S. Samuel Weigt

IL-13 Is Pivotal in the Fibro-Obliterative Process of Bronchiolitis Obliterans Syndrome

Acute allograft rejection is considered to be a predominately type 1 immune mediated response to the donor alloantigen. However, the type 2 immune mediated response has been implicated in multiple fibroproliferative diseases. Based on the fibro-obliterative lesion found during bronchiolitis obliterans syndrome (BOS), we hypothesized that the type 2 immune mediated response is involved in chronic lung allograft rejection. Specifically, whereas acute rejection is, in part, a type 1 immune response, chronic rejection is, in part, a type 2 immune response. We found the type 2 cytokine, IL-13, to be elevated and biologically active in human bronchoalveolar lavage fluid during BOS. Translational studies using a murine model of BOS demonstrated increased expression of IL-13 and its receptors that paralleled fibro-obliteration. In addition, in vivo neutralization of IL-13 reduced airway allograft matrix deposition and murine BOS, by a mechanism that was independent of IL-4. Furthermore, using IL-13Rα2−/− mice, we found increased fibro-obliteration. Moreover, anti-IL-13 therapy in combination with cyclosporin A had profound effects on reducing murine BOS. This supports the notion that IL-13 biological axis plays an important role during the pathogenesis of BOS independent of the IL-4 biological axis.

Respiratory Viral Infections in Hematopoietic Stem Cell and Solid Organ Transplant Recipients

Respiratory viral infections (RVIs) are common causes of mild illness in immunocompetent children and adults with rare occurrences of significant morbidity or mortality. Complications are more common in the very young, very old, and those with underlying lung diseases. However, RVIs are increasingly recognized as a cause of morbidity and mortality in recipients of hematopoietic stem cell transplants (HSCT) and solid organ transplants (SOTs). Diagnostic techniques for respiratory syncytial virus (RSV), parainfluenza, influenza, and adenovirus have been clinically available for decades, and these infections are known to cause serious disease in transplant recipients. Modern molecular technology has now made it possible to detect other RVIs including human metapneumovirus, coronavirus, and bocavirus, and the role of these viruses in causing serious disease in transplant recipients is still being worked out. This article reviews the current information regarding epidemiology, pathogenesis, clinical presentation, diagnosis, and treatment of these infections, as well as the aspects of clinical significance of RVIs unique to HSCT or SOT.

Bronchiolitis Obliterans Syndrome: The Achilles' Heel of Lung Transplantation

Lung transplantation is a therapeutic option for patients with end-stage pulmonary disorders. Unfortunately, chronic lung allograft dysfunction (CLAD), most commonly manifest as bronchiolitis obliterans syndrome (BOS), continues to be highly prevalent and is the major limitation to long-term survival. The pathogenesis of BOS is complex and involves alloimmune and nonalloimmune pathways. Clinically, BOS manifests as airway obstruction and dyspnea that are classically progressive and ultimately fatal; however, the course is highly variable, and distinguishable phenotypes may exist. There are few controlled studies assessing treatment efficacy, but only a minority of patients respond to current treatment modalities. Ultimately, preventive strategies may prove more effective at prolonging survival after lung transplantation, but their remains considerable debate and little data regarding the best strategies to prevent BOS. A better understanding of the risk factors and their relationship to the pathological mechanisms of chronic lung allograft rejection should lead to better pharmacological targets to prevent or treat this syndrome.

Chronic Allograft Rejection: Epidemiology, Diagnosis, Pathogenesis, and Treatment

Lung transplantation is a therapeutic option for patients with end-stage pulmonary disorders. Unfortunately, chronic lung allograft rejection, in the form of obliterative bronchiolitis and its clinical correlate bronchiolitis obliterans syndrome (BOS), continues to be highly prevalent and is the major limitation to long-term survival. The pathogenesis of BOS is complex and involves alloimmune and nonalloimmune pathways. The airway obstruction involved is classically progressive and unresponsive to treatment; however, the course is highly variable, and distinguishable phenotypes may exist. A better understanding of the risk factors and their relationship to the pathological mechanisms of chronic lung allograft rejection should lead to better pharmacological targets to prevent or treat this syndrome.

Bronchoalveolar Immunologic Profile of Acute Human Lung Transplant Allograft Rejection

Bronchoalveolar lavage fluid (BALF) offers a potential means to diagnose acute rejection and could provide insight into the immune mechanisms responsible for lung allograft rejection. Transbronchial biopsies from 29 bronchoscopic procedures were assessed for rejection. Concurrent BALF lymphocyte subsets were examined by flow cytometry, including CD4 and CD8 T cells and their activation status by CD38 expression, natural killer (NK), NK-like T (NT), B, regulatory T, and invariant receptor NK-T cells. Percentages of CD4 were reduced, and CD8 and activation of CD4 T cells correlated with rejection. There were trends for increased NT, reduced NK, and increased B cell percentages with rejection, suggesting potential roles of these cells. Among regulatory cells, the percentages of regulatory T cells decreased and CD4/CD8 invariant NK-T cells increased during rejection, suggesting a proinflammatory profile. A unique BALF lymphocyte profile was associated with rejection and may provide insight into the pathogenesis of allograft rejection.

