scholarly journals POS0331 LUNG TARGETED DELIVERY OF EVEROLIMUS AS A NEW TREATMENT OF SCLERODERMA-RELATED INTERSTITIAL LUNG DISEASE (SSc-ILD) DEVELOPED BY PSGL-1 KO MICE

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 393.1-393
Author(s):  
E. González Sánchez ◽  
J. Gómez-Román ◽  
A. Muñoz-Callejas ◽  
A. Marengo ◽  
N. Tsapis ◽  
...  
Keyword(s):  
T Cells ◽  
Hyaluronic Acid ◽  
Interstitial Lung Disease ◽  
Observational Study ◽  
Lung Disease ◽  
High Dose ◽  
Lung Pathology ◽  
Intratracheal Administration ◽  
Interstitial Inflammation ◽  
Autoimmune Syndrome

Background:Interstitial lung disease (ILD), the main cause of mortality in scleroderma (SSc) patients (1), has no treatment (2). P-selectin glycoprotein ligand 1 (PSGL-1), the main ligand for P-Selectin, is expressed on leukocytes and responsible for the initial steps of extravasation (3). The absence of PSGL-1 in mice spontaneously develops an autoimmune syndrome similar to human SSc with fibrosis, vascular damage, autoantibodies and pulmonary arterial hypertension in females, and almost 60% of animals older than 12 months develop ILD with aging (4). In this work, the therapeutic action of everolimus-loaded nanomedicine given by local administration as a treatment for ILD was evaluated. The intratracheal administration of everolimus loaded into in liposomes decorated with hyaluronic acid (HA) is studied as an administration strategy to reach the inflammatory and fibrotic cells, targeting these cells and avoiding systemic effects and possible toxicity on epithelial cellsObjectives:1) To study the effect of everolimus on bronchoalveolar lavage (BAL) cell populations and in lung pathology in SSc-ILD PSGL-1 KO mice2) To analyze the intratracheal application of everolimus included in empty liposomes (Lip+Ev) vs. liposomes decorated with hyaluronic acid (Lip-HA+Ev) as an administration strategy to decrease drug toxicity and increase drug effectivityMethods:In an observational study, PSGL-1−/− C57BL/6 males older than 12 months (n=4) were treated intratracheally with 4 doses of Lip or Lip-HA (with or without everolimus included), once a week (Lip+Ev 295.67µg/mL; Lip+Ev 82.73µg/mL; Lip-HA+Ev 82.73µg/mL). Then, animals were euthanatized and BAL and lungs were obtained. BAL cells were stained for flow cytometry analysis. Lungs were embedded in paraffin blocks for blind histological analysis by a pathologist and evaluated for interstitial inflammation and fibrosis degree. Lip-HA was selected as the treatment of choice for a second experiment (n=8) following the same experimental design (86.22µg/mL)Results:The observational study showed an increase in CD45+, alveolar macrophages (AM), eosinophils (Eos), granulocytes (Gr1+) and T cells in the BAL of untreated PSGL-1-/- mice compared with WT mice. Everolimus reduced these populations to WT levels in all casesLip-HA+Ev administration was chosen for further experiments because a lower dose of the drug gave a better result than the high dose in undecorated liposomes. Reduction of CD45+, AM, eosinophils, and CD45- cells populations by Lip-HA+Ev was confirmed. Lip-HA treatment increased the number of neutrophils and T cells, but this effect is controlled by the everolimus administrationHistological lung analysis showed an increase in interstitial inflammation and fibrosis in untreated PSGL-1-/- and empty Lip-HA experimental groups. Treatment with everolimus included in Lip-HA reduced the fibrotic and inflammatory interstitial lung lesions, reaching values similar to those observed in WT miceConclusion:PSGL-1 KO mice present ILD associated with scleroderma (SSc-ILD) with an increase of CD45+, Gr1+, Eos, T cells and AM populations in the BAL. Intratracheal treatment with everolimus included in liposomes decorated with hyaluronic acid reduces immune cell infiltration and fibrosis once SSc-ILD is establishedReferences:[1]Solomon JJ, Olson AL, Fischer A, Bull T, Brown KK, Raghu G (2013). Scleroderma lung disease[2]Singh D, Parihar AK, Patel S, Srivastava S, Diwan P, Singh MR (2019). Scleroderma: An insight into causes, pathogenesis and treatment strategies. Pathophysiology, 26(2)[3]Zarbock A, McEver RP, Hidalgo A (2011). Leukocyte Ligands for Endothelial Selectins: Specialized Glycoconjugates That Mediate Rolling and Signaling Under Flow. BLOOD[4]Pérez-Frías A, Núñez-Andrade N, et al. (2014). Development of an autoimmune syndrome affecting the skin and internal organs in P-selectin glycoprotein ligand 1 leukocyte receptor-deficient mice. Arthritis RheumatolDisclosure of Interests:None declared

