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1. BNT162b vaccines protect rhesus macaques from SARS-CoV-2

Author

Bernadette Jesionek, Charles Tan, Christoph Kröner, Jennifer Obregon, Stephanie Hein, Kathleen M. Brasky, Andreas Kuhn, Leyla Fischer, Guy Singh, Diana Schneider, Kathrin U. Jansen, Jane Fontenot, Seungil Han, Michal Gazi, Corinna Rosenbaum, Ingrid L. Scully, Pei Yong Shi, Parag Sahasrabudhe, Stefanie A. Krumm, Hanna Junginger, Camila R. Fontes-Garfias, Julia Schlereth, Bonny Gaby Lui, Mathias Vormehr, Andre P. Heinen, Alptekin Güler, Stephanie Fesser, Sarah C. Dany, Ellene H. Mashalidis, Danka Pavliakova, Shambhunath Choudhary, Mohan S. Maddur, Petra Adams-Quack, Yvonne Feuchter, Matthew C. Griffor, Ferdia Bates, Ramón de la Caridad Güimil Garcia, Tara Ciolino, Özlem Türeci, Stefan Schille, Kena A. Swanson, Kerstin C. Walzer, Alexander Muik, Jakob Loschko, Ayuko Ota-Setlik, Nicole L. Nedoma, Lena M. Kranz, Tompkins Kristin Rachael, Thorsten Klamp, Ugur Sahin, Ann Kathrin Wallisch, Warren Kalina, Olga Gonzalez, Fulvia Vascotto, Philip R. Dormitzer, Ye Che, Kendra J. Alfson, Ricardo Carrion, Thomas Ziegenhals, Shannan Hall-Ursone, Rani S. Sellers, Thomas Hiller, Isis Kanevsky, Matthew R. Gutman, Michael W. Pride, Stephanie Erbar, Bianca Sänger, Deepak Kaushal, Journey Cole, David Eisel, Andreas A.H. Su, Joshua A. Lees, Annette B. Vogel, and Arianne Plaschke

Subjects
Male, Models, Molecular, 0301 basic medicine, Aging, Internationality, T-Lymphocytes, Respiratory System, Antibodies, Viral, Mice, 0302 clinical medicine, Antigens, Viral, chemistry.chemical_classification, Clinical Trials as Topic, Mice, Inbred BALB C, Vaccines, Synthetic, Multidisciplinary, Vaccination, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Spike Glycoprotein, Coronavirus, RNA, Viral, Female, Antibody, COVID-19 Vaccines, T cell, Biology, Cell Line, 03 medical and health sciences, Antigen, medicine, Animals, Humans, BNT162 Vaccine, COVID-19 Serotherapy, SARS-CoV-2, Immunization, Passive, COVID-19, RNA, Antibodies, Neutralizing, Macaca mulatta, Virology, Disease Models, Animal, 030104 developmental biology, Solubility, Immunization, chemistry, biology.protein, Protein Multimerization, Glycoprotein, CD8
Abstract

A safe and effective vaccine against COVID-19 is urgently needed in quantities that are sufficient to immunize large populations. Here we report the preclinical development of two vaccine candidates (BNT162b1 and BNT162b2) that contain nucleoside-modified messenger RNA that encodes immunogens derived from the spike glycoprotein (S) of SARS-CoV-2, formulated in lipid nanoparticles. BNT162b1 encodes a soluble, secreted trimerized receptor-binding domain (known as the RBD–foldon). BNT162b2 encodes the full-length transmembrane S glycoprotein, locked in its prefusion conformation by the substitution of two residues with proline (S(K986P/V987P); hereafter, S(P2) (also known as P2 S)). The flexibly tethered RBDs of the RBD–foldon bind to human ACE2 with high avidity. Approximately 20% of the S(P2) trimers are in the two-RBD ‘down’, one-RBD ‘up’ state. In mice, one intramuscular dose of either candidate vaccine elicits a dose-dependent antibody response with high virus-entry inhibition titres and strong T-helper-1 CD4+ and IFNγ+CD8+ T cell responses. Prime–boost vaccination of rhesus macaques (Macaca mulatta) with the BNT162b candidates elicits SARS-CoV-2-neutralizing geometric mean titres that are 8.2–18.2× that of a panel of SARS-CoV-2-convalescent human sera. The vaccine candidates protect macaques against challenge with SARS-CoV-2; in particular, BNT162b2 protects the lower respiratory tract against the presence of viral RNA and shows no evidence of disease enhancement. Both candidates are being evaluated in phase I trials in Germany and the USA1–3, and BNT162b2 is being evaluated in an ongoing global phase II/III trial (NCT04380701 and NCT04368728). BNT162b1 and BNT162b2 are two candidate mRNA vaccines against COVID-19 that elicit high virus-entry inhibition titres in mice, elicit high virus-neutralizing titres in rhesus macaques and protect macaques from SARS-CoV-2 challenge.

Published
2021
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2. Vaccine Efficacy in Adults in a Respiratory Syncytial Virus Challenge Study

Author

Beate Schmoele-Thoma, Agnieszka M. Zareba, Qin Jiang, Mohan S. Maddur, Rana Danaf, Alex Mann, Kingsley Eze, Juin Fok-Seang, Golam Kabir, Andrew Catchpole, Daniel A. Scott, Alejandra C. Gurtman, Kathrin U. Jansen, William C. Gruber, Philip R. Dormitzer, and Kena A. Swanson

Subjects
Respiratory Syncytial Virus, Human, Respiratory Syncytial Virus Vaccines, Humans, Vaccine Efficacy, General Medicine, Respiratory Syncytial Virus Infections, Antibodies, Viral, Antibodies, Neutralizing, Injections, Intramuscular, Aged
Abstract

Although human respiratory syncytial virus (RSV) is an important cause of illness and death in older adults, no RSV vaccine has been licensed.In a phase 2a study, we randomly assigned healthy adults (18 to 50 years of age), in a 1:1 ratio, to receive a single intramuscular injection of either bivalent prefusion F (RSVpreF) vaccine or placebo. Approximately 28 days after injection, participants were inoculated intranasally with the RSV A Memphis 37b challenge virus and observed for 12 days. The per-protocol prespecified primary end points were the following: reverse-transcriptase-quantitative polymerase-chain-reaction (RT-qPCR)-confirmed detectable RSV infection on at least 2 consecutive days with at least one clinical symptom of any grade from two categories or at least one grade 2 symptom from any category, the total symptom score from day 1 to discharge, and the area under the curve (AUC) for the RSV viral load in nasal-wash samples measured by means of RT-qPCR from day 2 after challenge to discharge. In addition, we assessed immunogenicity and safety.After participants were inoculated with the challenge virus, vaccine efficacy of 86.7% (95% CI, 53.8 to 96.5) was observed for symptomatic RSV infection confirmed by any detectable viral RNA on at least 2 consecutive days. The median AUC for the RSV viral load (hours × logRSVpreF vaccine was effective against symptomatic RSV infection and viral shedding. No evident safety concerns were identified. These findings provide support for further evaluation of RSVpreF vaccine in a phase 3 efficacy study. (Funded by Pfizer; EudraCT number, 2020-003887-21; ClinicalTrials.gov number, NCT04785612.).

Published
2022

3. Natural Antibodies: from First-Line Defense Against Pathogens to Perpetual Immune Homeostasis

Author

Jordan D. Dimitrov, Mohan S. Maddur, Sébastien Lacroix-Desmazes, Jagadeesh Bayry, Srini V. Kaveri, Michel Kazatchkine, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), United Nations Special Envoy for AIDS in Eastern Europe and Central Asia, and Lacroix-Desmazes, Sébastien

Subjects
0301 basic medicine, [SDV.IMM] Life Sciences [q-bio]/Immunology, medicine.medical_treatment, Autoimmunity, medicine.disease_cause, Epitope, Antibodies, Immunomodulation, 03 medical and health sciences, 0302 clinical medicine, Immune system, medicine, Immune Tolerance, Immunology and Allergy, Animals, Homeostasis, Humans, B cell, Intravenous immunoglobulin, Disease Resistance, 030203 arthritis & rheumatology, IVIG, Immune homeostasis, biology, Autoantibody, Immunity, General Medicine, Immunotherapy, Immunity, Innate, 3. Good health, Immunoglobulin Isotypes, 030104 developmental biology, medicine.anatomical_structure, Polyclonal antibodies, Organ Specificity, Immunology, Antibody Formation, Host-Pathogen Interactions, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, Therapy, Antibody, Natural IgG, Natural IgM
Abstract

International audience; Natural antibodies (nAbs) are most commonly defined as immunoglobulins present in the absence of pathological conditions or deliberate immunizations. Occurrence of nAbs in germ- and antigen-free mice suggest that their production is driven, at least in part, by self-antigens. Accordingly, nAbs are constituted of natural autoantibodies (nAAbs), and can belong to the IgM, IgG, or IgA subclasses. These nAbs provide immediate protection against infection while the adaptive arm of the immune system mounts a specific and long-term response. Beyond immediate protection from infection, nAbs have been shown to play various functional roles in the immune system, which include clearance of apoptotic debris, suppression of autoimmune and inflammatory responses, regulation of B cell responses, selection of the B cell repertoires, and regulation of B cell development. These various functions of nAbs are afforded by their reactivity, which is broad, cross-reactive, and shown to recognize evolutionarily fixed epitopes shared between foreign and self-antigens. Furthermore, nAbs have unique characteristics that also contribute to their functional roles and set them apart from antigen-specific antibodies. In further support for the role of nAbs in the protection against infections and in the maintenance of immune homeostasis, the therapeutic preparation of polyclonal immunoglobulins, intravenous immunoglobulin (IVIG), rich in nAbs is commonly used in the replacement therapy of primary and secondary immunodeficiencies and in the immunotherapy of a large number of autoimmune and inflammatory diseases. Here, we review several topics on nAbs features and functions, and therapeutic applications in human diseases.

