Methods: Endobronchial biopsies were collected and graded during surveillance after lung transplantation. We assessed samples with negative cultures collected in the first 90 days from 298 subjects and compared large-airway lymphocytic bronchitis assessed by a 0-2 "E-score" and with standard A and BR pathology scores for acute rejection and small-airway lymphocytic bronchiolitis, respectively. Measurements and Main Results: We found surprisingly little association between large-and small-airway lymphocytic inflammation scores from a given bronchoscopy. Endobronchial lymphocytic bronchitis was more prevalent in subjects in BOS stage 0p and BOS stages 1-3 at the time of biopsy. Within 90 days after transplantation, increasing maximum E-score was associated with greater risk of BOS (adjusted hazard ratio, 1.76; 95% confidence interval, 1.11-2.78; P ¼ 0.02) and in this analysis 90-day maximum E-scores were the only score type predictive of BOS (P , 0.01). Conclusions: These results support a multicenter study to evaluate endoscopic biopsies for the identification of patients at increased risk for BOS. The association of endobronchial lymphocytic inflammation and BOS may have mechanistic implications.Keywords: bronchiolitis obliterans; graft rejection; bronchoscopy; lung transplantation Lung transplantation can offer improved quality of life and survival from otherwise terminal lung diseases. However, the development of chronic rejection, manifested as bronchiolitis obliterans syndrome (BOS), is a major barrier to long-term patient survival (1). BOS can cause death from graft failure and can occur despite potent immunosuppression (2, 3). One risk factor for BOS is symptomatic acute rejection (4). When confirmed by transbronchial biopsy, acute rejection generally is treated with additional immunosuppressive medications (5). Most lung transplantation centers also use surveillance bronchoscopy to identify otherwise silent episodes of acute rejection (6), presuming that untreated acute rejection increases the risk of BOS (7,8).Previous studies revealed that small-airways lymphocytic bronchiolitis in transbronchial biopsy specimens also is associated with increased risk of BOS (9). Endobronchial biopsies have been evaluated in lung transplant recipients, in whom acute rejection and current BOS were associated with largeairway lymphocytosis (10). This lymphocytosis is predominantly CD4 1 and CD45 1 (10). Work from the present laboratory showed differential expression of gene transcripts in patients with large-airway, but not small-ai...

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“…This large-airway inflammation does not appear to correlate with lymphocytic bronchiolitis or bronchitis seen in small airways obtained by transbronchial biopsies. [52][53][54][55] In spite of this lack of correlation, one recent study found an association between largeairway inflammation and BOS. 56 The utility of large-airway biopsies and their prognostic features needs to be further analyzed.…”

Section: Clinical Significance Of Acute Cellular Rejectionmentioning

confidence: 99%

Acute Cellular and Antibody-Mediated Allograft Rejection

McManigle

Pavlisko

Martinu

2013

Semin Respir Crit Care Med

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Survival post-lung transplantation remains limited to ∼ 50% at 5 years, far below survival after other solid organ transplants. Allograft rejection is a major cause of this limited survival. At least a third of lung transplant recipients experience acute rejection within 1 year posttransplantation. Acute rejection, though rarely a direct cause of death, represents the principal risk factor for chronic rejection, which is the greatest obstacle to long-term post-lung transplant survival. This article reviews in detail the two major subtypes of acute rejection: acute cellular rejection (ACR) and antibody-mediated rejection (AMR). ACR is diagnosed primarily by bronchoscopic transbronchial biopsies and is defined as perivascular or peribronchiolar lymphocytic infiltrates in the absence of infection. AMR remains poorly defined but is thought to involve anti-donor antibodies, allograft dysfunction, and pathological evidence of lung tissue injury or deposition of complement. Pathophysiological mechanisms, clinical presentation, clinical significance, known risk factors, and treatment strategies are discussed. Additionally, the limitations of current diagnostic modalities for both ACR and AMR are explained. Emerging data on the importance of donor-specific and non-donor-specific anti-human leukocyte antigen (anti-HLA) antibodies as well as non-HLA antibodies are presented. Larger cohorts have improved statistical analyses in recent years, leading to a clearer understanding of important topics related to ACR and AMR. Further collaborative studies and multicenter trials will be key in further advancing lung transplantation knowledge and improving outcomes in years to come.

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Transcript Signatures of Lymphocytic Bronchitis in Lung Allograft Biopsy Specimens

Abstract: Background-Rejection and obliterative bronchiolitis are barriers to sustained graft function in recipients of transplanted lungs. Early detection is hindered by inadequate tests and an incomplete understanding of the molecular events preceding or accompanying graft deterioration.

Cited by 17 publications

References 37 publications

IL-12 p80 Is an Innate Epithelial Cell Effector That Mediates Chronic Allograft Dysfunction

IL-12 p80 Is an Innate Epithelial Cell Effector That Mediates Chronic Allograft Dysfunction

Association of Large-Airway Lymphocytic Bronchitis with Bronchiolitis Obliterans Syndrome

Acute Cellular and Antibody-Mediated Allograft Rejection

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