Publications by authors named "Joseph R Arron"

74 Publications

IL-1R1-dependent signaling coordinates epithelial regeneration in response to intestinal damage.

Sci Immunol 2021 May;6(59)

Department of Immunology, Genentech Inc., South San Francisco, CA 94080, USA.

Repair of the intestinal epithelium is tightly regulated to maintain homeostasis. The response after epithelial damage needs to be local and proportional to the insult. How different types of damage are coupled to repair remains incompletely understood. We report that after distinct types of intestinal epithelial damage, IL-1R1 signaling in GREM1 mesenchymal cells increases production of R-spondin 3 (RSPO3), a Wnt agonist required for intestinal stem cell self-renewal. In parallel, IL-1R1 signaling regulates IL-22 production by innate lymphoid cells and promotes epithelial hyperplasia and regeneration. Although the regulation of both RSPO3 and IL-22 is critical for epithelial recovery from infection, IL-1R1-dependent RSPO3 production by GREM1 mesenchymal cells alone is sufficient and required for recovery after dextran sulfate sodium-induced colitis. These data demonstrate how IL-1R1-dependent signaling orchestrates distinct repair programs tailored to the type of injury sustained that are required to restore intestinal epithelial barrier function.
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http://dx.doi.org/10.1126/sciimmunol.abe8856DOI Listing
May 2021

The transition from normal lung anatomy to minimal and established fibrosis in idiopathic pulmonary fibrosis (IPF).

EBioMedicine 2021 Apr 13;66:103325. Epub 2021 Apr 13.

Center for Heart Lung Innovation, The University of British Columbia, Vancouver, Canada.

Background: The transition from normal lung anatomy to minimal and established fibrosis is an important feature of the pathology of idiopathic pulmonary fibrosis (IPF). The purpose of this report is to examine the molecular and cellular mechanisms associated with this transition.

Methods: Pre-operative thoracic Multidetector Computed Tomography (MDCT) scans of patients with severe IPF (n = 9) were used to identify regions of minimal(n = 27) and established fibrosis(n = 27). MDCT, Micro-CT, quantitative histology, and next-generation sequencing were used to compare 24 samples from donor controls (n = 4) to minimal and established fibrosis samples.

Findings: The present results extended earlier reports about the transition from normal lung anatomy to minimal and established fibrosis by showing that there are activations of TGFBI, T cell co-stimulatory genes, and the down-regulation of inhibitory immune-checkpoint genes compared to controls. The expression patterns of these genes indicated activation of a field immune response, which is further supported by the increased infiltration of inflammatory immune cells dominated by lymphocytes that are capable of forming lymphoid follicles. Moreover, fibrosis pathways, mucin secretion, surfactant, TLRs, and cytokine storm-related genes also participate in the transitions from normal lung anatomy to minimal and established fibrosis.

Interpretation: The transition from normal lung anatomy to minimal and established fibrosis is associated with genes that are involved in the tissue repair processes, the activation of immune responses as well as the increased infiltration of CD4, CD8, B cell lymphocytes, and macrophages. These molecular and cellular events correlate with the development of structural abnormality of IPF and probably contribute to its pathogenesis.
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http://dx.doi.org/10.1016/j.ebiom.2021.103325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054143PMC
April 2021

Molecular mapping of interstitial lung disease reveals a phenotypically distinct senescent basal epithelial cell population.

JCI Insight 2021 Apr 22;6(8). Epub 2021 Apr 22.

Department of Immunology Discovery.

Compromised regenerative capacity of lung epithelial cells can lead to cellular senescence, which may precipitate fibrosis. While increased markers of senescence have been reported in idiopathic pulmonary fibrosis (IPF), the origin and identity of these senescent cells remain unclear, and tools to characterize context-specific cellular senescence in human lung are lacking. We observed that the senescent marker p16 is predominantly localized to bronchiolized epithelial structures in scarred regions of IPF and systemic sclerosis-associated interstitial lung disease (SSc-ILD) lung tissue, overlapping with the basal epithelial markers Keratin 5 and Keratin 17. Using in vitro models, we derived transcriptional signatures of senescence programming specific to different types of lung epithelial cells and interrogated these signatures in a single-cell RNA-Seq data set derived from control, IPF, and SSc-ILD lung tissue. We identified a population of basal epithelial cells defined by, and enriched for, markers of cellular senescence and identified candidate markers specific to senescent basal epithelial cells in ILD that can enable future functional studies. Notably, gene expression of these cells significantly overlaps with terminally differentiating cells in stratified epithelia, where it is driven by p53 activation as part of the senescence program.
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http://dx.doi.org/10.1172/jci.insight.143626DOI Listing
April 2021

Osteopontin Links Myeloid Activation and Disease Progression in Systemic Sclerosis.

Cell Rep Med 2020 Nov 17;1(8):100140. Epub 2020 Nov 17.

Genentech, South San Francisco, CA, USA.

Progressive lung fibrosis is a major cause of mortality in systemic sclerosis (SSc) patients, but the underlying mechanisms remain unclear. We demonstrate that immune complexes (ICs) activate human monocytes to promote lung fibroblast migration partly via osteopontin (OPN) secretion, which is amplified by autocrine monocyte colony stimulating factor (MCSF) and interleukin-6 (IL-6) activity. Bulk and single-cell RNA sequencing demonstrate that elevated OPN expression in SSc lung tissue is enriched in macrophages, partially overlapping with CCL18 expression. Serum OPN is elevated in SSc patients with interstitial lung disease (ILD) and prognosticates future lung function deterioration in SSc cohorts. Serum OPN levels decrease following tocilizumab (monoclonal anti-IL-6 receptor) treatment, confirming the connection between IL-6 and OPN in SSc patients. Collectively, these data suggest a plausible link between autoantibodies and lung fibrosis progression, where circulating OPN serves as a systemic proxy for IC-driven profibrotic macrophage activity, highlighting its potential as a promising biomarker in SSc ILD.
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http://dx.doi.org/10.1016/j.xcrm.2020.100140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691442PMC
November 2020

Composite type-2 biomarker strategy versus a symptom-risk-based algorithm to adjust corticosteroid dose in patients with severe asthma: a multicentre, single-blind, parallel group, randomised controlled trial.

Lancet Respir Med 2021 01 8;9(1):57-68. Epub 2020 Sep 8.

Oxford Respiratory NIHR BRC, Nuffield Department of Medicine, University of Oxford, Oxford, UK.