scholarly journals AB0026 DECREASE OF ANGIOGENIC T CELLS IN CONNECTIVE TISSUE DISEASE-ASSOCIATED INTERSTITIAL LUNG DISEASE

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 1046.3-1047
Author(s):  
V. Pulito-Cueto ◽  
S. Remuzgo Martinez ◽  
F. Genre ◽  
B. Atienza-Mateo ◽  
V. M. Mora-Cuesta ◽  
...  
Keyword(s):  
T Cells ◽  
Interstitial Lung Disease ◽  
Connective Tissue ◽  
Lung Disease ◽  
Cell Subset ◽  
Vascular Damage ◽  
Type I ◽  
Research Support ◽  
Angiogenic T Cells

Background:Interstitial lung disease (ILD) is one of the most significant complications of connective tissue diseases (CTD), leading to an increase of the morbidity and mortality in patients with CTD [1]. A specific T cell subset termed angiogenic T cells (TAng), that promote endothelial repair and revascularization, have been involved in the pathogenesis of CTD [2-4]. However, to the best of our knowledge, no information regarding the role of TAng in CTD-ILD+ is available.Objectives:To study, for the first time, the potential role of TAng related to vascular damage in CTD-ILD+.Methods:Peripheral venous blood was collected from 40 patients with CTD-ILD+ and three comparative groups: 44 CTD-ILD- patients, 21 idiopathic pulmonary fibrosis (IPF) patients and 20 healthy controls (HC). All subjects were recruited from the Rheumatology and Pneumology departments of Hospital Universitario Marqués de Valdecilla, Santander, Spain. Quantification of TAng was performed by flow cytometry. TAng were considered as triple-positive for CD3, CD31 and CXCR4.Results:Patients with CTD-ILD+ exhibited a significantly lower TAng frequency than CTD-ILD- patients (p<0.001). Similar results were obtained when patients with CTD-ILD+ were compared with HC (p=0.004) although no difference was observed between CTD-ILD+ and IPF. In addition, a significant increase of TAng frequency was shown in patients with CTD-ILD- in relation to IPF patients (p<0.001), while no difference was observed between CTD-ILD- and HC.Conclusion:Our results reveal a decrease of TAng frequency related to vascular damage in CTD-ILD+. Furthermore, we disclose that the presence of ILD is associated with lower TAng frequency.References:[1]Expert Rev Clin Immunol 2018;14(1):69-82.[2]Circulation 2007;116(15):1671-82.[3]Ann Rheum Dis 2015 74(5):921-7.[4]PLoS One 2017;12(8):e0183102.Acknowledgements:Personal funds, VP-C: PREVAL18/01 (IDIVAL); SR-M: RD16/0012/0009 (ISCIII-ERDF); LL-G: INNVAL20/06 (IDIVAL); RP-F: START PROJECT (FOREUM); RL-M: Miguel Servet type I CP16/00033 (ISCIII-ESF).Disclosure of Interests:Verónica Pulito-Cueto: None declared, Sara Remuzgo Martinez: None declared, Fernanda Genre: None declared, Belén Atienza-Mateo: None declared, Victor Manuel Mora-Cuesta: None declared, David Iturbe-Fernández: None declared, Leticia Lera-Gómez: None declared, Raquel Pérez-Fernández: None declared, Pilar Alonso Lecue: None declared, Javier Rodriguez Carrio: None declared, Diana Prieto-Peña: None declared, Virginia Portilla: None declared, Ricardo Blanco Speakers bureau: Abbvie, Pfizer, Roche, Bristol-Myers, Janssen and MSD, Consultant of: Abbvie, Pfizer, Roche, Bristol-Myers, Janssen and MSD, Grant/research support from: Abbvie, MSD and Roche, Alfonso Corrales: None declared, Jose Manuel Cifrián-Martínez: None declared, Raquel López-Mejías: None declared, Miguel A González-Gay Speakers bureau: Pfizer, Abbvie, MSD, Grant/research support from: Pfizer, Abbvie, MSD