Usefulness of immune monitoring in lung transplantation using adenosine triphosphate production in activated lymphocytes

BACKGROUND The ImmuKnow (Cylex Inc, Columbia, MD) assay measures the amount of adenosine triphosphate (ATP) produced by helper CD4(+) cells after stimulation with a T-cell mitogen. We hypothesized that this assay can be used to assess the immune function of lung transplant recipients and identify those at risk of developing acute cellular rejection and respiratory infection. METHODS Lung transplant recipients at University of California Los Angeles between January 1, 2006 and December 31, 2009 received a bronchoscopy with broncheoalveolar lavage, transbronchial biopsy and ImmuKnow values drawn at regular intervals as well as during episodes of clinical deterioration. The recipients clinical condition at each time-point was classified as healthy, acute cellular rejection, or respiratory infection. Mixed-effects models were used to compare the ATP levels among these groups, and odds ratios for rejection and infection were calculated. RESULTS The mean ATP level was 431 ± 189 ng/ml for the rejection group vs 377 ± 187 ng/ml for the healthy group (p = 0.10). A recipient with an ATP level > 525 ng/ml was 2.1 times more likely to have acute cellular rejection (95% confidence interval [CI] 1.1-3.8). Similarly, the mean ATP level was 323 ± 169 ng/ml for the infection group vs 377 ± 187 ng/ml for the healthy group (p = 0.03). A recipient with an ATP level < 225 ng/ml was 1.9 times more likely to have respiratory infection (95% CI, 1.1-3.3). However, the test was associated with poor performance characteristics. It had low sensitivity, specificity with an area under the receiver operating characteristic curve of only 0.61 to diagnose rejection and 0.59 to diagnose infection. CONCLUSIONS The ImmuKnow assay appears to have some ability to assess the overall immune function of lung transplant recipients. However, this study does not support its use as a reliable predictor of episodes of acute cellular rejection or respiratory infection.

Protection against bronchiolitis obliterans syndrome is associated with allograft CCR7+ CD45RA- T regulatory cells.

Bronchiolitis obliterans syndrome (BOS) is the major obstacle to long-term survival after lung transplantation, yet markers for early detection and intervention are currently lacking. Given the role of regulatory T cells (Treg) in modulation of immunity, we hypothesized that frequencies of Treg in bronchoalveolar lavage fluid (BALF) after lung transplantation would predict subsequent development of BOS. Seventy BALF specimens obtained from 47 lung transplant recipients were analyzed for Treg lymphocyte subsets by flow cytometry, in parallel with ELISA measurements of chemokines. Allograft biopsy tissue was stained for chemokines of interest. Treg were essentially all CD45RA−, and total Treg frequency did not correlate to BOS outcome. The majority of Treg were CCR4+ and CD103− and neither of these subsets correlated to risk for BOS. In contrast, higher percentages of CCR7+ Treg correlated to reduced risk of BOS. Additionally, the CCR7 ligand CCL21 correlated with CCR7+ Treg frequency and inversely with BOS. Higher frequencies of CCR7+ CD3+CD4+CD25hiFoxp3+CD45RA− lymphocytes in lung allografts is associated with protection against subsequent development of BOS, suggesting that this subset of putative Treg may down-modulate alloimmunity. CCL21 may be pivotal for the recruitment of this distinct subset to the lung allograft and thereby decrease the risk for chronic rejection.

Pulmonary hypertension associated with lung transplantation obliterative bronchiolitis and vascular remodeling of the allograft.

Pathologic obliterative bronchiolitis (OB)/Bronchiolitis obliterans syndrome (pathologic OB/BOS) is the major obstacle to long‐term survival post‐lung transplantation (LT). Our group has demonstrated that pulmonary hypertension (PH) complicates the course of chronic inflammatory lung diseases that have similarities to pathologic OB/BOS and that vascular remodeling of the bronchial circulation occurs during BOS. Consequently, we hypothesized that PH is associated with pathologic OB/BOS and may result from a vasculopathy of the allograft pulmonary circulation.

Time Course and Degree of Hyperinflation with Metronome-Paced Tachypnea in COPD Patients

In COPD patients, tachypnea should increase (dynamic) hyperinflation by shortening expiratory time. We developed a method to evaluate the time course and degree of dynamic hyperinflation during metronome-paced tachypnea. Fourteen patients with stable COPD (FEV1 43 ± 13% predicted) were studied. Inspiratory capacity (IC) was measured breathing through a flow transducer. Subjects paced their respiratory rate (fR) at 20/min, 30/min and 40/min for 60-second periods in response to audible tones generated by a computer. IC measurements were obtained at baseline and after 30 and 60 seconds at each fR. End-tidal carbon dioxide was monitored and fR was allowed to return to baseline between periods of tachypnea. Tachypnea produced reductions in IC of 200 ± 240 ml, 380 ± 330 ml and 540 ± 300 ml after 30 seconds at 20/min, 30/min and 40/min, respectively. IC reduction at 60 seconds was similar to 30 seconds for each fR. In patients with moderate-to-severe COPD, the dynamic hyperinflation induced by metronome-paced tachypnea was shown to occur rapidly and be complete by 30 seconds for a given fR. Controlled increments in fR produced stepwise increases in dynamic hyperinflation. This standardized method could be a useful and easier method of assessing dynamic hyperinflation in COPD patients before and after therapeutic interventions.

Pulmonary arterial hypertension and lung transplantation.

Heart-lung transplantation (HLT) and lung transplantation (LT) remain important therapies for idiopathic pulmonary arterial hypertension (IPAH), but recent advances in medical therapy can substantially delay or even obviate the need for transplantation, especially in certain PAH populations. By the early 1990s, the advent of epoprostenol, initially introduced as a bridge therapy to transplantation, in fact resulted in a survival advantage for IPAH. These benefits were comparable to those of HLT, and many patients who were thought to be destined for HLT were subsequently removed from active listing. Since 2005, however, the impact of the new lung allocation score (LAS) on IPAH has increased waiting list mortality. In the new millennium, the balance between the role of available medical therapies for PAH, the existing issues of the current LAS regarding the PAH patient, and the inherent morbidity associated with transplantation of PAH, will be critical to optimizing patient outcomes. The following discussion mainly focuses on adult IPAH, with some reference to congenital heart disease (CHD) and secondary PAH.