Background: Asthma treatment guidelines recommend increasing corticosteroid dose to control symptoms and reduce exacerbations. This approach is potentially flawed because symptomatic asthma can occur without corticosteroid responsive type-2 (T2)-driven eosinophilic inflammation, and inappropriately high-dose corticosteroid treatment might have little therapeutic benefit with increased risk of side-effects. We compared a biomarker strategy to adjust corticosteroid dose using a composite score of T2 biomarkers (fractional exhaled nitric oxide [FENO], blood eosinophils, and serum periostin) with a standardised symptom-risk-based algorithm (control).

Methods: We did a single-blind, parallel group, randomised controlled trial in adults (18-80 years of age) with severe asthma (at treatment steps 4 and 5 of the Global Initiative for Asthma) and FENO of less than 45 parts per billion at 12 specialist severe asthma centres across England, Scotland, and Northern Ireland. Patients were randomly assigned (4:1) to either the biomarker strategy group or the control group by an online electronic case-report form, in blocks of ten, stratified by asthma control and use of rescue systemic steroids in the previous year. Patients were masked to study group allocation throughout the entirety of the study. Patients attended clinic every 8 weeks, with treatment adjustment following automated treatment-group-specific algorithms: those in the biomarker strategy group received a default advisory to maintain treatment and those in the control group had their treatment adjusted according to the steps indicated by the trial algorithm. The primary outcome was the proportion of patients with corticosteroid dose reduction at week 48, in the intention-to-treat (ITT) population. Secondary outcomes were inhaled corticosteroid (ICS) dose at the end of the study; cumulative dose of ICS during the study; proportion of patients on maintenance oral corticosteroids (OCS) at study end; rate of protocol-defined severe exacerbations per patient year; time to first severe exacerbation; number of hospital admissions for asthma; changes in lung function, Asthma Control Questionnaire-7 score, Asthma Quality of Life Questionnaire score, and T2 biomarkers from baseline to week 48; and whether patients declined to progress to OCS. A secondary aim of our study was to establish the proportion of patients with severe asthma in whom T2 biomarkers remained low when corticosteroid therapy was decreased to a minimum ICS dose. This study is registered with ClinicalTrials.gov, NCT02717689 and has been completed.

Findings: Patients were recruited from Jan 8, 2016, to July 12, 2018. Of 549 patients assessed, 301 patients were included in the ITT population and were randomly assigned to the biomarker strategy group (n=240) or to the control group (n=61). 28·4% of patients in the biomarker strategy group were on a lower corticosteroid dose at week 48 compared with 18·5% of patients in the control group (adjusted odds ratio [aOR] 1·71 [95% CI 0·80-3·63]; p=0·17). In the per-protocol (PP) population (n=121), a significantly greater proportion of patients were on a lower corticosteroid dose at week 48 in the biomarker strategy group (30·7% of patients) compared with the control group (5·0% of patients; aOR 11·48 [95% CI 1·35-97·83]; p=0·026). Patient choice to not follow treatment advice was the principle reason for loss to PP analysis. There was no difference in secondary outcomes between study groups and no loss of asthma control among patients in the biomarker strategy group who reduced their corticosteroid dose.

Interpretation: Biomarker-based corticosteroid adjustment did not result in a greater proportion of patients reducing corticosteroid dose versus control. Understanding the reasons for patients not following treatment advice in both treatment strategies is an important area for future research. The prevalence of T2 biomarker-low severe asthma was low.

Funding: This study was funded, in part, by the Medical Research Council UK.
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http://dx.doi.org/10.1016/S2213-2600(20)30397-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783382PMC
January 2021

A randomized, placebo-controlled trial evaluating effects of lebrikizumab on airway eosinophilic inflammation and remodelling in uncontrolled asthma (CLAVIER).

Clin Exp Allergy 2020 12 4;50(12):1342-1351. Epub 2020 Oct 4.

San Francisco Medical Center, University of California, San Francisco, CA, USA.

Background: The anti-interleukin 13 (IL-13) monoclonal antibody lebrikizumab improves lung function in patients with moderate-to-severe uncontrolled asthma, but its effects on airway inflammation and remodelling are unknown. CLAVIER was designed to assess lebrikizumab's effect on eosinophilic inflammation and remodelling.

Objective: To report safety and efficacy results from enrolled participants with available data from CLAVIER.

Methods: We performed bronchoscopy on patients with uncontrolled asthma before and after 12 weeks of randomized double-blinded treatment with lebrikizumab (n = 31) or placebo (n = 33). The pre-specified primary end-point was relative change in airway subepithelial eosinophils per mm of basement membrane (cells/mm ). Pre-specified secondary and exploratory outcomes included change in IL-13-associated biomarkers and measures of airway remodelling.

Results: There was a baseline imbalance in tissue eosinophils and high variability between treatment groups. There was no discernible change in adjusted mean subepithelial eosinophils/mm in response to lebrikizumab (95% CI, -82.5%, 97.5%). As previously observed, FEV increased after lebrikizumab treatment. Moreover, subepithelial collagen thickness decreased 21.5% after lebrikizumab treatment (95% CI, -32.9%, -10.2%), and fractional exhaled nitric oxide, CCL26 and SERPINB2 mRNA expression in bronchial tissues also reduced. Lebrikizumab was well tolerated, with a safety profile consistent with other lebrikizumab asthma studies.

Conclusions & Clinical Relevance: We did not observe reduced tissue eosinophil numbers in association with lebrikizumab treatment. However, in pre-specified exploratory analyses, lebrikizumab treatment was associated with reduced degree of subepithelial fibrosis, a feature of airway remodelling, as well as improved lung function and reduced key pharmacodynamic biomarkers in bronchial tissues. These results reinforce the importance of IL-13 in airway pathobiology and suggest that neutralization of IL-13 may reduce asthmatic airway remodelling.

Clinical Trial Registration: NCT02099656.
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http://dx.doi.org/10.1111/cea.13731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756263PMC
December 2020

Galectin-8 Is Upregulated in Keratinocytes by IL-17A and Promotes Proliferation by Regulating Mitosis in Psoriasis.

J Invest Dermatol 2021 Mar 15;141(3):503-511.e9. Epub 2020 Aug 15.

