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

Capillary Proliferation in Systemic-Sclerosis-Related Pulmonary Fibrosis: Association with Pulmonary Hypertension

We sought to determine if any histopathologic component of the pulmonary microcirculation can distinguish systemic sclerosis (SSc)-related pulmonary fibrosis (PF) with and without pulmonary hypertension (PH)

New Trial Designs and Potential Therapies for Pulmonary Artery Hypertension

A greater understanding of the epidemiology, pathogenesis, and pathophysiology of pulmonary artery hypertension (PAH) has led to significant advances, but the disease remains fatal. Treatment options are neither universally available nor always effective, underscoring the need for development of novel therapies and therapeutic strategies. Clinical trials to date have provided evidence of efficacy, but were limited in evaluating the scope and duration of treatment effects. Numerous potential targets in varied stages of drug development exist, in addition to novel uses of familiar therapies. The pursuit of gene and cell-based therapy continues, and device use to help acute deterioration and chronic management is emerging. This rapid surge of drug development has led to multicenter pivotal clinical trials and has resulted in novel ethical and global clinical trial concerns. This paper will provide an overview of the opportunities and challenges that await the development of novel treatments for PAH. A greater understanding of the epidemiology, pathogenesis, and pathophysiology of pulmonary artery hypertension (PAH) has led to significant advances over the past 2 decades in treatment of this disorder. However, these treatment options are neither universally available nor always effective, underscoring the need for development of novel therapies and therapeutic strategies. Because PAH is considered an orphan disease that is uniformly progressive and fatal, prior clinical trials evaluating novel therapies were relatively short in duration and were comprised of small populations of affected patients. These studies provided evidence of efficacy, but were limited in evaluating the scope and duration of treatment effects. Accordingly, clinical development of novel therapies for PAH in the future will require trials of larger and perhaps more diverse patient cohorts who are studied for longer periods and with more robust and meaningful efficacy endpoints. The challenges posed by these requirements are substantial, and include From th

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Exercise-induced Pulmonary Hypertension: Physiological Basis and Methodological Concerns.

Exercise stresses the pulmonary circulation through increases in cardiac output ($$\stackrel{.}{\hbox{ Q }}$$) and left atrial pressure. Invasive as well as noninvasive studies in healthy volunteers show that the slope of mean pulmonary artery pressure (mPAP)-flow relationships ranges from 0.5 to 3 mm Hg⋅min⋅L(-1). The upper limit of normal mPAP at exercise thus approximates 30 mm Hg at a $$\stackrel{.}{\hbox{ Q }}$$ of less than 10 L⋅min(-1) or a total pulmonary vascular resistance at exercise of less than 3 Wood units. Left atrial pressure increases at exercise with an average upstream transmission to PAP in a close to one-for-one mm Hg fashion. Multipoint PAP-flow relationships are usually described by a linear approximation, but present with a slight curvilinearity, which is explained by resistive vessel distensibility. When mPAP is expressed as a function of oxygen uptake or workload, plateau patterns may be observed in patients with systolic heart failure who cannot further increase $$\stackrel{.}{\hbox{ Q }}$$ at the highest levels of exercise. Exercise has to be dynamic to avoid the increase in systemic vascular resistance and abrupt changes in intrathoracic pressure that occur with resistive exercise and can lead to unpredictable effects on the pulmonary circulation. Postexercise measurements are unreliable because of the rapid return of pulmonary vascular pressures and flows to the baseline resting state. Recent studies suggest that exercise-induced increase in PAP to a mean higher than 30 mm Hg may be associated with dyspnea-fatigue symptomatology.Journal ArticleSCOPUS: re.jinfo:eu-repo/semantics/publishe

Treatment with imatinib results in reduced IL-4-producing T cells, but increased CD4(+) T cells in the broncho-alveolar lavage of patients with systemic sclerosis.

T cells, particularly those producing IL-4, are implicated in inflammation-mediated fibrosis. In our phase I/IIa open-label pilot study in 15 patients with scleroderma-interstitial lung disease (SSc-ILD), high-dose imatinib treatment showed modest improvement in lung function and skin score, but with several adverse events. Here, we investigated T cell phenotype and cytokine production in bronchoalveolar lavage (BAL) from patients enrolled in this trial. We found that IL-4(+) T cells showed a stronger correlation with ground glass opacity (GGO) than fibrosis scores on lung high-resolution computer tomography scans. Frequencies of IL-4(+) T cells also discriminated patients with high (≥20) versus low (<20) GGO scores. Functional annotation clustering of proteins that correlated with T cells identified two major clusters that belonged to immune/inflammatory and wounding response. Repeat analyses after 1 year of treatment in 10 BAL samples, one each from the right middle and lower lobes of lung from 5 patients, showed that post-imatinib, IL-4(+) T cells were profoundly reduced but CD4(+) T cells increased, except in one patient who showed worsening of SSc-ILD. Post-imatinib increase in CD4(+) T cells correlated with soluble ICAM-3 and PECAM-1 levels in BAL, which associated with the lack of worsening in SSc-ILD. Thus, imatinib might confer its therapeutic effect in fibrosis via re-directing T cell responses from type 2 to other, non-type 2 cytokine producing CD4(+) T cells