Published
2019
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4. Induction of human dendritic cell maturation by naïve and memory B-cell subsets requires different activation stimuli

Author

Jagadeesh Bayry, Mohan S. Maddur, Srini V. Kaveri, Immunopathologie et immunointervention thérapeutique (CRC - Inserm U1138), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Pfizer, Inc [Pearl River, New-York], and Bayry, Jagadeesh

Subjects
0301 basic medicine, T-Lymphocytes, Immunology, B-Lymphocyte Subsets, Receptors, Antigen, B-Cell, Biology, Lymphocyte Activation, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, 03 medical and health sciences, Text mining, Correspondence, Humans, Immunology and Allergy, CD40 Antigens, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, Memory B cell, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, B-Lymphocytes, business.industry, Granulocyte-Macrophage Colony-Stimulating Factor, Cell Differentiation, Dendritic Cells, Dendritic cell, Tumor Necrosis Factor Receptor Superfamily, Member 7, 030104 developmental biology, Infectious Diseases, Interleukin-4, business, Immunologic Memory, Neuroscience, [SDV.IMM.ALL] Life Sciences [q-bio]/Immunology/Allergology, Signal Transduction
Abstract

International audience

Published
2018
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5. Regulatory T cells induce activation rather than suppression of human basophils

Author

Emmanuel Stephen-Victor, Meenu Sharma, Caroline Galeotti, Patrick Bruneval, Anupama Karnam, Srini V. Kaveri, Mrinmoy Das, Mohan S. Maddur, Jagadeesh Bayry, Université de Technologie de Compiègne (UTC), Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Génie Enzymatique et Cellulaire (GEC), Université de Technologie de Compiègne (UTC)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Pathologie [AP-HP Hôpital Européen Georges Pompidou], Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5), Université Sorbonne Paris Cité (USPC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)

Subjects
Adult, 0301 basic medicine, Immunology, Population, chemical and pharmacologic phenomena, Basophil, T-Lymphocytes, Regulatory, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Immune tolerance, 03 medical and health sciences, 0302 clinical medicine, Immune system, parasitic diseases, medicine, Humans, IL-2 receptor, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, education, Cells, Cultured, STAT5, education.field_of_study, biology, FOXP3, hemic and immune systems, Dendritic Cells, General Medicine, Basophils, 3. Good health, Basophil activation, 030104 developmental biology, medicine.anatomical_structure, biology.protein, Cytokines, [SDV.IMM]Life Sciences [q-bio]/Immunology, Spleen, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030215 immunology
Abstract

International audience; Basophils are a rare granulocyte population that has been associated with allergic and inflammatory responses. It is essential to understand the regulatory mechanisms by which basophils are kept in check, considering the impact of dysregulated basophil function on immune responses under different pathological conditions. Among immunoregulatory cells, CD4+CD25+FoxP3+ regulatory T cells (Tregs) are the key players that maintain immune tolerance. The mechanisms by which Tregs regulate and suppress diverse immune cell subsets have been studied extensively, but the impact of Tregs on basophil functions is not well understood. We report that human basophils are refractory to Treg-mediated suppression and found that Tregs stimulate resting basophils to induce the expression of activation markers including CD69, CD203c, and CD13 and the release of basophil cytokines including IL-13, IL-8, and IL-4. Mechanistically, Tregs could induce human basophil activation via IL-3 and STAT5 activation, whereas cellular contact was dispensable. Inhibition of either IL-3–IL-3 receptor interactions or STAT5 phosphorylation abrogated Treg-mediated activation of basophils. These results provide evidence of direct positive effects that human Tregs have on basophil activation and reveal a previously unrecognized feature of this cell subset well known for immunosuppressive functions.

Published
2018
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6. Circulating Normal IgG as Stimulator of Regulatory T Cells: Lessons from Intravenous Immunoglobulin

Author

Srini V. Kaveri, Mohan S. Maddur, Jagadeesh Bayry, HAL-UPMC, Gestionnaire, Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pfizer, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Université Sorbonne Paris Cité (USPC), Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Centre de Recherche des Cordeliers ( CRC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), and Pfizer Inc

Subjects
0301 basic medicine, DCIR, medicine.medical_treatment, Immunology, [ SDV.IMM.IMM ] Life Sciences [q-bio]/Immunology/Immunotherapy, Tregitopes, Lymphocyte Activation, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, DC-SIGN, T-Lymphocytes, Regulatory, regulatory T cells, 03 medical and health sciences, Mice, 0302 clinical medicine, hemic and lymphatic diseases, antibody, Immunology and Allergy, Medicine, Animals, Humans, Prostaglandin E2, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, ComputingMilieux_MISCELLANEOUS, Intravenous immunoglobulin, prostaglandin E2, biology, business.industry, Immunoglobulins, Intravenous, Immunotherapy, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Dendritic Cells, 3. Good health, Interleukin 33, 030104 developmental biology, Immunoglobulin G, Blood Circulation, biology.protein, IL-33, Immunization, Antibody, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, business, 030215 immunology, medicine.drug
Abstract

International audience; Intravenous immunoglobulin (IVIG), a pooled normal IgG formulation prepared from thousands of healthy donors’ plasma, is extensively used for the immunotherapy of autoimmune and inflammatory disorders. Recent reports demonstrate that IVIG exerts anti-inflammatory actions by stimulating the activation and expansion of regulatory T (Treg) cells by multiple mechanisms via antigen-presenting cells (APCs).

Published
2017
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7. Metabolic Phenotypes Of Response to Vaccination in Humans

Author

Adriana Weinberg, Myron J. Levin, Christopher Chiu, Jennifer A. Whitaker, Mohan S. Maddur, Dean P. Jones, Tianwei Yu, Aneesh K. Mehta, Sheri Dubey, Sai Duraisingham, Andreas Wieland, Nicole L. Sullivan, Shankar Subramaniam, Vi Linh Tran, Bali Pulendran, Jennifer Canniff, Shuzhao Li, Kalpit A. Vora, Alessandro Sette, Thomas Hagan, Mark J. Mulligan, Helder I. Nakaya, Nadine Rouphael, Megan McCausland, Ken Liu, Rafi Ahmed, and Sophia Banton

Subjects
0301 basic medicine, Adult, CD4-Positive T-Lymphocytes, Male, Aging, medicine.medical_treatment, Inositol Phosphates, Biology, Adaptive Immunity, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Immune system, Immunity, medicine, Herpes Zoster Vaccine, Humans, Metabolomics, Gene Regulatory Networks, VACINAÇÃO, Longitudinal Studies, Aged, Sex Characteristics, Gene Expression Profiling, biochemical phenomena, metabolism, and nutrition, Middle Aged, Viral Load, medicine.disease, Flow Cytometry, Phenotype, Virology, Vaccination, Sterols, 030104 developmental biology, Cytokine, Immunology, Antibody Formation, biology.protein, bacteria, Female, Antibody, CD8, Shingles
Abstract

Herpes zoster (shingles) causes significant morbidity in immune compromised hosts and older adults. Whereas a vaccine is available for prevention of shingles, its efficacy declines with age. To help to understand the mechanisms driving vaccinal responses, we constructed a multiscale, multifactorial response network (MMRN) of immunity in healthy young and older adults immunized with the live attenuated shingles vaccine Zostavax. Vaccination induces robust antigen-specific antibody, plasmablasts, and CD4+ T cells yet limited CD8+ T cell and antiviral responses. The MMRN reveals striking associations between orthogonal datasets, such as transcriptomic and metabolomics signatures, cell populations, and cytokine levels, and identifies immune and metabolic correlates of vaccine immunity. Networks associated with inositol phosphate, glycerophospholipids, and sterol metabolism are tightly coupled with immunity. Critically, the sterol regulatory binding protein 1 and its targets are key integrators of antibody and T follicular cell responses. Our approach is broadly applicable to study human immunity and can help to identify predictors of efficacy as well as mechanisms controlling immunity to vaccination.