Graduate Institute of Immunology, National Taiwan University, Taipei, Taiwan; Institute of Biomedical Science, Academia Sinica, Taipei, Taiwan; Department of Dermatology, University of California Davis, Davis, California, USA. Electronic address:

Psoriasis is a chronic inflammatory skin disease that develops under the influence of the IL-23/T helper 17 cell axis and is characterized by intense inflammation and prominent epidermal hyperplasia. In this study, we demonstrate that galectin-8, a β-galactoside‒binding lectin, is upregulated in the epidermis of human psoriatic skin lesions as well as in a mouse model of psoriasis induced by intradermal IL-23 injections and in IL-17A‒treated keratinocytes. We show that keratinocyte proliferation is less prominent in galectin-8‒knockout mice after intradermal IL-23 treatment than in wild-type mice. In addition, we show that galectin-8 levels in keratinocytes are positively correlated with the ability of the cells to proliferate and that transitioning from mitosis into G1 phase is delayed in galectin-8‒knockout HaCaT cells after cell-cycle synchronization and release. We demonstrate by immunofluorescence staining and immunoblotting the presence of galectin-8 within the mitotic apparatus. We reveal by coimmunoprecipitation and mass spectrometry analysis that α-tubulin interacts with galectin-8 during mitosis. Finally, we show that in the absence of galectin-8, pericentrin compactness is lessened and mitotic microtubule length is shortened, as demonstrated by immunofluorescence staining. We conclude that galectin-8 is upregulated in psoriasis and contributes to the hyperproliferation of keratinocytes by maintaining centrosome integrity during mitosis through interacting with α-tubulin.
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http://dx.doi.org/10.1016/j.jid.2020.07.021DOI Listing
March 2021

ACE2, TMPRSS2, and furin gene expression in the airways of people with asthma-implications for COVID-19.

J Allergy Clin Immunol 2020 07 22;146(1):208-211. Epub 2020 May 22.

National Institute for Health Research (NIHR) Leicester Biomedical Research Centre (Respiratory theme) and College of Life Sciences, University of Leicester, Leicester, United Kingdom.

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http://dx.doi.org/10.1016/j.jaci.2020.05.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243787PMC
July 2020

30 Years of Biotherapeutics Development-What Have We Learned?

Annu Rev Immunol 2020 04;38:249-287

Research-Biology, Genentech, South San Francisco, California 94080, USA; email:

Since the birth of biotechnology, hundreds of biotherapeutics have been developed and approved by the US Food and Drug Administration (FDA) for human use. These novel medicines not only bring significant benefit to patients but also represent precision tools to interrogate human disease biology. Accordingly, much has been learned from the successes and failures of hundreds of high-quality clinical trials. In this review, we discuss general and broadly applicable themes that have emerged from this collective experience. We base our discussion on insights gained from exploring some of the most important target classes, including interleukin-1 (IL-1), tumor necrosis factor α (TNF-α), IL-6, IL-12/23, IL-17, IL-4/13, IL-5, immunoglobulin E (IgE), integrins and B cells. We also describe current challenges and speculate about how emerging technological capabilities may enable the discovery and development of the next generation of biotherapeutics.
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http://dx.doi.org/10.1146/annurev-immunol-101619-031510DOI Listing
April 2020

Beyond type 2 cytokines in asthma - new insights from old clinical trials.

Expert Opin Ther Targets 2020 05 30;24(5):463-475. Epub 2020 Mar 30.

Genentech, Inc., South San Francisco, CA, USA.

: Human asthma is a heterogeneous disorder on molecular, pathological, and clinical levels. The paradigm of asthma as an allergic process driven by type 2 cytokines and mediators has led to targeted biologic therapies resulting in some clinical benefit in patient subsets. However, some patient subsets and clinical manifestations do not benefit from these interventions, thus redefining unmet needs. Clinical studies of type 2 directed therapies have identified new targets under investigation in clinical development; these include epithelial alarmins, non-type 2 cytokines, cytokine receptor signaling, mast cells and neuroinflammation.: We consider lessons learned concerning asthma pathogenesis from observational studies and clinical trials of biologic agents that target type 2 mediators. We also provide a perspective on emerging therapeutic hypotheses to target processes independent of or orthogonal to type 2 inflammation in asthma.: Type 2 inflammation is continuous, not discrete, and is likely a modifier of underlying dysregulated airway physiology. Non-type 2 inflammatory mediators (e.g., IL17, IL6, IFNs), microbiome, alarmins (e.g., TSLP, IL33), mast cells and sensory neurons may represent orthogonal targets to type 2 mediators. There is a need to better match targets and outcome measures in biologically defined patient populations to appropriately test hypotheses in the clinic.
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http://dx.doi.org/10.1080/14728222.2020.1744567DOI Listing
May 2020

Seasonal variability of lung function and Asthma Quality of Life Questionnaire Scores in adults with uncontrolled asthma.

BMJ Open Respir Res 2019 11;6(1):e000406. Epub 2019 Nov 11.

Genentech, Inc, South San Francisco, California, USA.

Introduction: Asthma exacerbations spike in the spring and autumn months, yet the seasonal variation of asthma symptoms and lung function is poorly studied.

Methods: Seasonal variation of lung function, rescue medication use and patient-reported symptoms was evaluated by analyses of the Phase III lebrikizumab (anti-IL-13) LAVOLTA I and II studies in 2148 subjects with uncontrolled asthma. Lung function measurements (prebronchodilator FEV, forced vital capacity (FVC) and peak expiratory flow (PEF)), rescue medication use and Standardised Asthma Quality of Life Questionnaire (AQLQ(S)) were measured every 4 weeks over 52 weeks. By-month estimates normalised by hemispheric season were based on mixed-effect models with repeated measures (MMRM), adjusted by study stratification factors as covariates when appropriate. The dependency of clinical outcomes with seasonal variability was assessed by employing linear contrasts comparing hemisphere normalised December versus July group means from an MMRM regression and presented as the difference in means (adjusted 95% CI).

Results: FEV, FVC and PEF, rescue medication use and AQLQ(S) progressively worsened towards winter, unlike spring and autumn surges in asthma exacerbations. The December versus July mean differences were: (1) PEF=-6.5 (-8.7 to -4.2) L/min, 2) prebronchodilator FEV=-42 (-57 to -27) mL, (3) FVC=-41 (-59 to -23) mL and (4) AQLQ(S)=-0.15 (-0.19 to -0.1) units. Among AQLQ questions, discomfort or distress related to cough was most variable with respect to season (-0.33 (-0.42 to -0.24) units).

Discussion: Interpretation of interventional studies biased by seasonal exposures may be confounded by seasonal variability.

Trials Registration Numbers: NCT01867125 and NCT01868061.
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http://dx.doi.org/10.1136/bmjresp-2019-000406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6890391PMC
July 2020

An Allosteric Anti-tryptase Antibody for the Treatment of Mast Cell-Mediated Severe Asthma.

