Calcineurin inhibitors impair neutrophil activity against Aspergillus fumigatus in allogeneic hematopoietic stem cell transplant recipients Sébastien.

Slides:

Advertisements

Similar presentations

Impaired TH17 responses in patients with chronic mucocutaneous candidiasis with and without autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy

Advertisements

Multiple-checkpoint inhibition of thymic stromal lymphopoietin–induced TH2 response by TH17-related cytokines Sofia I. Bogiatzi, BSc, Maude Guillot-Delost,

Defective calcium signaling and disrupted CD20–B-cell receptor dissociation in patients with common variable immunodeficiency disorders Annick A.J.M.

Increased phenotypic differentiation and reduced corticosteroid sensitivity of fibrocytes in severe asthma Chun-Yu Lo, MD, Charalambos Michaeloudes,

Induction of anergic allergen-specific suppressor T cells using tolerogenic dendritic cells derived from children with allergies to house dust mites

Ambient particulate matter directs nonclassic dendritic cell activation and a mixed TH1/TH2-like cytokine response by naive CD4+ T cells Marc A. Williams,

Cell-to-cell contact between activated CD4+ T lymphocytes and unprimed monocytes interferes with a TH1 response Miriam Wittmann, MD, Mareike Alter, Tanja.

Cell-specific activation profile of extracellular signal-regulated kinase 1/2, Jun N-terminal kinase, and p38 mitogen-activated protein kinases in asthmatic.

Impaired TH17 responses in patients with chronic mucocutaneous candidiasis with and without autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy

IgE cross-linking impairs monocyte antiviral responses and inhibits influenza-driven TH1 differentiation Regina K. Rowe, MD, PhD, David M. Pyle, MD,

Differential cytokine induction by the human skin–associated autoallergen thioredoxin in sensitized patients with atopic dermatitis and healthy control.

IL-10 disrupts the Brd4-docking sites to inhibit LPS-induced CXCL8 and TNF-α expression in monocytes: Implications for chronic obstructive pulmonary disease

Defective nuclear entry of hydrolases prevents neutrophil extracellular trap formation in patients with chronic granulomatous disease Susana Romao, PhD,

Targeting Toll-like receptors on dendritic cells modifies the TH2 response to peanut allergens in vitro Pierre Pochard, PhD, Brian Vickery, MD, M. Cecilia.

Assessing basophil activation by using flow cytometry and mass cytometry in blood stored 24 hours before analysis Kaori Mukai, PhD, Nicolas Gaudenzio,

Defective killing of Staphylococcus aureus in atopic dermatitis is associated with reduced mobilization of human β-defensin-3 Kevin O. Kisich, PhD, Charles.

Identification of a distinct glucocorticosteroid-insensitive pulmonary macrophage phenotype in patients with chronic obstructive pulmonary disease Kirandeep.

Cell-specific activation profile of extracellular signal-regulated kinase 1/2, Jun N-terminal kinase, and p38 mitogen-activated protein kinases in asthmatic.

Inhibition of differentiation, amplification, and function of human TH17 cells by intravenous immunoglobulin Mohan S. Maddur, DVM, Janakiraman Vani,

Expansion of cytotoxic CD56bright natural killer cells during T-cell deficiency after allogeneic hematopoietic stem cell transplantation Gertjan Lugthart,

Signaling through FcRγ-associated receptors on dendritic cells drives IL-33–dependent TH2-type responses Melissa Y. Tjota, BA, Cara L. Hrusch, PhD, Kelly.

Identification of a distinct glucocorticosteroid-insensitive pulmonary macrophage phenotype in patients with chronic obstructive pulmonary disease Kirandeep.

S1PR5 is essential for human natural killer cell migration toward sphingosine-1 phosphate Annabelle Drouillard, MSc, Anne-Laure Mathieu, PhD, Antoine.

Maternal allergy modulates cord blood hematopoietic progenitor Toll-like receptor expression and function Pia Reece, BSc, Amudhinie Thanendran, BSc,

Nitric oxide induces human CLA+CD25+Foxp3+ regulatory T cells with skin-homing potential Cunjing Yu, PhD, Amanda Fitzpatrick, PhD, Duanduan Cong, MMedSci,

CD19 controls Toll-like receptor 9 responses in human B cells

Mass cytometry profiling the response of basophils and the complete peripheral blood compartment to peanut Leticia Tordesillas, PhD, Adeeb H. Rahman,

Human IL-31 is induced by IL-4 and promotes TH2-driven inflammation

Clara cell 16-kd protein downregulates TH2 differentiation of human naive neonatal T cells Sofi Johansson, MSc, Göran Wennergren, MD, PhD, Nils Åberg,

Tacrolimus and TGF-β act synergistically on the generation of Langerhans cells Bartlomiej Kwiek, MD, Wen-Ming Peng, MSc, Jean-Pierre Allam, MD, Andrzej.