Immune-checkpoint kinetics for T cells in anti-MDA5 positive interstitial lung disease

Rheumatology ◽  
2020 ◽  
Vol 60 (1) ◽  
pp. e14-e16
Author(s):  
Kunihiro Suzuki ◽  
Toyoshi Yanagihara ◽  
Koichiro Matsumoto ◽  
Sy Giin Chong ◽  
Hiroyuki Ando ◽  
...  
Keyword(s):  
T Cells ◽  
Interstitial Lung Disease ◽  
Lung Disease ◽  
Immune Checkpoint

scholarly journals S99 Pulmonary Rehabilitation in Interstitial Lung Disease – a prospective, observational study

Thorax ◽  
2015 ◽  
Vol 70 (Suppl 3) ◽  
pp. A56.2-A57
Author(s):  
C Sharp ◽  
M McCabe ◽  
MJ Hussain ◽  
H Adamali ◽  
DL Smith ◽  
...  
Keyword(s):  
Interstitial Lung Disease ◽  
Observational Study ◽  
Lung Disease ◽  
Pulmonary Rehabilitation ◽  
Prospective Observational Study

scholarly journals Cyclophosphamide Versus Obinutuzumab for the Treatment of Anti-MDA5 Positive Inflammatory Myopathy with Interstitial Lung Disease: A Study Protocol and Literature Review

2019 ◽  
Vol 19 (02) ◽  
pp. 53-58
Author(s):  
Ho So ◽  
Chi Chiu Mok
Keyword(s):  
Interstitial Lung Disease ◽  
Lung Disease ◽  
Primary Outcome ◽  
Treatment Guidelines ◽  
Controlled Trial ◽  
Treatment Options ◽  
Inflammatory Myopathy ◽  
Idiopathic Inflammatory Myopathy ◽  
High Dose ◽  
Multicenter Randomized Controlled Trial

In patients with idiopathic inflammatory myopathy, the presence of the melanoma differentiation-associated gene 5 (MDA5) antibody carries an extremely poor prognosis as a result of the associated interstitial lung disease (ILD) that is often rapidly progressive and refractory to therapies. Management of anti-MDA5 associated ILD is a challenging task as there is a paucity of clinical data and treatment guidelines in the literature. We hereby describe a proposed protocol for a multicenter randomized controlled trial to compare the efficacy of intravenous cyclophosphamide and obinutuzumab in combination with high-dose glucocorticoids and tacrolimus in terms of mortality at six months (primary outcome). The epidemiology, pathogenesis and treatment options of anti-MDA5 associated ILD are briefly reviewed.

scholarly journals A defect in thymic tolerance causes T cell-mediated autoimmunity in a murine model of COPA syndrome

2020 ◽  
Author(s):  
Zimu Deng ◽  
Christopher S. Law ◽  
Frances O. Ho ◽  
Kristin M. Wang ◽  
Kirk D. Jones ◽  
...  
Keyword(s):  
T Cells ◽  
Mouse Model ◽  
Lung Disease ◽  
Pulmonary Hemorrhage ◽  
Autoimmune Disorder ◽  
Cell Types ◽  
Lung Pathology ◽  
Missense Mutations ◽  
Peripheral Tissues ◽  
Copa Syndrome