Cell 2019 Oct;179(2):417-431.e19

Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.

Severe asthma patients with low type 2 inflammation derive less clinical benefit from therapies targeting type 2 cytokines and represent an unmet need. We show that mast cell tryptase is elevated in severe asthma patients independent of type 2 biomarker status. Active β-tryptase allele count correlates with blood tryptase levels, and asthma patients carrying more active alleles benefit less from anti-IgE treatment. We generated a noncompetitive inhibitory antibody against human β-tryptase, which dissociates active tetramers into inactive monomers. A 2.15 Å crystal structure of a β-tryptase/antibody complex coupled with biochemical studies reveal the molecular basis for allosteric destabilization of small and large interfaces required for tetramerization. This anti-tryptase antibody potently blocks tryptase enzymatic activity in a humanized mouse model, reducing IgE-mediated systemic anaphylaxis, and inhibits airway tryptase in Ascaris-sensitized cynomolgus monkeys with favorable pharmacokinetics. These data provide a foundation for developing anti-tryptase as a clinical therapy for severe asthma.
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http://dx.doi.org/10.1016/j.cell.2019.09.009DOI Listing
October 2019

Rare Protein-Altering Telomere-related Gene Variants in Patients with Chronic Hypersensitivity Pneumonitis.

Am J Respir Crit Care Med 2019 11;200(9):1154-1163

Department of Medicine.

Rare genetic variants in telomere-related genes have been identified in familial, idiopathic, and rheumatoid arthritis-associated pulmonary fibrosis. Short peripheral blood leukocyte (PBL) telomere length predicts poor outcomes in chronic hypersensitivity pneumonitis (CHP). Determine the prevalence and clinical relevance of rare protein-altering variants in telomere-related genes in patients with CHP. Next-generation sequences from two CHP cohorts were analyzed to identify variants in (telomerase reverse transcriptase), (telomerase RNA component), (dyskerin pseudouridine synthase 1), (regulator of telomere elongation helicase 1), (poly[A]-specific RNase), and (TERF1-interacting nuclear factor 2). To qualify, variants were required to have a minor allele frequency less than 0.005 and be predicted to be damaging to protein function. Variant status (binary variable) was used in statistical association tests, including Cox proportional hazard models for transplant-free survival. PBL telomere length was measured using quantitative PCR. Qualifying variants were identified in 16 of 144 patients (11.1%; 95% confidence interval [CI], 6.5-17.4) in the discovery cohort and 17 of 209 patients (8.1%; 95% CI, 4.8-12.7) in the replication cohort. Age- and ancestry-adjusted PBL telomere length was significantly shorter in the presence of a variant in both cohorts (discovery: -561 bp; 95% CI, -933 to -190;  = 0.003; replication: -612 bp; 95% CI, -870 to -354;  = 5.30 × 10). Variant status was significantly associated with transplant-free survival in both cohorts (discovery: age-, sex-, and ancestry-adjusted hazard ratio, 3.73; 95% CI, 1.92-7.28;  = 0.0001; replication: hazard ratio, 2.72; 95% CI, 1.26-5.88;  = 0.011). A substantial proportion of patients diagnosed with CHP have rare, protein-altering variants in telomere-related genes, which are associated with short peripheral blood telomere length and significantly reduced transplant-free survival.
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http://dx.doi.org/10.1164/rccm.201902-0360OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6888660PMC
November 2019

TAZ is required for lung alveolar epithelial cell differentiation after injury.

JCI Insight 2019 06 18;5. Epub 2019 Jun 18.

Department of Immunology.

The lung is a relatively quiescent organ during homeostasis, but has a remarkable capacity for repair after injury. Alveolar epithelial type I cells (AEC1s) line airspaces and mediate gas exchange. After injury, they are regenerated by differentiation from their progenitors - alveolar epithelial type II cells (AEC2s) - which also secrete surfactant to maintain surface tension and alveolar patency. While recent studies showed that the maintenance of AEC2 stemness is Wnt dependent, the molecular mechanisms underlying AEC2-AEC1 differentiation in adult lung repair are still incompletely understood. Here we show that WWTR1 (TAZ) plays a crucial role in AEC differentiation. Using an in vitro organoid culture system, we found that tankyrase inhibition can efficiently block AEC2-AEC1 differentiation, and this effect was due to the inhibition of TAZ. In a bleomycin induced lung injury model, conditional deletion of TAZ in AEC2s dramatically reduced AEC1 regeneration during recovery, leading to exacerbated alveolar lesions and fibrosis. In patients with idiopathic pulmonary fibrosis (IPF), decreased blood levels of RAGE, a biomarker of AEC1 health, were associated with more rapid disease progression. Our findings implicate TAZ as a critical factor involved in AEC2 to AEC1 differentiation, and hence the maintenance of alveolar integrity after injury.
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http://dx.doi.org/10.1172/jci.insight.128674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6675554PMC
June 2019

Prognostic and predictive biomarkers for patients with idiopathic pulmonary fibrosis treated with pirfenidone: post-hoc assessment of the CAPACITY and ASCEND trials.

Lancet Respir Med 2018 08 29;6(8):615-626. Epub 2018 Jun 29.

Genentech Inc, San Francisco, CA, USA.

Background: Heterogeneity in the progression of idiopathic pulmonary fibrosis (IPF) might reflect diversity in underlying pathobiology, and represents a major challenge in the prediction of clinical progression and treatment benefit. Previous studies have found peripheral blood concentrations of several protein biomarkers to be prognostic for overall survival duration in patients with IPF, but these findings have generally not been directly compared and replicated between cohorts. We aimed to use the pivotal trials for pirfenidone to evaluate prognostic and predictive properties of biomarkers across multiple endpoints, and whether they are modulated by pirfenidone treatment.

Methods: We did post-hoc analyses of test and replication cohorts from CAPACITY 004 (NCT00287716), CAPACITY 006 (NCT00287729), and ASCEND (NCT01366209) trials for the plasma proteins CCL13, CCL17, CCL18, CXCL13, CXCL14, COMP, interleukin 13, MMP3, MMP7, osteopontin, periostin, and YKL40. Eligible participants had IPF and received pirfenidone 2403 mg/day or placebo in CAPACITY (test cohort) or ASCEND (replication cohort), were aged 40-80 years, and without missing biomarker data at baseline. To identify biomarkers that were consistently prognostic for clinical outcome measures, the primary analysis was the association between biomarker concentrations at baseline and absolute change in percentage of predicted forced vital capacity (FVC) at 12 months (CAPACITY week 48, ASCEND week 52) in the placebo group. Biomarkers within the test cohort that met predefined success criteria of a prognostic p value less than 0·10 from multivariate analysis were further assessed in the replication cohort. Furthermore, the predictive effect size (ie, biomarkers that were predictive for benefit from pirfenidone) was calculated as the difference in FVC treatment effect (pirfenidone in relation to placebo) between high versus low biomarker subgroups at week 48 (test cohort) or week 52 (replication cohort).