Published
2017

8. Regulatory T cell frequency, but not plasma IL-33 levels, represents potential immunological biomarker to predict clinical response to intravenous immunoglobulin therapy

Author

Laurent Magy, Emmanuel Stephen-Victor, Jagadeesh Bayry, Francis Bolgert, Jean-Michel Vallat, Vikas Pratap Singh, Magalie Rabin, Praveen Prakhar, Srini V. Kaveri, Mrinmoy Das, Jamma Trinath, Mohan S. Maddur, Varun K. Sharma, Kithiganahalli Narayanaswamy Balaji, Emory University [Atlanta, GA], Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Indian Institute of Science, Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Centre de référence national neuropathies périphériques rares [CHU Limoges], CHU Limoges, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Emory Vaccine Center [Atlanta, GA, USA], Indian Institute of Science [Bangalore] (IISc Bangalore), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Neurologie [CHU Limoges], Supported by Institut National de la Santé et de la Recherche Médicale, Université Pierre et Marie Curie, Université Paris Descartes (SVK and JB), Centre National de la Recherche Scientifique (SVK), European Community’s Seventh Framework Programme [FP7/2007-2013] under grant agreement 260338 ALLFUN (JB), and fellowship from Journées de Neurologie de Langue Française (MR). KNB is a J. C. Bose National fellow of Department of Science and Technology, New Delhi, India., European Project: 260338,EC:FP7:HEALTH,FP7-HEALTH-2010-single-stage,ALLFUN(2010), École Pratique des Hautes Études (EPHE), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Bayry, Jagadeesh, Fungi in the setting of inflammation, allergy and autoimmune diseases:Translating basic science into clinical practices - ALLFUN - - EC:FP7:HEALTH2010-12-01 - 2014-05-31 - 260338 - VALID, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Male, 0301 basic medicine, Severity of Illness Index, T-Lymphocytes, Regulatory, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Immunoglobulin G, 0302 clinical medicine, Intravenous Immunoglobulin Therapy, hemic and lymphatic diseases, Outcome Assessment, Health Care, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, Aged, 80 and over, Microbiology & Cell Biology, biology, medicine.diagnostic_test, General Neuroscience, Immunoglobulins, Intravenous, FOXP3, Regulatory T cells, Middle Aged, Flow Cytometry, Guillain-Barré syndrome, 3. Good health, medicine.anatomical_structure, Neurology, Female, Antibody, [SDV.IMM.ALL] Life Sciences [q-bio]/Immunology/Allergology, Regulatory T cell, Immunology, Short Report, Enzyme-Linked Immunosorbent Assay, [ SDV.IMM.IMM ] Life Sciences [q-bio]/Immunology/Immunotherapy, Guillain-Barre Syndrome, Peripheral blood mononuclear cell, Dinoprostone, Statistics, Nonparametric, Flow cytometry, 03 medical and health sciences, Cellular and Molecular Neuroscience, Predictive Value of Tests, medicine, Humans, Immunologic Factors, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, Aged, IVIG, business.industry, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Interleukin-33, Interleukin 33, 030104 developmental biology, TNF-α, biology.protein, IL-33, Clinical response, business, 030217 neurology & neurosurgery, Treg cells, Follow-Up Studies
Abstract

Background: Intravenous immunoglobulin (IVIG) is a polyspecific pooled immunoglobulin G preparation and one of the commonly used therapeutics for autoimmune diseases including those of neurological origin. A recent report in murine model proposed that IVIG expands regulatory T (Treg) cells via induction of interleukin 33 (IL-33). However, translational insight on these observations is lacking.Methods: Ten newly diagnosed Guillain-Barré syndrome (GBS) patients were treated with IVIG at the rate of 0.4 g/kg for three to five consecutive days. Clinical evaluation for muscular weakness was performed by Medical Research Council (MRC) and modified Rankin scoring (MRS) system. Heparinized blood samples were collected before and 1, 2, and 4–5 weeks post-IVIG therapy. Peripheral blood mononuclear cells were stained for surface CD4 and intracellular Foxp3, IFN-γ, and tumor necrosis factor alpha (TNF-α) and were analyzed by flow cytometry. IL-33 and prostaglandin E2 in the plasma were measured by ELISA.Results: The fold changes in plasma IL-33 at week 1 showed no correlation with the MRC and MRS scores at weeks 1, 2, and ≥4 post-IVIG therapy. Clinical recovery following IVIG therapy appears to be associated with Treg cell response. Contrary to murine study, there was no association between the fold changes in IL-33 at week 1 and Treg cell frequency at weeks 1, 2, and ≥4 post-IVIG therapy. Treg cell-mediated clinical response to IVIG therapy in GBS patients was associated with reciprocal regulation of effector T cells-expressing TNF-α.Conclusion: Treg cell expansion by IVIG in patients with autoimmune diseases lack correlation with IL-33. Treg cell frequency, but not plasma IL-33 levels, represents potential immunological biomarker to predict clinical response to IVIG therapy.

Published
2017
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9. Intravenous immunoglobulin exerts reciprocal regulation of Th1/Th17 cells and regulatory T cells in Guillain–Barré syndrome patients

Author

Jean-Michel Vallat, Pushpa Hegde, Moneger Guy, Magalie Rabin, Francis Bolgert, Mohan S. Maddur, Laurent Magy, Jagadeesh Bayry, Srini V. Kaveri, Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de référence national neuropathies périphériques rares [CHU Limoges], CHU Limoges, International Associated Laboratory IMPACT, Institut National de la Santé et de la Recherche Médicale (INSERM)-Indian Council of Medical Research [New Dehli] (ICMR), Administateur, HAL Sorbonne Université, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Service de Neurologie [CHU Limoges], Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Université Sorbonne Paris Cité (USPC), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Indian Council of Medical Research, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
IVIg, Allergy, T-Lymphocytes, Regulatory, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Guillain–Barré syndrome, 0302 clinical medicine, Immunophenotyping, T-Lymphocyte Subsets, hemic and lymphatic diseases, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Medicine, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, biology, Guillain-Barre syndrome, Immunoglobulins, Intravenous, FOXP3, hemic and immune systems, Regulatory T cells, Middle Aged, 3. Good health, medicine.anatomical_structure, Peripheral nervous system, [SDV.IMM]Life Sciences [q-bio]/Immunology, Antibody, [SDV.IMM] Life Sciences [q-bio]/Immunology, T cell, Immunology, chemical and pharmacologic phenomena, Motor Activity, Guillain-Barre Syndrome, Immunomodulation, 03 medical and health sciences, Th1 cells, Humans, Lymphocyte Count, Th17 cells, Intravenous immunoglobulin, Aged, 030304 developmental biology, business.industry, bacterial infections and mycoses, medicine.disease, Case-Control Studies, Concomitant, biology.protein, business, 030217 neurology & neurosurgery
Abstract

International audience; Guillain-Barré syndrome (GBS) is an acute, autoimmune inflammatory disorder of peripheral nervous system characterized by a severe functional motor weakness. Treatment with intravenous immunoglobulin (IVIg) is one of the approved and preferred therapeutic strategies for GBS. However, the mechanisms underlying the therapeutic benefit with IVIg in GBS are not completely understood. In the present study, we observed that GBS patients have increased frequencies of Th1 and Th17 cells, but reduced number of Foxp3(+) regulatory T cells (Treg cells) with defective functions. We show that IVIg treatment in GBS patients results in a marked reduction in the frequency of Th1 and Th17 cells with a concomitant expansion of Treg cells. Importantly, IVIg-expanded Treg cells exhibited an increased T cell suppressive function. Together our results demonstrate that therapeutic benefit of IVIg in GBS patients implicates the reciprocal regulation of Th1/Th17 and Treg cells.

Published
2014
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10. Vaccine Activation of the Nutrient Sensor GCN2 in Dendritic Cells Enhances Antigen Presentation

Author

Herbert W. Virgin, Pascal Chappert, David Ron, Jens Loebbermann, Helder I. Nakaya, Jean Davoust, David S. Weiss, Bali Pulendran, Mohan S. Maddur, Shuzhao Li, Youngja Park, Dean P. Jones, Rajesh Ravindran, and Nooruddin Khan

Subjects
CD4-Positive T-Lymphocytes, Systems biology, Antigen presentation, Yellow fever vaccine, CD8-Positive T-Lymphocytes, Protein Serine-Threonine Kinases, Biology, Autophagy-Related Protein 7, Article, Autophagy-Related Protein 5, Cell Line, Mice, Cricetinae, medicine, Animals, Humans, Integrated stress response, Antigen Presentation, Multidisciplinary, Yellow Fever Vaccine, Autophagy, Dendritic Cells, Acquired immune system, Mice, Mutant Strains, Enzyme Activation, Mice, Inbred C57BL, Cell culture, Immunology, Microtubule-Associated Proteins, CD8, medicine.drug
Abstract

The Secret Life of a Vaccine Antigen-specific CD8 ÷ T cells play a central role in the adaptive immune response to viral infections and to cancer. Ravindran et al. (p. 313 , published online 5 December) studied the successful yellow fever virus vaccine YF-17D to gain insight into its mechanism of action. The vaccine activated the nutrient deprivation sensor, GCN2 kinase, in dendritic cells. In transgenic mouse models, GCN2 activation promoted autophagy and antigen cross-presentation, enhancing the virus-specific CD8 ÷ T cell response. The findings suggest an important role for nutrient availability and autophagy in vaccine efficacy, which could aid more successful vaccine development.