Transmembrane activator and CAML interactor (TACI) haploinsufficiency results in B- cell dysfunction in patients with Smith-Magenis syndrome Javier Chinen,

Miriam Wittmann, MD, Jana Zeitvogel, Dong Wang, MD, Thomas Werfel, MD

Kathleen R. Bartemes, BA, Gail M. Kephart, BS, Stephanie J

Steroid resistance of airway type 2 innate lymphoid cells from patients with severe asthma: The role of thymic stromal lymphopoietin Sucai Liu, PhD,

David M. Pyle, BS, Victoria S. Yang, MD, Rebecca S

Human mast cells drive memory CD4+ T cells toward an inflammatory IL-22+ phenotype Nicolas Gaudenzio, PhD, Camille Laurent, MD, Salvatore Valitutti,

Multiple-checkpoint inhibition of thymic stromal lymphopoietin–induced TH2 response by TH17-related cytokines Sofia I. Bogiatzi, BSc, Maude Guillot-Delost,

Targeting allergen to FcγRI reveals a novel TH2 regulatory pathway linked to thymic stromal lymphopoietin receptor Kathryn E. Hulse, PhD, Amanda J. Reefer,

A thymic stromal lymphopoietin–responsive dendritic cell subset mediates allergic responses in the upper airway mucosa Guro R. Melum, MD, Lorant Farkas,

Role of hyaluronan and hyaluronan-binding proteins in human asthma

Impaired natural killer cell functions in patients with signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations Giovanna.

Elucidating the effects of disease-causing mutations on STAT3 function in autosomal- dominant hyper-IgE syndrome Simon J. Pelham, MSc, Helen C. Lenthall,

Thymic stromal lymphopoietin activity is increased in nasal polyps of patients with chronic rhinosinusitis Deepti R. Nagarkar, PhD, Julie A. Poposki,

Airway epithelial cells activate TH2 cytokine production in mast cells through IL-1 and thymic stromal lymphopoietin Deepti R. Nagarkar, PhD, Julie A.

Jill A. Poole, MD, Neil E. Alexis, PhD, Conrad Parks, BS, Amy K

Mammalian target of rapamycin inhibition counterbalances the inflammatory status of immune cells in patients with chronic granulomatous disease Aurélie.

Human epidermal Langerhans' cells are targets for the immunosuppressive macrolide tacrolimus (FK506) Andrea Panhans-Groß, MD, Natalija Novak, MD, Stefan.

Roflumilast N-oxide reverses corticosteroid resistance in neutrophils from patients with chronic obstructive pulmonary disease Javier Milara, PhD, PharmD,

Invasive fungal disease in autosomal-dominant hyper-IgE syndrome

Glucocorticoid-induced surface expression of annexin 1 blocks β2-integrin adhesion of human eosinophils to intercellular adhesion molecule 1 surrogate.

Matthew J. Loza, PhD, Susan Foster, PhD, Stephen P

Sara Paveglio, PhD, MS, Erin Bennett, MS, Kelly L. Hawley, PhD, Adam P

Acquisition and alteration of adhesion molecules during cultured human mast cell differentiation Hiroshi Tachimoto, MD, PhD, Sherry A. Hudson, MSB, Bruce.

Toll-like receptor 2 ligands activate human basophils for both IgE-dependent and IgE- independent secretion Anja P. Bieneman, BS, Kristin L. Chichester,

Dysregulation of innate immune receptors on neutrophils in chronic granulomatous disease Dominik Hartl, MD, Natalie Lehmann, MD, Florian Hoffmann, MD,

Correlation between CCL26 production by human bronchial epithelial cells and airway eosinophils: Involvement in patients with severe eosinophilic asthma

Jenny Seltmann, PhD, Lennart M

IL-10/Janus kinase/signal transducer and activator of transcription 3 signaling dysregulates Bim expression in autoimmune lymphoproliferative syndrome

CCL17/thymus and activation-regulated chemokine induces calcitonin gene–related peptide in human airway epithelial cells through CCR4 Kandace Bonner,

IL-10, TGF-β, and glucocorticoid prevent the production of type 2 cytokines in human group 2 innate lymphoid cells Noriko Ogasawara, MD, PhD, Julie A.