Findings: Several baseline biomarkers (CCL13, CCL18, COMP, CXCL13, CXCL14, periostin, and YKL40) were prognostic for progression outcomes in the placebo groups of the test cohort. However, only CCL18 was consistently prognostic for absolute change in percentage of FVC in both the test (p=0·032) and replication (p=0·004) cohorts. Pirfenidone treatment benefit was consistent regardless of baseline biomarker concentration.

Interpretation: Blood CCL18 concentrations were the most consistent predictor of disease progression across IPF cohorts with potential to inform new target discovery and clinical trial design. Future validation of these findings in prospective studies is warranted.

Funding: Genentech Inc.
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http://dx.doi.org/10.1016/S2213-2600(18)30185-1DOI Listing
August 2018

Analysis of protein-altering variants in telomerase genes and their association with MUC5B common variant status in patients with idiopathic pulmonary fibrosis: a candidate gene sequencing study.

Lancet Respir Med 2018 08 18;6(8):603-614. Epub 2018 Jun 18.

Genentech, South San Francisco, CA, USA. Electronic address:

Background: Idiopathic pulmonary fibrosis (IPF) risk has a strong genetic component. Studies have implicated variations at several loci, including TERT, surfactant genes, and a single nucleotide polymorphism at chr11p15 (rs35705950) in the intergenic region between TOLLIP and MUC5B. Patients with IPF who have risk alleles at rs35705950 have longer survival from the time of IPF diagnosis than do patients homozygous for the non-risk allele, whereas patients with shorter telomeres have shorter survival times. We aimed to assess whether rare protein-altering variants in genes regulating telomere length are enriched in patients with IPF homozygous for the non-risk alleles at rs35705950.

Methods: Between Nov 1, 2014, and Nov 1, 2016, we assessed blood samples from patients aged 40 years or older and of European ancestry with sporadic IPF from three international phase 3 clinical trials (INSPIRE, CAPACITY, ASCEND), one phase 2 study (RIFF), and US-based observational studies (Vanderbilt Clinical Interstitial Lung Disease Registry and the UCSF Interstitial Lung Disease Clinic registry cohorts) at the Broad Institute (Cambridge, MA, USA) and Human Longevity (San Diego, CA, USA). We also assessed blood samples from non-IPF controls in several clinical trials. We did whole-genome sequencing to assess telomere length and identify rare protein-altering variants, stratified by rs35705950 genotype. We also assessed rare functional variation in TERT exons and compared telomere length and disease progression across genotypes.

Findings: We assessed samples from 1510 patients with IPF and 1874 non-IPF controls. 30 (3%) of 1046 patients with an rs35705950 risk allele had a rare protein-altering variant in TERT compared with 34 (7%) of 464 non-risk allele carriers (odds ratio 0·40 [95% CI 0·24-0·66], p=0·00039). Subsequent analyses identified enrichment of rare protein-altering variants in PARN and RTEL1, and rare variation in TERC in patients with IPF compared with controls. We expanded our study population to provide a more accurate estimation of rare variant frequency in these four loci, and to calculate telomere length. The proportion of patients with at least one rare variant in TERT, PARN, TERC, or RTEL1 was higher in patients with IPF than in controls (149 [9%] of 1739 patients vs 205 [2%] of 8645 controls, p=2·44 × 10). Patients with IPF who had a variant in any of the four identified telomerase component genes had telomeres that were 3·69-16·10% shorter than patients without a variant in any of the four genes and had an earlier mean age of disease onset than patients without one or more variants (65·1 years [SD 7·8] vs 67·1 years [7·9], p=0·004). In the placebo arms of clinical trials, shorter telomeres were significantly associated with faster disease progression (1·7% predicted forced vital capacity per kb per year, p=0·002). Pirfenidone had treatment benefit regardless of telomere length (p=4·24 × 10 for telomere length lower than the median, p=0·0044 for telomere length greater than the median).

Interpretation: Rare protein-altering variants in TERT, PARN, TERC, and RTEL1 are enriched in patients with IPF compared with controls, and, in the case of TERT, particularly in individuals without a risk allele at the rs35705950 locus. This suggests that multiple genetic factors contribute to sporadic IPF, which might implicate distinct mechanisms of pathogenesis and disease progression.

Funding: Genentech, National Institutes of Health, Francis Family Foundation, Pulmonary Fibrosis Foundation, Nina Ireland Program for Lung Health, US Department of Veterans Affairs.
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http://dx.doi.org/10.1016/S2213-2600(18)30135-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6487850PMC
August 2018

Revisiting the NIH Taskforce on the Research needs of Eosinophil-Associated Diseases (RE-TREAD).

J Leukoc Biol 2018 07 19;104(1):69-83. Epub 2018 Apr 19.

Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.

Eosinophil-associated diseases (EADs) are rare, heterogeneous disorders characterized by the presence of eosinophils in tissues and/or peripheral blood resulting in immunopathology. The heterogeneity of tissue involvement, lack of sufficient animal models, technical challenges in working with eosinophils, and lack of standardized histopathologic approaches have hampered progress in basic research. Additionally, clinical trials and drug development for rare EADs are limited by the lack of primary and surrogate endpoints, biomarkers, and validated patient-reported outcomes. Researchers with expertise in eosinophil biology and eosinophil-related diseases reviewed the state of current eosinophil research, resources, progress, and unmet needs in the field since the 2012 meeting of the NIH Taskforce on the Research of Eosinophil-Associated Diseases (TREAD). RE-TREAD focused on gaps in basic science, translational, and clinical research on eosinophils and eosinophil-related pathogenesis. Improved recapitulation of human eosinophil biology and pathogenesis in murine models was felt to be of importance. Characterization of eosinophil phenotypes, the role of eosinophil subsets in tissues, identification of biomarkers of eosinophil activation and tissue load, and a better understanding of the role of eosinophils in human disease were prioritized. Finally, an unmet need for tools for use in clinical trials was emphasized. Histopathologic scoring, patient- and clinician-reported outcomes, and appropriate coding were deemed of paramount importance for research collaborations, drug development, and approval by regulatory agencies. Further exploration of the eosinophil genome, epigenome, and proteome was also encouraged. Although progress has been made since 2012, unmet needs in eosinophil research remain a priority.
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http://dx.doi.org/10.1002/JLB.5MR0118-028RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6171343PMC
July 2018

Airway pathological heterogeneity in asthma: Visualization of disease microclusters using topological data analysis.