Combination of Echocardiographic and Pulmonary Function Test Measures Improves Sensitivity for Diagnosis of Systemic Sclerosis-associated Pulmonary Arterial Hypertension: Analysis of 2 Cohorts

ObjectiveTo evaluate routinely collected non-invasive tests from 2 systemic sclerosis (SSc) cohorts to determine their predictive value alone and in combination versus right heart catheterization (RHC)-confirmed pulmonary arterial hypertension (PAH).MethodsWe evaluated 2 cohorts of patients who were at risk or with incident PAH: (1) The Pulmonary Hypertension Assessment and Recognition Outcomes in Scleroderma (PHAROS) cohort and (2) an inception SSc cohort at Cochin Hospital, Paris, France. Estimated right ventricular systolic pressure (eRVSP) as determined by transthoracic echocardiogram (TTE) and pulmonary function test (PFT) measures was evaluated, and the predictive values determined. We then evaluated patients with PAH missed on TTE cutoffs that were subsequently identified by a PFT measure.ResultsIn the PHAROS cohort (n = 206), 59 (29%) had RHC-defined PAH. An eRVSP threshold of 35-50 mm Hg failed to diagnose PAH in 7% to 31% of patients, 50% to 70% of which (n = 2-13) were captured by PFT measures. In the Cochin cohort (n = 141), 10 (7%) patients had RHC confirmed PAH. An eRVSP threshold of 35-50 mm Hg missed 0% to 70% (n = 0-7) of patients, of which 0% to 68% (n = 0-6) were met by PFT measures. The combination of TTE and PFT improved the negative predictive value for diagnosing PAH.ConclusionIn 2 large SSc cohorts, screening with TTE and PFT captured a majority of patients with PAH. TTE and PFT complement each other for the diagnosis of PAH

Sarcoidosis and colon cancer: A possible association

Sarcoidosis is a multisystem inflammatory disease characterized by non-caseating granulomas which mainly affect the pulmonary lymphatic system and lungs; although any organs can be interested. The association between sarcoidosis and cancer is still controversial, but many studies demonstrated an increased risk of cancer in patients with sarcoidosis, whereas few cases of sarcoidosis occurring after cancer have been reported. This report outlines and describes clinical, biologic and radiologic features of 3 patients with a history of surgical treatment and adjuvant chemotherapy for colon cancer, followed by a diagnosis of sarcoidosis some years later. The history of cancer and the lymph nodes positivity found through PET scan induced us to hypothesize a relapsing cancer disease. However, this hypothesis was not confirmed by the lymph nodes biopsy, which is the core method of diagnosis of sarcoidosis

Right Ventricular Functional Reserve in Early-Stage Idiopathic Pulmonary Fibrosis: An Exercise Two-Dimensional Speckle Tracking Doppler Echocardiography Study.

BACKGROUND: The most important determinant of long-term survival in patients with idiopathic pulmonary fibrosis is the right ventricular (RV) adaptation to the increased pulmonary vascular resistance. Our aim was to explore RV contractile reserve during stress echocardiography in early-stage IPF. METHODS: Fifty early-stage patients with IPF and 50 healthy control patients underwent rest and stress echocardiography, including RV two-dimensional speckle tracking echocardiography. At peak exertion, blood gas analysis and spirometry were also assessed. RESULTS: At rest, RV diameters were mildly increased in IPF; however, although RV conventional systolic function indexes were similar between the IPF and control groups, RV global longitudinal strain and RV lateral wall longitudinal strain (LWLS) were significantly reduced in the IPF cohort. During physical exercise, patients with IPF showed a reduced exercise tolerance with lower maximal workload (P < .01), level of oxygen saturation (P < .001), and peak heart rate (P < .01). Systolic and diastolic BP values were similar in both groups. Systolic pulmonary artery pressure (PAPs) increase (ΔPAPs) during exertion was higher in IPF vs healthy subjects (P < .0001); RV LWLS increase (ΔRV LWLS) during exercise was lower in patients with IPF vs control patients (P < .00001). By multivariable analysis, RV LWLS at rest and ΔRV LWLS were directly related to peak exertion capacity, PAPs, and blood oxygen saturation level (Spo(2); P < .0001). Δ RV LWLS was directly related to diffusion lung carbon monoxide (P < .0001). CONCLUSIONS: RV myocardial dysfunction is already present at rest in early-stage IPF and worsens during exertion as detected by two-dimensional speckle-tracking echocardiography. The RV altered contractile reserve appears to be related to reduced exercise tolerability and impaired pulmonary hemodynamic