Published
2014
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11. Antibiotics-Driven Gut Microbiome Perturbation Alters Immunity to Vaccines in Humans

Author

Caroline Petitdemange, Jenna J. Guthmiller, Barbara Cervasi, Hana Golding, Amit A. Uphadhyay, Patrick C. Wilson, Nadine Rouphael, Megan Hahn, Shuzhao Li, Caitlin Linde, Alexis Bretin, Michele Paine McCullough, Sara Jo Johnson, Mario Cortese, Steve E. Bosinger, Min Huang, Galit Alter, Carolyn M. Boudreau, Luiz Gustavo Gardinassi, Kiran Gill, Jun Zou, Hong Wang, Nai-Ying Zheng, Mohan S. Maddur, Bali Pulendran, Thomas Hagan, Surender Khurana, Andrew T. Gewirtz, and Jishnu Das

Subjects
Adult, Male, Adolescent, medicine.drug_class, Antibiotics, Antibodies, Viral, Article, General Biochemistry, Genetics and Molecular Biology, Young Adult, 03 medical and health sciences, Immunogenicity, Vaccine, Influenza A Virus, H1N1 Subtype, 0302 clinical medicine, Immunity, Influenza, Human, medicine, Humans, Microbiome, 030304 developmental biology, 0303 health sciences, biology, Antibody titer, Inflammasome, Dendritic cell, Healthy Volunteers, Anti-Bacterial Agents, Gastrointestinal Microbiome, Vaccination, Influenza Vaccines, Antibody Formation, Immunology, biology.protein, Female, Antibody, 030217 neurology & neurosurgery, medicine.drug
Abstract

Emerging evidence indicates a central role for the microbiome in immunity. However, causal evidence in humans is sparse. Here, we administered broad-spectrum antibiotics to healthy adults prior and subsequent to seasonal influenza vaccination. Despite a 10,000-fold reduction in gut bacterial load and long-lasting diminution in bacterial diversity, antibody responses were not significantly affected. However, in a second trial of subjects with low pre-existing antibody titers, there was significant impairment in H1N1-specific neutralization and binding IgG1 and IgA responses. In addition, in both studies antibiotics treatment resulted in (1) enhanced inflammatory signatures (including AP-1/NR4A expression), observed previously in the elderly, and increased dendritic cell activation; (2) divergent metabolic trajectories, with a 1,000-fold reduction in serum secondary bile acids, which was highly correlated with AP-1/NR4A signaling and inflammasome activation. Multi-omics integration revealed significant associations between bacterial species and metabolic phenotypes, highlighting a key role for the microbiome in modulating human immunity.

Published
2019
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12. Intravenous immunoglobulin induces IL-4 in human basophils by signaling through surface-bound IgE

Author

Jordan D. Dimitrov, Olivier Benveniste, Mohan S. Maddur, Jagadeesh Bayry, Pierre Bruhns, Alain Chevailler, Caroline Galeotti, Emmanuel Stephen-Victor, Anupama Karnam, Laurent Gilardin, Srini V. Kaveri, Mrinmoy Das, Cédric Vonarburg, and Sandra Wymann

Subjects
Antigens, Differentiation, T-Lymphocyte, 0301 basic medicine, Thymic stromal lymphopoietin, Immunology, Anti-Inflammatory Agents, Fc receptor, Syk, chemical and pharmacologic phenomena, Basophil, Immunoglobulin E, Histamine Release, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Antigens, CD, hemic and lymphatic diseases, medicine, Animals, Humans, Syk Kinase, Immunology and Allergy, Lectins, C-Type, Cells, Cultured, Interleukin 4, biology, Chemistry, Immunoglobulins, Intravenous, hemic and immune systems, Basophils, Immunoglobulin Fc Fragments, Up-Regulation, 3. Good health, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, biology.protein, Interleukin-3, Antibody, Histamine, 030215 immunology
Abstract

Background Therapeutic normal IgG or intravenous immunoglobulin (IVIG) exerts anti-inflammatory effects through several mutually nonexclusive mechanisms. Recent data in mouse models of autoimmune disease suggest that IVIG induces IL-4 in basophils by enhancing IL-33 in SIGN-related 1–positive innate cells. However, translational insight on these data is lacking. Objective We sought to investigate the effect of IVIG on human basophil functions. Methods Isolated circulating basophils from healthy donors were cultured in the presence of IL-3, IL-33, GM-CSF, thymic stromal lymphopoietin, or IL-25. The effect of IVIG and F(ab')2 and Fc IVIG fragments was examined based on expression of various surface molecules, phosphorylation of spleen tyrosine kinase, induction of cytokines, and histamine release. Basophil phenotypes were also analyzed from IVIG-treated patients with myopathy. Approaches, such as depletion of anti-IgE reactivity from IVIG, blocking antibodies, or inhibitors, were used to investigate the mechanisms. Results We report that IVIG directly induces activation of IL-3–primed human basophils, but IL-33 and other cytokines were dispensable for this effect. Activation of basophils by IVIG led to enhanced expression of CD69 and secretion of IL-4, IL-6, and IL-8. IVIG-treated patients with myopathy displayed enhanced expression of CD69 on basophils. The spleen tyrosine kinase pathway is implicated in these functions of IVIG and were mediated by F(ab')2 fragments. Mechanistically, IVIG induced IL-4 in human basophils by interacting with basophil surface-bound IgE but independent of FcγRII, type II Fc receptors, C-type lectin receptors, and sialic acid–binding immunoglobulin-like lectins. Conclusion These results uncovered a pathway of promoting the TH2 response by IVIG through direct interaction of IgG with human basophils.

Published
2019
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13. Intravenous immunoglobulins in immunodeficiencies: more than mere replacement therapy

Author

Sébastien Lacroix-Desmazes, Jagadeesh Bayry, Pushpa Hegde, Srini V. Kaveri, and Mohan S. Maddur

Subjects
Autoimmune disease, Severe combined immunodeficiency, biology, business.industry, Common variable immunodeficiency, Immunology, Immunologic Deficiency Syndromes, Immunoglobulins, Intravenous, medicine.disease, Immunoglobulin E, Autoimmune Diseases, Treatment Outcome, Intravenous Immunoglobulins, hemic and lymphatic diseases, Immunopathology, medicine, biology.protein, Humans, Immunology and Allergy, Antibody, business, Review Articles, Immunodeficiency
Abstract

Summary Intravenous immunoglobulin (IVIG) is a therapeutic compound prepared from pools of plasma obtained from several thousand healthy blood donors. For more than 20 years, IVIG has been used in the treatment of a wide range of primary and secondary immunodeficiencies. IVIG now represents a standard therapeutic option for most antibody deficiencies. Routinely, IVIG is used in patients with X-linked agammaglobulinaemia (XLA), common variable immunodeficiency (CVID), X-linked hyper-IgM, severe combined immunodeficiency, Wiskott-Aldrich syndrome, and selective IgG class deficiency. In addition, IVIG is used extensively in the treatment of a wide variety of autoimmune disorders. IVIG is administered at distinct doses in the two clinical settings: whereas immunodeficient patients are treated with replacement levels of IVIG, patients with autoimmune and inflammatory diseases are administered with very high doses of IVIG. Several lines of experimental evidence gathered in the recent years suggest that the therapeutic beneficial effect of IVIG in immunodeficiencies reflects an active role for IVIG, rather than a mere passive transfer of antibodies.

Published
2011
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14. Intravenous immunoglobulin-mediated expansion of regulatory T cells in autoimmune patients is associated with increased prostaglandin E2 levels in the circulation

Author

Kithiganahalli Narayanaswamy Balaji, Moneger Guy, Jean-Michel Vallat, Laurent Magy, Magalie Rabin, Mohan S. Maddur, Jagadeesh Bayry, Francis Bolgert, Srini V. Kaveri, Jamma Trinath, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Indian Institute of Science, Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Neurologie [CHU Limoges], CHU Limoges, Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Université Sorbonne Paris Cité (USPC), Institut National de la Santé et de la Recherche Médicale (INSERM), Bayry, Jagadeesh, Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), École Pratique des Hautes Études (EPHE), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Male, Short Communication, Immunology, chemical and pharmacologic phenomena, T-Lymphocytes, Regulatory, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Dinoprostone, Autoimmune Diseases, Immune tolerance, Immune system, hemic and lymphatic diseases, medicine, Humans, Immunology and Allergy, Prostaglandin E2, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, ComputingMilieux_MISCELLANEOUS, Aged, Cell Proliferation, Microbiology & Cell Biology, Aged, 80 and over, biology, business.industry, Immunoglobulins, Intravenous, FOXP3, hemic and immune systems, Middle Aged, 3. Good health, Infectious Diseases, Circulatory system, biology.protein, Female, Antibody, business, [SDV.IMM.ALL] Life Sciences [q-bio]/Immunology/Allergology, medicine.drug
Abstract

CD4+FoxP3+ regulatory T cells (Tregs) are immunosuppressive cells that are critical for immune tolerance. Several studies have demonstrated that one of the anti-inflammatory mechanisms of action of intravenous immunoglobulin (IVIg) involves the expansion of Tregs. Recently, we demonstrated that IVIg-mediated Treg expansion involves the cyclooxygenase-2 (COX-2)-dependent induction of prostaglandin E2 (PGE2) in human dendritic cells (DCs). However, the validity of these findings in autoimmune patients is lacking. In this report, we demonstrate that the IVIg-mediated expansion of Tregs in autoimmune patients is associated with increased levels of circulatory PGE2. Due to its immunomodulatory effects on various immune cells, this increase in PGE2 represents one of the pathways by which IVIg exerts anti-inflammatory effects.