J Allergy Clin Immunol 2018 11 14;142(5):1457-1468. Epub 2018 Mar 14.

Department of Infection Immunity and Inflammation, Institute for Lung Health, University of Leicester, Glenfield Hospital, Leicester, United Kingdom.

Background: Asthma is a complex chronic disease underpinned by pathological changes within the airway wall. How variations in structural airway pathology and cellular inflammation contribute to the expression and severity of asthma are poorly understood.

Objectives: Therefore we evaluated pathological heterogeneity using topological data analysis (TDA) with the aim of visualizing disease clusters and microclusters.

Methods: A discovery population of 202 adult patients (142 asthmatic patients and 60 healthy subjects) and an external replication population (59 patients with severe asthma) were evaluated. Pathology and gene expression were examined in bronchial biopsy samples. TDA was applied by using pathological variables alone to create pathology-driven visual networks.

Results: In the discovery cohort TDA identified 4 groups/networks with multiple microclusters/regions of interest that were masked by group-level statistics. Specifically, TDA group 1 consisted of a high proportion of healthy subjects, with a microcluster representing a topological continuum connecting healthy subjects to patients with mild-to-moderate asthma. Three additional TDA groups with moderate-to-severe asthma (Airway Smooth Muscle, Reticular Basement Membrane, and Remodeling groups) were identified and contained numerous microclusters with varying pathological and clinical features. Mutually exclusive T2 and T17 tissue gene expression signatures were identified in all pathological groups. Discovery and external replication applied to the severe asthma subgroup identified only highly similar "pathological data shapes" through analyses of persistent homology.

Conclusions: We have identified and replicated novel pathological phenotypes of asthma using TDA. Our methodology is applicable to other complex chronic diseases.
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http://dx.doi.org/10.1016/j.jaci.2017.12.982DOI Listing
November 2018

A randomised pragmatic trial of corticosteroid optimization in severe asthma using a composite biomarker algorithm to adjust corticosteroid dose versus standard care: study protocol for a randomised trial.

Trials 2018 Jan 4;19(1). Epub 2018 Jan 4.

Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University, Belfast, UK.

Background: Patients with difficult-to-control asthma consume 50-60% of healthcare costs attributed to asthma and cost approximately five-times more than patients with mild stable disease. Recent evidence demonstrates that not all patients with asthma have a typical type 2 (T2)-driven eosinophilic inflammation. These asthmatics have been called 'T2-low asthma' and have a minimal response to corticosteroid therapy. Adjustment of corticosteroid treatment using sputum eosinophil counts from induced sputum has demonstrated reduced severe exacerbation rates and optimized corticosteroid dose. However, it has been challenging to move induced sputum into the clinical setting. There is therefore a need to examine novel algorithms to target appropriate levels of corticosteroid treatment in difficult asthma, particularly in T2-low asthmatics. This study examines whether a composite non-invasive biomarker algorithm predicts exacerbation risk in patients with asthma on high-dose inhaled corticosteroids (ICS) (± long-acting beta agonist) treatment, and evaluates the utility of this composite score to facilitate personalized biomarker-specific titration of corticosteroid therapy.

Methods/design: Patients recruited to this pragmatic, multi-centre, single-blinded randomised controlled trial are randomly allocated into either a biomarker controlled treatment advisory algorithm or usual care group in a ratio of 4:1. The primary outcome measure is the proportion of patients with any reduction in ICS or oral corticosteroid dose from baseline to week 48. Secondary outcomes include the rate of protocol-defined severe exacerbations per patient per year, time to first severe exacerbation from randomisation, dose of inhaled steroid at the end of the study, cumulative dose of inhaled corticosteroid during the study, proportion of patients on oral corticosteroids at the end of the study, proportion of patients who decline to progress to oral corticosteroids despite composite biomarker score of 2, frequency of hospital admission for asthma, change in the 7-item Asthma Control Questionnaire (ACQ-7), Asthma Quality of Life Questionnaire (AQLQ), forced expiratory volume in 1 s (FEV1), exhaled nitric oxide, blood eosinophil count, and periostin levels from baseline to week 48. Blood will also be taken for whole blood gene expression; serum, plasma, and urine will be stored for validation of additional biomarkers.

Discussion: Multi-centre trials present numerous logistical issues that have been addressed to ensure minimal bias and robustness of study conduct.

Trial Registration: ClinicalTrials.gov, NCT02717689 . Registered on 16 March 2016.
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http://dx.doi.org/10.1186/s13063-017-2384-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5753571PMC
January 2018

IFN-stimulated Gene Expression, Type 2 Inflammation, and Endoplasmic Reticulum Stress in Asthma.

Am J Respir Crit Care Med 2018 02;197(3):313-324

1 Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine.

Rationale: Quantification of type 2 inflammation provided a molecular basis for heterogeneity in asthma. Non-type 2 pathways that contribute to asthma pathogenesis are not well understood.

Objectives: To identify dysregulated pathways beyond type 2 inflammation.

Methods: We applied RNA sequencing to airway epithelial brushings obtained from subjects with stable mild asthma not on corticosteroids (n = 19) and healthy control subjects (n = 16). Sequencing reads were mapped to human and viral genomes. In the same cohort, and in a separate group with severe asthma (n = 301), we profiled blood gene expression with microarrays.

Measurements And Main Results: In airway brushings from mild asthma on inhaled corticosteroids, RNA sequencing yielded 1,379 differentially expressed genes (false discovery rate < 0.01). Pathway analysis revealed increased expression of type 2 markers, IFN-stimulated genes (ISGs), and endoplasmic reticulum (ER) stress-related genes. Airway epithelial ISG expression was not associated with type 2 inflammation in asthma or with viral transcripts but was associated with reduced lung function by FEV (ρ = -0.72; P = 0.0004). ER stress was confirmed by an increase in XBP1 (X-box binding protein 1) splicing in mild asthma and was associated with both type 2 inflammation and ISG expression. ISGs were also the most activated genes in blood cells in asthma and were correlated with airway ISG expression (ρ = 0.55; P = 0.030). High blood ISG expression in severe asthma was similarly unrelated to type 2 inflammation.