Defective calcium signaling and disrupted CD20–B-cell receptor dissociation in patients with common variable immunodeficiency disorders Annick A.J.M.

Neil E. Alexis, PhD, John C. Lay, PhD, Martha Almond, RRT, David B

Reply Journal of Allergy and Clinical Immunology

Julie Negri, BA, S. Brandon Early, BA, John W

Soybean isoflavones regulate dendritic cell function and suppress allergic sensitization to peanut Madhan Masilamani, PhD, John Wei, BA, Shiven Bhatt,

Neuropeptide signaling through neurokinin-1 and neurokinin-2 receptors augments antigen presentation by human dendritic cells Junya Ohtake, PhD, Shun.

The effects of gastric digestion on codfish allergenicity

Perturbations of natural killer cell regulatory functions in respiratory allergic diseases Francesca Scordamaglia, MD, Mirna Balsamo, PhD, Antonio Scordamaglia,

Induction of anergic allergen-specific suppressor T cells using tolerogenic dendritic cells derived from children with allergies to house dust mites

CCL17/thymus and activation-regulated chemokine induces calcitonin gene–related peptide in human airway epithelial cells through CCR4 Kandace Bonner,

Presentation transcript:

Calcineurin inhibitors impair neutrophil activity against Aspergillus fumigatus in allogeneic hematopoietic stem cell transplant recipients Sébastien Imbert, MS, Priscillia Bresler, MS, Alexandre Boissonnas, PhD, Lauraine Gauthier, PharmD, Laëtitia Souchet, MD, Madalina Uzunov, MD, Véronique Leblond, MD, PhD, Dominique Mazier, MD, PhD, Stéphanie Nguyen, MD, PhD, Arnaud Fekkar, PharmD, PhD Journal of Allergy and Clinical Immunology Volume 138, Issue 3, Pages 860-868 (September 2016) DOI: 10.1016/j.jaci.2016.02.026 Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Postengraftment evolution of surface molecule expression and ROS production by neutrophils. A, Expression of CD11b and CD66, as determined by using flow cytometry. Neutrophils were collected at different time points after HSCT and stimulated with resting or germinating Aspergillus species conidia or LPS. Bars represent mean fluorescence intensity (MFI), with whiskers for the SEM. B, Expression of CD11b, CD66, and CD62L on neutrophils sampled from donors or recovering patients who underwent HSCT and stimulated by germinating Aspergillus species conidia. Long horizontal bars indicate MFI, with short bars for the SEM. C, Surface expression of TLR2, TLR4, and Dectin-1 on neutrophils sampled from donors or recovering patients who underwent HSCT. Long horizontal bars indicate MFI, with short bars for the SEM. D, ROS production by neutrophils according to different stimuli at different time points after HSCT. Bars represent MFI, with whiskers for the SEM. E, ROS production by neutrophils sampled from donors or recovering patients who underwent HSCT and stimulated by germinating Aspergillus species conidia. Long horizontal bars indicate means, with short bars for SEMs. *P < .05, **P < .01, and ***P < .001. ns, Not significant. Journal of Allergy and Clinical Immunology 2016 138, 860-868DOI: (10.1016/j.jaci.2016.02.026) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Ability of neutrophils to hamper Aspergillus species hyphae growth is impaired during recovery from neutropenia. Isolated neutrophils sampled from donors or allogeneic or autologous HSCT recipients during recovery were incubated with germinating conidia in a 96-well plate for 15 hours at 37°C with 5% CO2. After washing, fungal growth was assessed by using a fluorescent probe. Growth inhibition was calculated as 1 − (Ratio of the fluorescence intensity of the well with neutrophils and Aspergillus species to that of the well with Aspergillus species only) and expressed as a percentage. A, Comparison of inhibition between neutrophils from 23 donors and 33 allogeneic and 4 autologous graft recipients at a ratio of 16 neutrophils for 1 germinating conidia. Long horizontal bars indicate means, with short bars for SEMs. B, Paired comparison between neutrophils sampled from 19 HSCT recipients and their respective donors. **P < .005 and ***P < .001. ns, Not significant. Journal of Allergy and Clinical Immunology 2016 138, 860-868DOI: (10.1016/j.jaci.2016.02.026) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Calcineurin inhibitors reduce the ability of neutrophils to inhibit Aspergillus species hyphal growth. A, Neutrophils sampled from patients with normal calcineurin inhibitor trough levels (ie, >150 ng/mL for cyclosporine and >10 ng/mL for