Published
2015
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15. Zika Virus Antagonizes Type I Interferon Responses during Infection of Human Dendritic Cells

Author

James R. Bowen, Mehul S. Suthar, Bali Pulendran, Kendra M. Quicke, Vinita Puri, Circe E. McDonald, Mohan S. Maddur, Reed S. Shabman, Nadia Fedorova, and Justin T. O’Neal

Subjects
RNA viruses, 0301 basic medicine, Physiology, viruses, Gene Expression, Dengue virus, Pathology and Laboratory Medicine, medicine.disease_cause, Biochemistry, Polymerase Chain Reaction, Monocytes, Zika virus, White Blood Cells, Animal Cells, Interferon, Immune Physiology, Medicine and Health Sciences, Post-Translational Modification, Phosphorylation, Receptors, Immunologic, lcsh:QH301-705.5, Staining, Innate Immune System, Zika Virus Infection, Cell Staining, Flow Cytometry, 3. Good health, Flavivirus, Medical Microbiology, Viral Pathogens, Viruses, Interferon Type I, Cytokines, DEAD Box Protein 58, Pathogens, Cellular Types, Research Article, medicine.drug, lcsh:Immunologic diseases. Allergy, Immune Cells, Blotting, Western, Immunology, Biology, Research and Analysis Methods, Microbiology, Virus, 03 medical and health sciences, Virology, Genetics, medicine, Humans, Microbial Pathogens, Molecular Biology, Secretion, Immune Evasion, Blood Cells, Flaviviruses, Organisms, Biology and Life Sciences, Proteins, Zika Virus, Cell Biology, Dendritic Cells, Molecular Development, Japanese encephalitis, medicine.disease, biology.organism_classification, Viral Replication, 030104 developmental biology, lcsh:Biology (General), Viral replication, Specimen Preparation and Treatment, Immune System, Parasitology, Physiological Processes, lcsh:RC581-607, Interferon type I, Developmental Biology
Abstract

Zika virus (ZIKV) is an emerging mosquito-borne flavivirus that is causally linked to severe neonatal birth defects, including microcephaly, and is associated with Guillain-Barre syndrome in adults. Dendritic cells (DCs) are an important cell type during infection by multiple mosquito-borne flaviviruses, including dengue virus, West Nile virus, Japanese encephalitis virus, and yellow fever virus. Despite this, the interplay between ZIKV and DCs remains poorly defined. Here, we found human DCs supported productive infection by a contemporary Puerto Rican isolate with considerable variability in viral replication, but not viral binding, between DCs from different donors. Historic isolates from Africa and Asia also infected DCs with distinct viral replication kinetics between strains. African lineage viruses displayed more rapid replication kinetics and infection magnitude as compared to Asian lineage viruses, and uniquely induced cell death. Infection of DCs with both contemporary and historic ZIKV isolates led to minimal up-regulation of T cell co-stimulatory and MHC molecules, along with limited secretion of inflammatory cytokines. Inhibition of type I interferon (IFN) protein translation was observed during ZIKV infection, despite strong induction at the RNA transcript level and up-regulation of other host antiviral proteins. Treatment of human DCs with RIG-I agonist potently restricted ZIKV replication, while type I IFN had only modest effects. Mechanistically, we found all strains of ZIKV antagonized type I IFN-mediated phosphorylation of STAT1 and STAT2. Combined, our findings show that ZIKV subverts DC immunogenicity during infection, in part through evasion of type I IFN responses, but that the RLR signaling pathway is still capable of inducing an antiviral state, and therefore may serve as an antiviral therapeutic target., Author Summary Zika virus (ZIKV) is an emerging mosquito-borne flavivirus that, upon congenital infection, can cause severe neonatal birth defects. To better understand the early innate immune response to ZIKV, we compared infection of human dendritic cells (DCs) between a contemporary Puerto Rican isolate and historic isolates from Africa and Asia. Human DCs supported productive replication following infection with the contemporary strain and exhibited donor variability in viral replication, but not viral binding. While contemporary and historic Asian lineage viruses replicated similarly, the African strains displayed more rapid replication kinetics with higher infection magnitude and uniquely induced cell death. Minimal DC activation and antagonism of type I interferon (IFN) translation was observed during ZIKV infection, despite strong induction of IFNB1 transcription and translation of other antiviral effector proteins. Treatment with a RIG-I agonist potently blocked ZIKV replication in human DCs, while type I IFN treatment was significantly less effective. Mechanistically, all ZIKV strains inhibited type I IFN receptor signaling through blockade of STAT1 and STAT2 phosphorylation. Altogether, we found that while ZIKV efficiently evades type I IFN responses during infection of human DCs, RIG-I signaling remains capable of inducing a strong antiviral state.

Published
2017
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16. Human B cells induce dendritic cell maturation and favour Th2 polarization by inducing OX-40 ligand

Author

Pushpa Hegde, Bali Pulendran, Meenu Sharma, Emmanuel Stephen-Victor, Mohan S. Maddur, Srini V. Kaveri, Jagadeesh Bayry, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Emory Vaccine Center, Emory University [Atlanta, GA], Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Université Sorbonne Paris Cité (USPC), École pratique des hautes études (EPHE), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Bayry, Jagadeesh, and Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE)

Subjects
Antigens, Differentiation, T-Lymphocyte, Cellular differentiation, Transmembrane Activator and CAML Interactor Protein, Cell Culture Techniques, General Physics and Astronomy, chemical and pharmacologic phenomena, OX40 Ligand, Biology, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, 0302 clinical medicine, Immune system, Th2 Cells, Antigens, CD, Humans, Lectins, C-Type, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, education, Interleukin 5, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, Interleukin 4, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, education.field_of_study, B-Lymphocytes, Multidisciplinary, Interleukin-13, Cell Differentiation, General Chemistry, Dendritic cell, Dendritic Cells, OX40 ligand, Cell biology, Cell culture, Interleukin 13, Leukocytes, Mononuclear, Interleukin-4, Interleukin-5, [SDV.IMM.ALL] Life Sciences [q-bio]/Immunology/Allergology, 030215 immunology, B-Cell Activation Factor Receptor, Signal Transduction
Abstract

Dendritic cells (DCs) play a critical role in immune homeostasis by regulating the functions of various immune cells, including T and B cells. Notably, DCs also undergo education on reciprocal signalling by these immune cells and environmental factors. Various reports demonstrated that B cells have profound regulatory functions, although only few reports have explored the regulation of human DCs by B cells. Here we demonstrate that activated but not resting B cells induce maturation of DCs with distinct features to polarize Th2 cells that secrete interleukin (IL)-5, IL-4 and IL-13. B-cell-induced maturation of DCs is contact dependent and implicates signalling of B-cell activation molecules CD69, B-cell-activating factor receptor, and transmembrane activator and calcium-modulating cyclophilin ligand interactor. Mechanistically, differentiation of Th2 cells by B-cell-matured DCs is dependent on OX-40 ligand. Collectively, our results suggest that B cells have the ability to control their own effector functions by enhancing the ability of human DCs to mediate Th2 differentiation.