Conclusions: ISG activation is prominent in asthma, independent of viral transcripts, orthogonal to type 2 inflammation, and associated with distinct clinical features. ER stress is associated with both type 2 inflammation and ISG expression.
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http://dx.doi.org/10.1164/rccm.201706-1070OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5811952PMC
February 2018

Interleukin-13 in Asthma and Other Eosinophilic Disorders.

Front Med (Lausanne) 2017 19;4:139. Epub 2017 Sep 19.

Immunology Discovery, Genentech, Inc., South San Francisco, CA, United States.

Asthma is characterized by episodic, reversible airflow obstruction associated with variable levels of inflammation. Over the past several decades, there has been an increasing appreciation that the clinical presentation of asthma comprises a diverse set of underlying pathologies. Rather than being viewed as a single disease entity, asthma is now thought of as a clinical syndrome with the involvement of multiple pathological mechanisms. While it is appreciated that eosinophilia is present in only a subset of patients, it remains a key feature of asthma and other eosinophilic disorders such as atopic dermatitis, eosinophilic esophagitis, and chronic rhinosinusitis with nasal polyps. Eosinophils are bone marrow-derived leukocytes present in low numbers in health; however, during disease the type 2 cytokines [interleukins (IL)-4, -5, and -13] can induce rapid eosinophilopoiesis, prolonged eosinophil survival, and trafficking to the site of injury. In diseases such as allergic asthma there is an aberrant inflammatory response leading to eosinophilia, tissue damage, and airway pathology. IL-13 is a pleiotropic type 2 cytokine that has been shown to be integral in the pathogenesis of asthma and other eosinophilic disorders. IL-13 levels are elevated in animal models of eosinophilic inflammation and in the blood and tissue of patients diagnosed with eosinophilic disorders. IL-13 signaling elicits many pathogenic mechanisms including the promotion of eosinophil survival, activation, and trafficking. Data from preclinical models and clinical trials of IL-13 inhibitors in patients have revealed mechanistic insights into the role of this cytokine in driving eosinophilia. Promising results from clinical trials further support a key mechanistic role of IL-13 in asthma and other eosinophilic disorders. Here, we provide a perspective on the role of IL-13 in asthma and other eosinophilic disorders and describe ongoing clinical trials targeting this pathway in patients with significant unmet medical needs.
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http://dx.doi.org/10.3389/fmed.2017.00139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5627038PMC
September 2017

Type 2 immunity is protective in metabolic disease but exacerbates NAFLD collaboratively with TGF-β.

Sci Transl Med 2017 06;9(396)

Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

Nonalcoholic fatty liver disease (NAFLD) is now the most common progressive liver disease in developed countries and is the second leading indication for liver transplantation due to the extensive fibrosis it causes. NAFLD progression is thought to be tied to chronic low-level type 1 inflammation originating in the adipose tissue during obesity; however, the specific immunological mechanisms regulating the progression of NAFLD-associated fibrosis in the liver are unclear. To investigate the immunopathogenesis of NAFLD more completely, we investigated adipose dysfunction, nonalcoholic steatohepatitis (NASH), and fibrosis in mice that develop polarized type 1 or type 2 immune responses. Unexpectedly, obese interleukin-10 (IL-10)/IL-4-deficient mice (type 1-polarized) were highly resistant to NASH. This protection was associated with an increased hepatic interferon-γ (IFN-γ) signature. Conversely, IFN-γ-deficient mice progressed rapidly to NASH with evidence of fibrosis dependent on transforming growth factor-β (TGF-β) and IL-13 signaling. Unlike increasing type 1 inflammation and the marked loss of eosinophils seen in expanding adipose tissue, progression of NASH was associated with increasing eosinophilic type 2 liver inflammation in mice and human patient biopsies. Finally, simultaneous inhibition of TGF-β and IL-13 signaling attenuated the fibrotic machinery more completely than TGF-β alone in NAFLD-associated fibrosis. Thus, although type 2 immunity maintains healthy metabolic signaling in adipose tissues, it exacerbates the progression of NAFLD collaboratively with TGF-β in the liver.
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http://dx.doi.org/10.1126/scitranslmed.aal3694DOI Listing
June 2017

Increased Autophagy-Related 5 Gene Expression Is Associated with Collagen Expression in the Airways of Refractory Asthmatics.

Front Immunol 2017 29;8:355. Epub 2017 Mar 29.

Meakins-Christie Laboratories, Faculty of Medicine, McGill University, Montreal, QC, Canada.

Background: Fibrosis, particularly excessive collagen deposition, presents a challenge for treating asthmatic individuals. At present, no drugs can remove or reduce excessive collagen in asthmatic airways. Hence, the identification of pathways involved in collagen deposition would help to generate therapeutic targets to interfere with the airway remodeling process. Autophagy, a cellular degradation process, has been shown to be dysregulated in various fibrotic diseases, and genetic association studies in independent human populations have identified autophagy-related 5 (ATG5) to be associated with asthma pathogenesis. Hence, the dysregulation of autophagy may contribute to fibrosis in asthmatic airways.

Objective: This study aimed to determine if (1) collagen deposition in asthmatic airways is associated with ATG5 expression and (2) ATG5 protein expression is associated with asthma and severity.

Methods: Gene expression of transforming growth factor beta 1, various asthma-related collagen types [collagen, type I, alpha 1; collagen, type II, alpha 1; collagen, type III, alpha 1; collagen, type V, alpha 1 (COL5A1) and collagen, type V, alpha 2], and ATG5 were measured using mRNA isolated from bronchial biopsies of refractory asthmatic subjects and assessed for pairwise associations. Protein expression of ATG5 in the airways was measured and associations were assessed for asthma , severity, and lung function.

Main Results: In refractory asthmatic individuals, gene expression of ATG5 was positively associated with COL5A1 in the airways. No association was detected between ATG5 protein expression and asthma , severity, and lung function.

Conclusion And Clinical Relevance: Positive correlation between the gene expression patterns of ATG5 and COL5A1 suggests that dysregulated autophagy may contribute to subepithelial fibrosis in the airways of refractory asthmatic individuals. This finding highlights the therapeutic potential of ATG5 in ameliorating airway remodeling in the difficult-to-treat refractory asthmatic individuals.
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http://dx.doi.org/10.3389/fimmu.2017.00355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5372794PMC
March 2017

A CEACAM6-High Airway Neutrophil Phenotype and CEACAM6-High Epithelial Cells Are Features of Severe Asthma.