AbstractCOPA syndrome is a recently described Mendelian autoimmune disorder caused by missense mutations in the Coatomer protein complex subunit alpha (COPA) gene. Patients with COPA syndrome develop arthritis and lung disease that presents as pulmonary hemorrhage or interstitial lung disease (ILD). Immunosuppressive medications can stabilize the disease, but many patients develop progressive pulmonary fibrosis that requires life-saving measures such as lung transplantation. Because very little is understood about the pathogenesis of COPA syndrome, it has been difficult to devise effective treatments for patients. To date, it remains unknown which cell types are critical for mediating the disease as well as the mechanisms that lead to autoimmunity. To explore these issues, we generated a CopaE241K/+ germline knock-in mouse bearing one of the same Copa missense mutations in patients. Mutant mice spontaneously developed ILD that mirrors lung pathology in patients, as well as elevations of activated cytokine-secreting T cells. Here we show that mutant Copa in epithelial cells of the thymus impairs the thymic selection of T cells and results in both an increase in autoreactive T cells and decrease in regulatory T cells in peripheral tissues. We demonstrate that T cells from CopaE241K/+ mice are pathogenic and cause ILD through adoptive transfer experiments. In conclusion, we establish a new mouse model of COPA syndrome to identify a previously unknown function for Copa in thymocyte selection and demonstrate that a defect in central tolerance is a putative mechanism by which COPA mutations lead to autoimmunity in patients.One Sentence SummaryA new mouse model of COPA syndrome develops lung pathology that recapitulates patients and reveals that T cells are important drivers of the disease.

scholarly journals Interstitial Lung Disease Associated Acute Respiratory Failure Requiring Invasive Mechanical Ventilation: A Retrospective Analysis

2020 ◽  
Author(s):  
Cyrus Vahdatpour ◽  
Alexander Pichler ◽  
Harold I Palevsky ◽  
Michael J Kallan ◽  
Namrata B Patel ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Respiratory Failure ◽  
Interstitial Lung Disease ◽  
Acute Respiratory Failure ◽  
Lung Disease ◽  
Invasive Mechanical Ventilation ◽  
Ventilatory Support ◽  
Positive Pressure ◽  
High Dose ◽  
One Year

Abstract Background Interstitial lung disease (ILD) patients requiring invasive mechanical ventilation (IMV) for acute respiratory failure (ARF) are known to have a poor prognosis. Few studies have investigated determinants of outcomes and the utility of trialing non-invasive positive pressure ventilation (NIPPV) prior to IMV to see if there are any effect(s) on mortality or morbidity. Methods We designed a retrospective study using patients at four different intensive care units within one health care system. Our primary objective was to determine if there are differences in outcomes for in-hospital and one-year mortality between patients who undergo NIPPV prior to IMV and those who receive only IMV. A secondary objective was to identify potential determinants of outcomes. Results Of 54 ILD patients with ARF treated with IMV, 20 (37.0%) survived to hospital discharge and 10 (18.5%) were alive at one-year. There was no significant mortality difference between patients trialed on NIPPV prior to IMV and those receiving only IMV. Several key determinants of outcomes were identified with higher mortality, including: higher ventilatory support, idiopathic pulmonary fibrosis (IPF) subtype, high dose steroids, use of vasopressors, supraventricular tachycardias (SVTs), and higher body mass index. Conclusions Considering that patients trialed on NIPPV prior to IMV was associated with no mortality disadvantage to patients treated with only IMV, trialing patients on NIPPV may identify responders and avoid complications associated with IMV. Increased ventilator support, need of vasopressors, SVTs, and high dose steroids reflect higher mortality and palliative care involvement should be considered as early as possible if lung transplant is not an option.

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