Published
2014
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17. TLR5-Mediated Sensing of Gut Microbiota Is Necessary for Antibody Responses to Seasonal Influenza Vaccination

Author

Mohan S. Maddur, Bali Pulendran, Paul Hakimpour, Andrew T. Gewirtz, Maureen A. Bower, Frederic A. Carvalho, R. Balfour Sartor, Rajesh Ravindran, Kiran Gill, Felix Yarovinsky, Benoit Chassaing, Jason Z. Oh, Helder I. Nakaya, Emory Vaccine Center, Emory University [Atlanta, GA], Georgia State University, University System of Georgia (USG), Neuro-Dol (Neuro-Dol), and Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Influenza vaccine, [SDV]Life Sciences [q-bio], Plasma Cells, Immunology, Yellow fever vaccine, Antibodies, Viral, Article, Microbiology, Mice, Immunity, Influenza, Human, Plasma cell differentiation, Escherichia coli, medicine, Animals, Humans, Immunology and Allergy, ComputingMilieux_MISCELLANEOUS, Mice, Knockout, B-Lymphocytes, biology, Macrophages, Microbiota, Yellow Fever Vaccine, Antibody titer, Cell Differentiation, 3. Good health, Intestines, Mice, Inbred C57BL, Vaccination, Poliovirus Vaccine, Inactivated, Toll-Like Receptor 5, Infectious Diseases, Influenza Vaccines, TLR5, Antibody Formation, biology.protein, Lymph Nodes, Immunologic Memory, Flagellin, Signal Transduction, medicine.drug
Abstract

Summary Systems biological analysis of immunity to the trivalent inactivated influenza vaccine (TIV) in humans revealed a correlation between early expression of TLR5 and the magnitude of the antibody response. Vaccination of Trl5 −/− mice resulted in reduced antibody titers and lower frequencies of plasma cells, demonstrating a role for TLR5 in immunity to TIV. This was due to a failure to sense host microbiota. Thus, antibody responses in germ-free or antibiotic-treated mice were impaired, but restored by oral reconstitution with a flagellated, but not aflagellated, strain of E. coli . TLR5-mediated sensing of flagellin promoted plasma cell differentiation directly and by stimulating lymph node macrophages to produce plasma cell growth factors. Finally, TLR5-mediated sensing of the microbiota also impacted antibody responses to the inactivated polio vaccine, but not to adjuvanted vaccines or the live-attenuated yellow fever vaccine. These results reveal an unappreciated role for gut microbiota in promoting immunity to vaccination.

Published
2014
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18. Innate Immune Sensing and Response to Influenza

Author

Bali Pulendran and Mohan S. Maddur

Subjects
Intrinsic immunity, Innate immune system, Innate lymphoid cell, CCL18, Dendritic Cells, Adaptive Immunity, Biology, Acquired immune system, Virology, Immunity, Innate, Article, Virus, Natural killer cell, Killer Cells, Natural, Mice, medicine.anatomical_structure, Immunity, Influenza, Human, Immunology, medicine, Animals, Humans, Receptors, Virus
Abstract

Influenza viruses pose a substantial threat to human and animal health worldwide. Recent studies in mouse models have revealed an indispensable role for the innate immune system in defense against influenza virus. Recognition of the virus by innate immune receptors in a multitude of cell types activates intricate signaling networks, functioning to restrict viral replication. Downstream effector mechanisms include activation of innate immune cells and, induction and regulation of adaptive immunity. However, uncontrolled innate responses are associated with exaggerated disease, especially in pandemic influenza virus infection. Despite advances in the understanding of innate response to influenza in the mouse model, there is a large knowledge gap in humans, particularly in immunocom-promised groups such as infants and the elderly. We propose here, the need for further studies in humans to decipher the role of innate immunity to influenza virus, particularly at the site of infection. These studies will complement the existing work in mice and facilitate the quest to design improved vaccines and therapeutic strategies against influenza.

Published
2014
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19. Intravenous immunoglobulin expands regulatory T cells via induction of cyclooxygenase-2–dependent prostaglandin E2 in human dendritic cells

Author

Pushpa Hegde, Meenu Sharma, Laurent Magy, Srini V. Kaveri, Jagadeesh Bayry, Jean Michel Vallat, Jamma Trinath, Mohan S. Maddur, Kithiganahalli Narayanaswamy Balaji, Magalie Rabin, Indian Institute of Science, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurologie [CHU Limoges], CHU Limoges, Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Université Sorbonne Paris Cité (USPC), École pratique des hautes études (EPHE), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Bayry, Jagadeesh, and Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE)

Subjects
T-Lymphocytes, Regulatory, Biochemistry, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Immune tolerance, Mice, 0302 clinical medicine, hemic and lymphatic diseases, IL-2 receptor, Prostaglandin E2, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, ComputingMilieux_MISCELLANEOUS, Microbiology & Cell Biology, 0303 health sciences, education.field_of_study, biology, Experimental autoimmune encephalomyelitis, Immunoglobulins, Intravenous, FOXP3, hemic and immune systems, Hematology, 3. Good health, Female, Antibody, [SDV.IMM.ALL] Life Sciences [q-bio]/Immunology/Allergology, medicine.drug, Immunology, Receptors, Cell Surface, chemical and pharmacologic phenomena, Dinoprostone, 03 medical and health sciences, medicine, Animals, Humans, Lectins, C-Type, education, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, 030304 developmental biology, Dendritic Cells, Cell Biology, medicine.disease, Coculture Techniques, In vitro, OX40 ligand, Mice, Inbred C57BL, Disease Models, Animal, Cyclooxygenase 2, Leukocytes, Mononuclear, biology.protein, Cell Adhesion Molecules, 030215 immunology
Abstract

CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) play a critical role in the maintenance of immune tolerance. Intravenous immunoglobulin (IVIg), a therapeutic preparation of normal pooled human IgG, expands Tregs in various experimental models and in patients. However, the cellular and molecular mechanisms by which IVIg expands Tregs are relatively unknown. As Treg expansion in the periphery requires signaling by antigen-presenting cells such as dendritic cells (DCs) and IVIg has been demonstrated to modulate DC functions, we hypothesized that IVIg induces distinct signaling events in DCs that subsequently mediate Treg expansion. We demonstrate that IVIg expands Tregs via induction of cyclooxygenase (COX)-2-dependent prostaglandin E2 (PGE(2)) in human DCs. However, costimulatory molecules of DCs such as programmed death ligands, OX40 ligand, and inducible T-cell costimulator ligands were not implicated. Inhibition of PGE(2) synthesis by COX-2 inhibitors prevented IVIg-mediated Treg expansion in vitro and significantly diminished IVIg-mediated Treg expansion in vivo and protection from disease in experimental autoimmune encephalomyelitis model. IVIg-mediated COX-2 expression, PGE(2) production, and Treg expansion were mediated in part via interaction of IVIg and F(ab('))(2) fragments of IVIg with DC-specific intercellular adhesion molecule-3-grabbing nonintegrin. Our results thus uncover novel cellular and molecular mechanism by which IVIg expands Tregs.

Published
2013
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20. Dual role of CpG-stimulated B cells in the regulation of dendritic cells: comment on the article by Berggren et al

Author

Mohan S. Maddur, Jagadeesh Bayry, and Srini V. Kaveri

Subjects
0303 health sciences, B-Lymphocytes, Immunology, Interferon-alpha, Dendritic Cells, Biology, Cell biology, 03 medical and health sciences, 0302 clinical medicine, Dual role, Rheumatology, CpG site, Immunology and Allergy, Humans, Pharmacology (medical), 030304 developmental biology, 030215 immunology
Published
2013

21. Inhibitory Effect of IVIG on IL-17 Production by Th17 Cells is Independent of Anti-IL-17 Antibodies in the Immunoglobulin Preparations

Author

Meenu Sharma, Sébastien Lacroix-Desmazes, Jagadeesh Bayry, Mohan S. Maddur, Srini V. Kaveri, Pushpa Hegde, Bayry, Jagadeesh, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Université Sorbonne Paris Cité (USPC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), École Pratique des Hautes Études (EPHE), and Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE)

Subjects
CD4-Positive T-Lymphocytes, medicine.medical_treatment, Immunology, Interleukin-23, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Neutralization, Antibodies, Pathogenesis, 03 medical and health sciences, 0302 clinical medicine, Intracellular signaling pathways, hemic and lymphatic diseases, Interleukin 23, medicine, Immunology and Allergy, Humans, Immunologic Factors, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, Inhibitory effect, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, biology, Chemistry, Interleukin-17, Immunoglobulins, Intravenous, Cell Differentiation, 3. Good health, Cytokine, biology.protein, Th17 Cells, Interleukin 17, Antibody, [SDV.IMM.ALL] Life Sciences [q-bio]/Immunology/Allergology, 030215 immunology
Abstract

Purpose Th17 cells and their cytokines play a critical role in the pathogenesis of various autoimmune and inflammatory diseases. Recently, we have demonstrated that intravenous immunoglobulin (IVIG) suppresses differentiation, amplification, and functions of human Th17 cells. In this report we investigated whether IVIG inhibits IL-17 production by Th17 cells cultured in the presence of IL-23 and whether the inhibitory effect of IVIG on IL-17 production implicates anti-IL-17 antibodies. Methods Naive CD4 + T cells were stimulated in the presence of TGF-β, IL-21, and IL-23 for the differentiation of Th17 cells. Memory CD4 + T cells were stimulated with IL1β, IL-6, and IL-23 for the amplification of Th17 cells. IVIG (0.15 mM) was added to the cells 12 h after initiation of cultures. IL-17A cytokine and anti-IL-17 antibodies were measured by ELISA. Results IL-23 did not deter the inhibitory effect of IVIG on IL-17 production from the differentiating and expanding Th17 cells. Further, suppression of IL-17 by IVIG did not implicate anti-IL-17 antibodies in the immunoglobulin preparations. Conclusion The effect of IVIG on the inhibition of IL-17 production by Th17 cells is a consequence of modulation of Th17 cells and their intracellular signaling pathways and not due to passive neutralization of IL-17 by anti-IL-17 antibodies in the immunoglobulin preparations.

Published
2013
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22. Circulating human basophils lack the features of professional antigen presenting cells

Author

Pascal Poncet, Meenu Sharma, Mohan S. Maddur, Pushpa Hegde, Jean-Paul Latgé, Jagadeesh Bayry, Srini V. Kaveri, Rémi Beau, Vishukumar Aimanianda, Hélène Sénéchal, U872 Centre de Recherche des Cordeliers, Nutriomique, Équipe 7, Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Technologie de Compiègne (UTC), Aspergillus, Institut Pasteur [Paris] (IP), Laboratoire Colloïdes et Matériaux Divisés (LCMD), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Département Infection et Epidémiologie - Department of Infection and Epidemiology, Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Supported by European Community’s Seventh Framework Programme [FP7/2007–2013] under Grant Agreement No: 260338 ALLFUN and ANR-10-BLAN-1309 HYDROPHOBIN., ANR-10-BLAN-1309,HYDROPHOBIN,HYDROPHOBINE DES CONIDIES d'Aspergillus fumigatus : ANALYSE STRUCTURALE ET REPONSE IMMUNE(2010), European Project: 260338,EC:FP7:HEALTH,FP7-HEALTH-2010-single-stage,ALLFUN(2010), HAL-UPMC, Gestionnaire, BLANC - HYDROPHOBINE DES CONIDIES d'Aspergillus fumigatus : ANALYSE STRUCTURALE ET REPONSE IMMUNE - - HYDROPHOBIN2010 - ANR-10-BLAN-1309 - BLANC - VALID, Fungi in the setting of inflammation, allergy and autoimmune diseases:Translating basic science into clinical practices - ALLFUN - - EC:FP7:HEALTH2010-12-01 - 2014-05-31 - 260338 - VALID, Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Institut Pasteur [Paris], Centre National de la Recherche Scientifique (CNRS)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
CD4-Positive T-Lymphocytes, T cell, Antigen-Presenting Cells, chemical and pharmacologic phenomena, Biology, Immunoglobulin E, Peripheral blood mononuclear cell, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Article, Monocytes, Fungal Proteins, 03 medical and health sciences, 0302 clinical medicine, Antigen, parasitic diseases, medicine, Humans, Antigen-presenting cell, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, Interleukin 4, 030304 developmental biology, 0303 health sciences, MHC class II, Multidisciplinary, hemic and immune systems, Dendritic Cells, HLA-DR Antigens, Allergens, Antigens, Plant, Coculture Techniques, Recombinant Proteins, Basophils, medicine.anatomical_structure, Immunology, B7-1 Antigen, biology.protein, B7-2 Antigen, Interleukin-4, CD80, 030215 immunology
Abstract

International audience; Recent reports in mice demonstrate that basophils function as antigen presenting cells (APC). They express MHC class II and co-stimulatory molecules CD80 and CD86, capture and present soluble antigens or IgE-antigen complexes and polarize Th2 responses. Therefore, we explored whether human circulating basophils possess the features of professional APC. We found that unlike dendritic cells (DC) and monocytes, steady-state circulating human basophils did not express HLA-DR and co-stimulatory molecules CD80 and CD86. Basophils remained negative for these molecules following stimulation with soluble Asp f 1, one of the allergens of Aspergillus fumigatus; Bet v 1, the major birch allergen; TLR2-ligand or even upon IgE cross-linking. Unlike DC, Asp f 1-pulsed basophils did not promote Th2 responses as analyzed by the secretion of IL-4 in the basophil-CD4+ T cell co-culture. Together, these results demonstrate the inability of circulating human basophils to function as professional APC.

Published
2013
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23. Inhibition of differentiation, amplification, and function of human TH17 cells by intravenous immunoglobulin

Author

Mohan S. Maddur, Pushpa Hegde, Janakiraman Vani, Srini V. Kaveri, Sébastien Lacroix-Desmazes, Jagadeesh Bayry, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Université Sorbonne Paris Cité (USPC), Bayry, Jagadeesh, Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), École Pratique des Hautes Études (EPHE), and Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE)

Subjects
Immunology, Biology, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, 03 medical and health sciences, Interleukin 21, 0302 clinical medicine, Humans, Immunology and Allergy, Cytotoxic T cell, IL-2 receptor, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, Antigen-presenting cell, STAT4, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, ComputingMilieux_MISCELLANEOUS, Cell Proliferation, 030304 developmental biology, Interleukin 3, 0303 health sciences, ZAP70, Immunoglobulins, Intravenous, Cell Differentiation, Natural killer T cell, 3. Good health, Cytokines, Th17 Cells, [SDV.IMM.ALL] Life Sciences [q-bio]/Immunology/Allergology, Signal Transduction, 030215 immunology
Abstract

Background T H 17 cells play a critical role in the pathogenesis of several autoimmune and allergic diseases. Intravenous immunoglobulin (IVIg), a therapeutic preparation of polyclonal IgG that is increasingly used in the treatment of diverse autoimmune and allergic diseases, might target T H 17 cells to exert therapeutic effects. Objective We sought to examine whether IVIg interferes with the development and function of human T H 17 cells. Methods T H 17 cells were differentiated from naive human CD4 + T cells in the presence of TGF-β and IL-21. T H 17 cells were amplified by stimulating memory CD4 + T cells in the presence of IL-1β and IL-6. The effect of IVIg was examined on the differentiation and amplification of T H 17 cells, expression of the T H 17 lineage-specific transcription factor retinoic acid-related orphan receptor C, secretion of T H 17 effector cytokines, and phosphorylation of signal transducer and activator of transcription 3, a transcription factor that plays an important role in T H 17 cell development and function. Results IVIg inhibits the differentiation and amplification of human T H 17 cells, as well as the production of their effector cytokines IL-17A, IL-17F, IL-21, and CCL20. The inhibitory effects of IVIg on T H 17 cells are F(ab′) 2 dependent and involve interference with the expression of retinoic acid-related orphan receptor C and activation of signal transducer and activator of transcription 3. Also, IVIg significantly enhanced forkhead box protein 3–positive regulatory T cells among the memory CD4 + T cells. Conclusion These results reveal a novel mechanism of action of IVIg in achieving a therapeutic effect in autoimmune and allergic diseases, in which T H 17 cells play a key modulatory role in sustaining the chronic inflammatory response. Our results also suggest a reciprocal regulation of T H 17 and regulatory T-cell populations by IVIg.

Published
2011
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24. Intravenous immunoglobulin induces proliferation and immunoglobulin synthesis from B cells of pathients wit common variable immunodeficiency: a mechanism underlying the beneficial effect of IVIg in primary immunodeficiencies

Author

Olivier Hermine, Bharath Wootla, Luc Mouthon, Yoann Crabol, Janakiraman Vani, Sophie Sibéril, Jordan D. Dimitrov, Yves Levy, Sébastien Lacroix-Desmazes, Jagadeesh Bayry, Emilie M. Fournier, Mikael Berdah, Eric Oksenhendler, Srini V. Kaveri, Catherine Sautès-Fridman, Mohan S. Maddur, Slama, Catherine, Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Université Sorbonne Paris Cité (USPC), Institut National de la Santé et de la Recherche Médicale (INSERM), Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Department of Neurology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Immunopathologie Clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Supported by grants from Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Université Pierre et Marie Curie, Université Paris Descartes and Laboratoire Français du Fractionnement et des Biotechnologies, France. France IVIg (Tegeline®) is a kind gift from Laboratoire Français du Fractionnement et des Biotechnologies, France., Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), École Pratique des Hautes Études (EPHE), Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Department of Structural Biology, Weizmann Institute, Cytokines, hématopoïèse et réponse immune (CHRI), Bayry, Jagadeesh, Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Université de Lyon - Université de Lyon - Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre de référence français pour les maladies auto-immunes et systémiques rares [Hôpital Pitié-Salpêtrière - APHP], Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [APHP], and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)

Subjects
Adult, Male, medicine.medical_treatment, Immunology, Cell Separation, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Flow cytometry, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Immune system, hemic and lymphatic diseases, medicine, Immunology and Allergy, Humans, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, Transcription factor, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, B cell, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Aged, Cell Proliferation, 0303 health sciences, B-Lymphocytes, biology, medicine.diagnostic_test, Effector, business.industry, Common variable immunodeficiency, Immunoglobulins, Intravenous, Middle Aged, medicine.disease, Flow Cytometry, 3. Good health, Cytokine, medicine.anatomical_structure, Common Variable Immunodeficiency, Antibody Formation, biology.protein, Female, Antibody, business, [SDV.IMM.ALL] Life Sciences [q-bio]/Immunology/Allergology, 030215 immunology
Abstract

International audience; Common variable immunodeficiency (CVID) is associated with low serum immunoglobulin concentrations and an increased susceptibility to infections and autoimmune diseases. The treatment of choice for CVID patients is replacement intravenous immunoglobulin (IVIg) therapy. IVIg has been beneficial in preventing or alleviating the severity of infections and autoimmune and inflammatory process in majority of CVID patients. Although the mechanisms of action of IVIg given as 'therapeutic high dose' in patients with autoimmune diseases are well studied, the underlying mechanisms of beneficial effects of IVIg in primary immunodeficiencies are not completely understood. Therefore we investigated the effect of 'replacement dose' of IVIg by probing its action on B cells from CVID patients. We demonstrate that IVIg at low doses induces proliferation and immunoglobulin synthesis from B cells of CVID patients. Interestingly, B cell stimulation by IVIg is not associated with induction of B cell effector cytokine IFN-γ and of transcription factor T-bet. Together, our results indicate that in some CVID patients, IVIg rectifies the defective signaling of B cells normally provided by T cells and delivers T-independent signaling for B cells to proliferate. IVIg 'replacement therapy' in primary immunodeficiencies is therefore not a merepassive transfer of antibodies to prevent exclusively the recurrent infections; rather it has an active role in regulating autoimmune and inflammatory responses through modulating B cell functions and thus imposing dynamic equilibrium of the immune system.