tacrolimus) are less capable of inhibiting Aspergillus species growth than those retrieved from patients with low trough levels (ie, <120 ng/mL for cyclosporine and <6 ng/mL for tacrolimus). Long horizontal bars indicate means, with short bars for SEMs. B, Correlation (Pearson test) between the percentage of inhibition of Aspergillus species by neutrophils (y-axis) and the percentage of target plasma calcineurin inhibitor trough level (x-axis). Target concentration was defined as 150 ng/mL for cyclosporine and 10 ng/mL for tacrolimus. Analysis included 26 patients receiving cyclosporine and 3 patients receiving tacrolimus. Concentrations were determined the day of or the day before neutrophil sampling, except for 2 patients for whom concentration values had been determined 2 days before sampling and 1 patient for whom concentration values had been determined 5 days before sampling. ***P < .001. Journal of Allergy and Clinical Immunology 2016 138, 860-868DOI: (10.1016/j.jaci.2016.02.026) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 A calcineurin inhibitor diminishes the ability of neutrophils to inhibit Aspergillus species growth. Blood collected from healthy donors was incubated for 2 hours at 37°C with cyclosporine (CsA; final concentrations of 500 and 1000 ng/mL) or equivalent dimethyl sulfoxide vehicle as a control. Subsequently, isolated neutrophils were used for an Aspergillus species growth inhibition assay. Neutrophils preincubated with cyclosporine showed decreased fungal inhibition compared with untreated control cells. Long dashed bars indicate means, with short bars for SEMs. *P < .01 and **P < .005. Journal of Allergy and Clinical Immunology 2016 138, 860-868DOI: (10.1016/j.jaci.2016.02.026) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Neutrophil death and NET formation are decreased during recovery in allogeneic HSCT recipients. Neutrophils sampled from patients who underwent HSCT during recovery or from healthy donors were incubated with germinating Aspergillus species conidia for 3 hours at 37°C with 5% CO2 in a 96-well plate placed on a Zeiss Axio Microscope. Pictures were taken every minute. SYTOX Green was added in each well at a final dilution of 1:5000 at the end of the experiment. Images were processed, and hyphal lengths were measured with ImageJ software. Quantification of NET formation was evaluated, as previously described by Papayannopoulos et al,9 with ImageJ software. A, Growth of Aspergillus species hyphae (in micrometers) after 3 hours of culture with or without neutrophils sampled from patients who underwent HSCT or control subjects. Length was measured for hyphae in contact with neutrophils and for those that were not. Inhibition of Aspergillus species growth (in micrometers) by neutrophils requires contact and is altered in patients who underwent HSCT. Results are representative of experiments with 4 patients and 4 control subjects. Bars represent means, with whiskers for the SEM. B, The death rate (assessed by SYTOX Green) in neutrophils sampled from control subjects is higher than that in neutrophils collected from patients. C, Images of 2 independent experiments showing the typical aspect of NETosis in control subjects, whereas the neutrophils of patients show aspects evocative of apoptosis/necrosis. D-E, NET formation assessed by measurement of an area of greater than 400 μm2 is higher with control neutrophils than with neutrophils from patients who underwent HSCT, as assessed by the repartition of the SYTOX Green–positive neutrophils according to the area of the signal (Fig 5, D) and the percentage of the SYTOX Green–positive neutrophils that underwent NETosis (ie, with a signal area >400 μm2; Fig 5, E). *P < .01 and **P < .005. ns, Not significant. Journal of Allergy and Clinical Immunology 2016 138, 860-868DOI: (10.1016/j.jaci.2016.02.026) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Evolution of Aspergillus species hyphae growth inhibition by neutrophils sampled from HSCT recipients. Growth inhibition is impaired during recovery but restored after 10 months. Adjunction of corticosteroid in patients who had GvHD is related to a trend toward a reduction of the ability of neutrophils to inhibit fungal growth. Bars represent means, with whiskers for the SEM. *P < .01 and **P < .005. ns, Not significant. Journal of Allergy and Clinical Immunology 2016 138, 860-868DOI: (10.1016/j.jaci.2016.02.026) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions