Idiopathic pulmonary fibrosis (IPF) is an advancing and fatal lung disease with increasing incidence and prevalence. Nintedanib and pirfenidone were approved by the FDA for the treatment of IPF in ...2014 based on positive phase 3 trials, and both of these antifibrotic drugs are conditionally recommended in the 2015 ATS/ERS/JRS/ALAT Clinical Practice Guideline. Although an improvement over previously suggested therapies, their capacity to reduce, but not completely arrest or improve, lung function over time presents an opportunity for novel or add-on pharmacologic agents. The purpose of this review is to deliver a brief overview of the results of phase 3/4 IPF trials with pirfenidone and nintedanib, as well as highlight encouraging results of phase 1/2 trials with novel therapies. Long-term studies indicate that pirfenidone and nintedanib are effective IPF treatments, with acceptable safety and tolerability. The combination of pirfenidone and nintedanib appear safe. Promising results have recently been made public for several phase 2 trials with novel targets, including the autotaxin-lysophosphatidic acid (ATX/LPA) pathway, connective tissue growth factor (CTGF), pentraxin-2, G protein-coupled receptor agonists/antagonists, αvβ6 integrin, and galectin-3. Results of treatments directed at gastro-esophageal reflux in patients with IPF have also been published. Currently, monotherapy with pirfenidone or nintedanib is the mainstay of pharmacological treatment for IPF. Innovative therapies along with combinations of pharmacological agents hold great promise for the future.Idiopathic pulmonary fibrosis (IPF) is an advancing and fatal lung disease with increasing incidence and prevalence. Nintedanib and pirfenidone were approved by the FDA for the treatment of IPF in 2014 based on positive phase 3 trials, and both of these antifibrotic drugs are conditionally recommended in the 2015 ATS/ERS/JRS/ALAT Clinical Practice Guideline. Although an improvement over previously suggested therapies, their capacity to reduce, but not completely arrest or improve, lung function over time presents an opportunity for novel or add-on pharmacologic agents. The purpose of this review is to deliver a brief overview of the results of phase 3/4 IPF trials with pirfenidone and nintedanib, as well as highlight encouraging results of phase 1/2 trials with novel therapies. Long-term studies indicate that pirfenidone and nintedanib are effective IPF treatments, with acceptable safety and tolerability. The combination of pirfenidone and nintedanib appear safe. Promising results have recently been made public for several phase 2 trials with novel targets, including the autotaxin-lysophosphatidic acid (ATX/LPA) pathway, connective tissue growth factor (CTGF), pentraxin-2, G protein-coupled receptor agonists/antagonists, αvβ6 integrin, and galectin-3. Results of treatments directed at gastro-esophageal reflux in patients with IPF have also been published. Currently, monotherapy with pirfenidone or nintedanib is the mainstay of pharmacological treatment for IPF. Innovative therapies along with combinations of pharmacological agents hold great promise for the future.
Chronic Obstructive Pulmonary Disease (COPD) is characterized by airspace enlargement and peribronchial lymphoid follicles; however, the immunological mechanisms leading to these pathologic changes ...remain undefined. Here we show that cigarette smoke is a selective adjuvant that augments in vitro and in vivo Th17, but not Th1, cell differentiation via the aryl hydrocarbon receptor. Smoke exposed IL-17RA(-/-) mice failed to induce CCL2 and MMP12 compared to WT mice. Remarkably, in contrast to WT mice, IL-17RA(-/-) mice failed to develop emphysema after 6 months of cigarette smoke exposure. Taken together, these data demonstrate that cigarette smoke is a potent Th17 adjuvant and that IL-17RA signaling is required for chemokine expression necessary for MMP12 induction and tissue emphysema.
In this issue of Cell Host & Microbe, Abbas et al. (2019) uncover a previously undefined family of single-stranded DNA viruses, Redondoviridae, in human ororespiratory sites. The presence of ...Redondoviridae associates with critical illness such as respiratory failure and periodontitis, illustrating the power of metagenomics to define the human virome.
In this issue of Cell Host & Microbe, Abbas et al. (2019) uncover a previously undefined family of single-stranded DNA viruses, Redondoviridae, in human ororespiratory sites. The presence of Redondoviridae associates with critical illness such as respiratory failure and periodontitis, illustrating the power of metagenomics to define the human virome.
T cells play an important role during the immune response that accompanies atherosclerosis. To date, the role for interleukin (IL)-17A in atherogenesis is not well defined. Here, we tested the ...hypothesis that atherosclerosis-prone conditions induce the differentiation of IL-17A-producing T cells, which in turn promote atherosclerosis.
IL-17A was found to be elevated in the plasma and tissues of apolipoprotein E-deficient (Apoe(-/-)) mice. IL-17A-expressing T cells were significantly increased in the aortas, spleen, and lamina propria of aged Apoe(-/-) mice compared with age-matched C57BL/6 mice. IL-17A(+) T cells resided in both adventitia and aortas of aged Apoe(-/-) mice fed a chow diet. Elevated levels of IL-17A(+) T cells were also detected in the aortas of 21-week-old Apoe(-/-) mice fed a Western diet for 15 weeks. IL-17A(+) T cells were characterized as predominantly CD4(+) T helper 17 (Th17) cells and gammadelta(+) T cells. Blockade of IL-17A in Apoe(-/-) mice by use of adenovirus-produced IL-17 receptor A reduced plaque burden in Apoe(-/-) mice fed a Western diet for 15 weeks. In addition, the treatment diminished circulating IL-6 and granulocyte colony-stimulating factor levels and limited CXCL1 expression and macrophage content within the aortas. Conversely, IL-17A treatment of whole aorta isolated from Apoe(-/-) mice promoted aortic CXCL1 expression and monocyte adhesion in an ex vivo adhesion assay.
These results demonstrate that atherosclerosis-prone conditions induce the differentiation of IL-17A-producing T cells. IL-17A plays a proatherogenic inflammatory role during atherogenesis by promoting monocyte/macrophage recruitment into the aortic wall.
Regulatory T cells (Tregs) are a barrier to anti-tumor immunity. Neuropilin-1 (Nrp1) is required to maintain intratumoral Treg stability and function but is dispensable for peripheral immune ...tolerance. Treg-restricted Nrp1 deletion results in profound tumor resistance due to Treg functional fragility. Thus, identifying the basis for Nrp1 dependency and the key drivers of Treg fragility could help to improve immunotherapy for human cancer. We show that a high percentage of intratumoral NRP1+ Tregs correlates with poor prognosis in melanoma and head and neck squamous cell carcinoma. Using a mouse model of melanoma where Nrp1-deficient (Nrp1–/–) and wild-type (Nrp1+/+) Tregs can be assessed in a competitive environment, we find that a high proportion of intratumoral Nrp1–/– Tregs produce interferon-γ (IFNγ), which drives the fragility of surrounding wild-type Tregs, boosts anti-tumor immunity, and facilitates tumor clearance. We also show that IFNγ-induced Treg fragility is required for response to anti-PD1, suggesting that cancer therapies promoting Treg fragility may be efficacious.
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•Increased percentage of human NRP1+ intratumoral Tregs correlates with poor prognosis•Nrp1-deficient Tregs undermine the function of wild-type Tregs via IFNγ•Hypoxia may drive IFNγ-induced Treg fragility via Hif1α in the tumor microenvironment•IFNγ-mediated Treg functional fragility is required for response to PD1 blockade
Driving Treg fragility in the tumor microenvironment is critical for the efficacy of cancer checkpoint blockade therapy.
The current studies evaluated the role of interleukin (IL)-17A in the induction of protective immunity against pulmonary cryptococcosis in mice. Protection against pulmonary infection with C. ...neoformans strain H99γ was associated with increased IL-17A production. Signaling through the IFN-γ receptor (R) was required for increased IL-17A production, however, a Th17-type cytokine profile was not observed. Neutrophils were found to be the predominant leukocytic source of IL-17A, rather than T cells, suggesting that the IL-17A produced was not part of a T cell-mediated Th17-type immune response. Depletion of IL-17A in mice during pulmonary infection with C. neoformans strain H99γ resulted in an initial increase in pulmonary fungal burden, but had no effect on cryptococcal burden at later time points. Also, depletion of IL-17A did not affect the local production of other cytokines. IL-17RA⁻/⁻ mice infected with C. neoformans strain H99γ survived the primary infection as well as a secondary challenge with wild-type cryptococci. However, dissemination of the wild-type strain to the brain was noted in the surviving IL-17RA⁻/⁻ mice. Altogether, our results suggested that IL-17A may be important for optimal protective immune responsiveness during pulmonary C. neoformans infection, but protective Th1-type immune responses are sufficient for protection against cryptococcal infection.
Regulatory T cells (T
) are a barrier to anti-tumor immunity. Neuropilin-1 (Nrp1) is required to maintain intratumoral T
stability and function but is dispensable for peripheral immune tolerance. T
...-restricted Nrp1 deletion results in profound tumor resistance due to T
functional fragility. Thus, identifying the basis for Nrp1 dependency and the key drivers of T
fragility could help to improve immunotherapy for human cancer. We show that a high percentage of intratumoral NRP1
T
correlates with poor prognosis in melanoma and head and neck squamous cell carcinoma. Using a mouse model of melanoma where Nrp1-deficient (Nrp1
) and wild-type (Nrp1
) T
can be assessed in a competitive environment, we find that a high proportion of intratumoral Nrp1
T
produce interferon-γ (IFNγ), which drives the fragility of surrounding wild-type T
, boosts anti-tumor immunity, and facilitates tumor clearance. We also show that IFNγ-induced T
fragility is required for response to anti-PD1, suggesting that cancer therapies promoting T
fragility may be efficacious.
By injecting a silica slurry intratracheally, Zhang and colleagues were able to accurately simulate the pathophysiology of a fibrosing lung syndrome. A clinically well-known interstitial lung disease ...caused by breathing in aerosolized silica, silicosis is frequently linked to employment dangers. Silicosis often manifests on spirometry as a mixed restrictive/obstructive lung condition. Silica-containing nodules may exhibit the typical egg-shell calcification seen on radiographs. Depending on the presentation, current interventions include preventing more exposure, quitting smoking, avoiding chronic insults, and non-specific medicines like glucocorticoids or bronchodilators (like prednisolone).
Recently, there have been several reports of SARS-CoV-2 "breakthrough" infections that have occurred in recipients of the FDA-approved SARS-CoV-2 vaccines. These reports have the potential to ...undermine public confidence in the efficacy of these vaccines. Moreover, the use of the term "breakthrough" infections implies that the virus broke through a protective barrier provided by the vaccine. Here, Schieffelin et al argue that it is a mistake to think that these vaccines will prevent nasal (upper airway) infection.
In this study, we examined the biological action of IL-17 on human non-small cell lung cancer (NSCLC). Although IL-17 had no direct effect on the in vitro growth rate of NSCLC, IL-17 selectively ...augmented the secretion of an array of angiogenic CXC chemokines, including CXCL1, CXCL5, CXCL6, and CXCL8 but not angiostatic chemokines, by three different NSCLC lines. Endothelial cell chemotactic activity (as a measure of net angiogenic potential) was increased in response to conditioned medium from NSCLC stimulated with IL-17 compared with those from unstimulated NSCLC. Enhanced chemotactic activity was suppressed by neutralizing mAb(s) to CXCL1, CXCL5, and CXCL8 or to CXCR-2 but not to vascular endothelial growth factor-A. Transfection with IL-17 into NSCLC had no effect on the in vitro growth, whereas IL-17 transfectants grew more rapidly compared with controls when transplanted in SCID mice. This IL-17-elicited enhancement of NSCLC growth was associated with increased tumor vascularity. Moreover, treatment with anti-mouse CXCR-2-neutralizing Ab significantly attenuated the growth of both neomycin phosphotransferase gene-transfected and IL-17-transfected NSCLC tumors in SCID mice. A potential role for IL-17 in modulation of the human NSCLC phenotype was supported by the findings that, in primary NSCLC tissues, IL-17 expression was frequently detected in accumulating and infiltrating inflammatory cells and that high levels of IL-17 expression were associated with increased tumor vascularity. These results demonstrate that IL-17 increases the net angiogenic activity and in vivo growth of NSCLC via promoting CXCR-2-dependent angiogenesis and suggest that targeting CXCR-2 signaling may be a novel promising strategy to treat patients with NSCLC.
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