Published
2011
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25. Viscum album exerts anti-inflammatory effect by selectively inhibiting cytokine-induced expression of cyclooxygenase-2

Author

Jagadeesh Bayry, Mohan S. Maddur, Alain Friboulet, Srini V. Kaveri, Pushpa Hegde, Génie Enzymatique et Cellulaire (GEC), and Université de Technologie de Compiègne (UTC)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Angiogenesis, medicine.medical_treatment, Interleukin-1beta, Anti-Inflammatory Agents, lcsh:Medicine, Pharmacology, 0302 clinical medicine, lcsh:Science, 0303 health sciences, Multidisciplinary, biology, Chemistry, 3. Good health, Cytokine, 030220 oncology & carcinogenesis, Cytokines, Medicine, medicine.symptom, Research Article, Drugs and Devices, Viscum album, medicine.drug_class, Immunology, Inflammation, Immunopathology, Immune Suppression, Dinoprostone, Gene Expression Regulation, Enzymologic, Anti-inflammatory, Immunomodulation, 03 medical and health sciences, Complementary and Alternative Medicine, Cell Line, Tumor, medicine, Humans, Immunoassays, Biology, 030304 developmental biology, A549 cell, Plant Extracts, lcsh:R, Immunity, Immunoregulation, biology.organism_classification, Mechanism of action, Cyclooxygenase 2, Cell culture, Immune System, Immunologic Techniques, Clinical Immunology, lcsh:Q
Abstract

International audience; Viscum album (VA) preparations are extensively used as complementary therapy in cancer and are shown to exert anti-tumor activities which involve the cytotoxic properties, induction of apoptosis, inhibition of angiogenesis and several other immunomodulatory mechanisms. In addition to their application in cancer therapy, VA preparations have also been successfully utilized in the treatment of several inflammatory pathologies. Owing to the intricate association of inflammation and cancer and in view of the fact that several anti-tumor phytotherapeutics also exert a potent anti-inflammatory effect, we hypothesized that VA exerts an anti-inflammatory effect that is responsible for its therapeutic benefit. Since, inflammatory cytokine-induced cyclo-oxygenase-2 (COX-2) and prostaglandin E2 (PGE2) play a critical role in the pathogenesis of inflammatory diseases, we investigated the anti-inflammatory effect of VA on regulation of cyclo-oxygenase expression and PGE2 biosynthesis by using human lung adenocarcinoma cells (A549 cells) as a model. A549 cells were stimulated with IL-1β and treated with VA preparation (VA Qu Spez) for 18 hours. PGE2 was analysed in the culture supernatants by enzyme immunoassay. Expression of COX-2 and COX-1 proteins was analyzed by immunoblotting and the expression of COX-2 mRNA was assessed by semi-quantitative RT-PCR. We found that VA Qu Spez inhibit the secretion of IL-1β-induced PGE2 in a dose-dependent manner. Further, we also show that this inhibitory action was associated with a reduced expression of COX-2 without modulating the COX-1 expression. Together these results demonstrate a novel anti-inflammatory mechanism of action of VA preparations wherein VA exerts an anti-inflammatory effect by inhibiting cytokine-induced PGE2 via selective inhibition of COX-2.

Published
2011

26. Autoimmunity as a Predisposition for Infectious Diseases

Author

Sébastien Lacroix-Desmazes, Janakiraman Vani, Jagadeesh Bayry, Srinivas V. Kaveri, and Mohan S. Maddur

Subjects
lcsh:Immunologic diseases. Allergy, Opinion, Immunology, Inflammation, Autoimmunity, Biology, medicine.disease_cause, Microbiology, Communicable Diseases, Pathogenesis, Immune system, Virology, Genetics, medicine, Humans, Genetic Predisposition to Disease, Molecular Biology, Pathological, lcsh:QH301-705.5, Cytokine Therapy, Autoantibody, Infectious Diseases, lcsh:Biology (General), biology.protein, Parasitology, Antibody, medicine.symptom, lcsh:RC581-607
Abstract

Autoimmunity refers to an inappropriate immune response against self-components of the host that results in pathological conditions. Autoimmune diseases are characterized by an activation of autoreactive T and B cells, are associated in some cases with the production of pathogenic autoantibodies against self-molecules, culminating in inflammation and tissue damage. The reasons for the breakdown of tolerance mechanisms leading to autoimmunity are not clearly known. However, a combination of genetic, immunological, and environmental factors plays a critical role in the pathogenesis of autoimmunity [1]–[5].

Published
2010

27. Contribution of myeloid dendritic cells to type I interferon-induced cytokines and chemokines: comment on the article by Bilgic et al

Author

Mohan S, Maddur, Janakiraman, Vani, Sébastien, Lacroix-Desmazes, Srini V, Kaveri, and Jagadeesh, Bayry

Subjects
Interferon Type I, Gene Expression, Humans, RNA-Binding Proteins, Bone Marrow Cells, Dendritic Cells, Chemokines, Carrier Proteins, Biomarkers, Cells, Cultured, Dermatomyositis, Adaptor Proteins, Signal Transducing, Autoimmune Diseases
Published
2010

28. Immunomodulation by Intravenous Immunoglobulin: Role of Regulatory T Cells

Author

Pushpa Hegde, Srini V. Kaveri, Shivashankar Othy, Janakiraman Vani, Mohan S. Maddur, Sébastien Lacroix-Desmazes, Jagadeesh Bayry, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Université Sorbonne Paris Cité (USPC), Bayry, Jagadeesh, École Pratique des Hautes Études (EPHE), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Encephalomyelitis, Autoimmune, Experimental, Immunology, chemical and pharmacologic phenomena, Inflammation, T-Lymphocytes, Regulatory, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Autoimmune Diseases, 03 medical and health sciences, Mice, 0302 clinical medicine, hemic and lymphatic diseases, medicine, Immunology and Allergy, Animals, Humans, Immunologic Factors, In patient, Immune homeostasis, IL-2 receptor, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, Mode of action, Beneficial effects, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Immunity, Cellular, biology, business.industry, Models, Immunological, FOXP3, Immunoglobulins, Intravenous, hemic and immune systems, Adoptive Transfer, 3. Good health, biology.protein, medicine.symptom, Antibody, business, [SDV.IMM.ALL] Life Sciences [q-bio]/Immunology/Allergology, 030215 immunology
Abstract

An altered immune homeostasis as a result of deficiency or defective function of CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) is common in several autoimmune diseases. Hence, therapeutic strategies to render Tregs functionally competent are being investigated. Intravenous immunoglobulin (IVIG) is being increasingly used for the treatment of a wide range of autoimmune and inflammatory diseases. Recent studies have demonstrated that IVIG induces the expansion of Tregs and enhances their suppressive functions. These effects of IVIG on Tregs correlate with the beneficial effects of IVIG in patients with autoimmune diseases. Thus, modulation of Tregs by IVIG represents a novel mode of action that explains the therapeutic effects of IVIG in T cell-mediated autoimmune diseases. However, the molecular mechanisms involved in IVIG-mediated modulation of Tregs are unclear and need further investigation.

Published
2010
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29. Regulation of human dendritic cells by B cells depends on the signals they receive

Author

Srini V. Kaveri, Jagadeesh Bayry, and Mohan S. Maddur

Subjects
B-Lymphocytes, 0303 health sciences, CD40, biology, Immunology, Antigen presentation, Cell Communication, Dendritic Cells, Cell Biology, Hematology, Biochemistry, 3. Good health, Cell biology, 03 medical and health sciences, 0302 clinical medicine, Immune system, biology.protein, Interleukin 12, Humans, Antibody, Cells, Cultured, Signal Transduction, 030304 developmental biology, 030215 immunology
Abstract

To the editor: B cells are classically known for producing antibodies. However, several reports also indicate that B cells are potent regulators of immune responses including those mediated by dendritic cells (DCs), although direct effect of B cells on DC was relatively unexplored.[1][1][⇓][2

Published
2012
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