J Immunol 2017 04 8;198(8):3307-3317. Epub 2017 Mar 8.

Department of Infection, Immunity and Inflammation, Institute for Lung Health, University of Leicester, Leicester LE3 9QP, United Kingdom;

Severe asthma represents a major unmet clinical need; understanding the pathophysiology is essential for the development of new therapies. Using microarray analysis, we previously found three immunological clusters in asthma: Th2-high, Th17-high, and Th2/17-low. Although new therapies are emerging for Th2-high disease, identifying molecular pathways in Th2-low disease remains an important goal. Further interrogation of our previously described microarray dataset revealed upregulation of gene expression for carcinoembryonic Ag cell adhesion molecule (CEACAM) family members in the bronchi of patients with severe asthma. Our aim was therefore to explore the distribution and cellular localization of CEACAM6 using immunohistochemistry on bronchial biopsy tissue obtained from patients with mild-to-severe asthma and healthy control subjects. Human bronchial epithelial cells were used to investigate cytokine and corticosteroid in vitro regulation of CEACAM6 gene expression. CEACAM6 protein expression in bronchial biopsies was increased in airway epithelial cells and lamina propria inflammatory cells in severe asthma compared with healthy control subjects. CEACAM6 in the lamina propria was localized to neutrophils predominantly. Neutrophil density in the bronchial mucosa was similar across health and the spectrum of asthma severity, but the percentage of neutrophils expressing CEACAM6 was significantly increased in severe asthma, suggesting the presence of an altered neutrophil phenotype. CEACAM6 gene expression in cultured epithelial cells was upregulated by wounding and neutrophil elastase. In summary, CEACAM6 expression is increased in severe asthma and primarily associated with airway epithelial cells and tissue neutrophils. CEACAM6 may contribute to the pathology of treatment-resistant asthma via neutrophil and airway epithelial cell-dependent pathways.
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http://dx.doi.org/10.4049/jimmunol.1600606DOI Listing
April 2017

CXCL14 is a candidate biomarker for Hedgehog signalling in idiopathic pulmonary fibrosis.

Thorax 2017 09 1;72(9):780-787. Epub 2017 Mar 1.

Genentech, Inc., South San Francisco, California, USA.

Background: Idiopathic pulmonary fibrosis (IPF) is associated with aberrant expression of developmental pathways, including Hedgehog (Hh). As Hh signalling contributes to multiple pro-fibrotic processes, Hh inhibition may represent a therapeutic option for IPF. However, no non-invasive biomarkers are available to monitor lung Hh activity.

Methods: We assessed gene and protein expression in IPF and control lung biopsies, mouse lung, fibroblasts stimulated in vitro with sonic hedgehog (SHh), and plasma in IPF patients versus controls, and cancer patients before and after treatment with vismodegib, a Hh inhibitor.

Results: Lung tissue from IPF patients exhibited significantly greater expression of Hh-related genes versus controls. The gene most significantly upregulated in both IPF lung biopsies and fibroblasts stimulated in vitro with SHh was , which encodes a soluble secreted chemokine whose expression is inhibited in vitro by the addition of vismodegib. expression was induced by SHh overexpression in mouse lung. Circulating CXCL14 protein levels were significantly higher in plasma from IPF patients than controls. In cancer patients, circulating CXCL14 levels were significantly reduced upon vismodegib treatment.

Conclusions: CXCL14 is a systemic biomarker that could be used to identify IPF patients with increased Hh pathway activity and monitor the pharmacodynamic effects of Hh antagonist therapy in IPF.

Trial Registration Number: Post-results, NCT00968981.
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http://dx.doi.org/10.1136/thoraxjnl-2015-207682DOI Listing
September 2017

Seasonal variability of severe asthma exacerbations and clinical benefit from lebrikizumab.

J Allergy Clin Immunol 2017 05 24;139(5):1682-1684.e3. Epub 2017 Feb 24.

Genentech, Inc, South San Francisco, Calif. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2017.01.028DOI Listing
May 2017

IL-13 is a therapeutic target in radiation lung injury.

Sci Rep 2016 12 22;6:39714. Epub 2016 Dec 22.

Radiation Oncology Branch, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland, USA.

Pulmonary fibrosis is a potentially lethal late adverse event of thoracic irradiation. Prior research indicates that unrestrained TGF-β1 and/or type 2 cytokine-driven immune responses promote fibrosis following radiation injury, but the full spectrum of factors governing this pathology remains unclear. Interleukin 13 (IL-13) is a key factor in fibrotic disease associated with helminth infection, but it is unclear whether it plays a similar role in radiation-induced lung fibrosis. Using a mouse model, we tested the hypothesis that IL-13 drives the progression of radiation-induced pulmonary fibrosis. Irradiated lungs from wild-type c57BL/6NcR mice accumulated alternatively-activated macrophages, displayed elevated levels of IL-13, and extensive fibrosis, whereas IL-13 deficient mice were resistant to these changes. Furthermore, plasma from irradiated wild-type mice showed a transient increase in the IL-13 saturated fraction of the circulating decoy receptor IL-13Rα2. Finally, we determined that therapeutic neutralization of IL-13, during the period of IL-13Rα2 saturation was sufficient to protect mice from lung fibrosis. Taken together, our results demonstrate that IL-13 is a major regulator of radiation-induced lung injury and demonstrates that strategies focusing on IL-13 may be useful in screening for timely delivery of anti-IL-13 therapeutics.
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http://dx.doi.org/10.1038/srep39714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5177927PMC
December 2016

Fit-for-purpose biomarker immunoassay qualification and validation: three case studies.

Bioanalysis 2016 Nov 7;8(22):2329-2340. Epub 2016 Oct 7.

Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.

Aim: To improve on the efficiency of biomarker assay readiness, and for reliable biomarker data to support three drug programs, we implemented a fit-for-purpose approach, qualifying two biomarker assays and validating a third. Results/methodology: The qualification strategy and selection of experiments for two exploratory biomarkers (CXCL1, CCL19) was determined by the intended use of the biomarker data. The third biomarker, IL-6, was validated as the data would be used in monitoring patient safety during dose-escalation studies in a Phase I trial. All three assays passed a priori acceptance criteria.

Conclusion: These assays highlight strategies and methodologies for a fit-for-purpose approach. Minimum qualification, full qualification and validation were chosen and supported programs at different stages of drug development.
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http://dx.doi.org/10.4155/bio-2016-0184DOI Listing
November 2016