INNATE AND ADAPTIVE IMMUNE RESPONSES IN TH2-HIGH ASTHMA

Summary

Principal Investigator: John V Fahy
Abstract: This proposal for a collaborative Program Project Grant (PPG) focuses on mechanisms of TH2 inflammation in asthma. The unifying hypotheses are: (i) TH2 inflammation underlies the most common molecular phenotypes of asthma;(11) Epithelial cells secrete cytokines and chemokines to initiate and amplify TH2 inflammation in the airway;(ill) Innate helper type 2 (IH2) cells and CD4+T cells are key cellular targets of epithelial cytokines and chemokines and principal sources of TH2 cytokines in the airway. Project 1 will focus on the role of iH2 cells as proximal regulators of TH2 inflammation in the airway. This project proposes to characterize markers for these cells, delineate their role in allergic airway responses and collaborate with investigators in Project 3 to advance understanding of iH2 cells in human asthma. Project 2 will identify the miRNAs that regulate helper T cell functions relevant to asthma, examine miRNA expression patterns in CD4+T cells and iH2 cells in clinical samples from asthmatic patients, and characterize the mRNA targets and In vivo function of select miRNAs. Project 3 will investigate the role of Innate helper type 2 cells as cellular mediators of TH2-high asthma, determine how IL-33 amplifies TH2 inflammation in acute severe asthma, and explore how genetic variation in ST2 modulates airway TH2 inflammation in asthma. These projects will be supported by three cores, which will provide administrative support, access to high quality biospecimens from well-characterized asthmatic subjects and healthy controls, and expert biostatistical and bioinformatic support. The PPG represents a collaborative program of research that brings together mechanism-oriented clinical researchers from UCSF's Airway Clinical Research Center (ACRC) (Fahy and Woodruff) with disease-oriented basic immunologists from UCSF's Sandler Asthma Basic Research Center (SABRE) (Locksley and Ansel) Together, these investigators will work collaboratively using a variety of experimental approaches. Including studies in human biospecimens in a PPG that promises to advance understanding of airway TH2 inflammation in ways that are highly relevant to patients with asthma.
Funding Period: 2012-08-15 - 2017-05-31
more information: NIH RePORT

Top Publications

  1. pmc Interleukin-4- and interleukin-13-mediated alternatively activated macrophages: roles in homeostasis and disease
    Steven J Van Dyken
    Departments of Medicine and Microbiology and Immunology, Howard Hughes Medical Institute, University of California, San Francisco, California 94143, USA
    Annu Rev Immunol 31:317-43. 2013
  2. pmc Asthma: NHLBI Workshop on the Primary Prevention of Chronic Lung Diseases
    Daniel J Jackson
    1 Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
    Ann Am Thorac Soc 11:S139-45. 2014
  3. pmc Chitin activates parallel immune modules that direct distinct inflammatory responses via innate lymphoid type 2 and γδ T cells
    Steven J Van Dyken
    Howard Hughes Medical Institute and Departments of Medicine, Microbiology, and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA
    Immunity 40:414-24. 2014
  4. pmc MicroRNA regulation of the germinal center response
    Dirk Baumjohann
    Department of Microbiology and Immunology, Sandler Asthma Basic Research Center, University of California San Francisco, San Francisco, CA 94143, USA Electronic address
    Curr Opin Immunol 28:6-11. 2014
  5. pmc Measures of gene expression in sputum cells can identify TH2-high and TH2-low subtypes of asthma
    Michael C Peters
    Division of Pulmonary and Critical Care Medicine, University of California, San Francisco, Calif Cardiovascular Research Institute, University of California, San Francisco, Calif
    J Allergy Clin Immunol 133:388-94. 2014
  6. pmc Type 2 innate lymphoid cells control eosinophil homeostasis
    Jesse C Nussbaum
    Department of Medicine, University of California San Francisco, San Francisco, California 94143 0795, USA
    Nature 502:245-8. 2013
  7. pmc Type 2 innate lymphoid cells constitutively express arginase-I in the naive and inflamed lung
    Jennifer K Bando
    1 UCSF, 513 Parnassus Ave, S 1004, San Francisco, CA 94143, USA
    J Leukoc Biol 94:877-84. 2013
  8. pmc MicroRNA-mediated regulation of T helper cell differentiation and plasticity
    Dirk Baumjohann
    Department of Microbiology and Immunology, Sandler Asthma Basic Research Center, University of California, San Francisco, California 94143, USA
    Nat Rev Immunol 13:666-78. 2013
  9. pmc The microRNA cluster miR-17∼92 promotes TFH cell differentiation and represses subset-inappropriate gene expression
    Dirk Baumjohann
    Department of Microbiology and Immunology, Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, California, USA
    Nat Immunol 14:840-8. 2013
  10. pmc Regulation of miRNA biogenesis and turnover in the immune system
    Yelena Bronevetsky
    Department of Microbiology and Immunology, Sandler Asthma Basic Research Center, University of California San Francisco, San Francisco, CA, USA
    Immunol Rev 253:304-16. 2013

Research Grants

  1. CHEMISTRY AND BIOLOGY OF HEPARAN SULFATE
    UMESH RAMANLAL DESAI; Fiscal Year: 2013
  2. CENTER FOR BIOMEDICAL RESEARCH
    Timothy Turner; Fiscal Year: 2013
  3. Neuro-Circulatory Function in Chronic Heart Failure
    Irving H Zucker; Fiscal Year: 2013
  4. Neutralizing Antibody &AAV FIX Gene Therapy
    Richard J Samulski; Fiscal Year: 2013
  5. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
  6. INTEGRATED MECHANISMS OF CARDIAC MALADAPTATION
    R John Solaro; Fiscal Year: 2013
  7. UNMC EPPLEY CANCER CENTER SUPPORT GRANT
    Kenneth H Cowan; Fiscal Year: 2013
  8. Glycan Modulation of Inflammatory Responses
    Ajit P Varki; Fiscal Year: 2013
  9. Thrombus Formation and Antithrombotic Intervention
    John H Griffin; Fiscal Year: 2013

Detail Information

Publications14

  1. pmc Interleukin-4- and interleukin-13-mediated alternatively activated macrophages: roles in homeostasis and disease
    Steven J Van Dyken
    Departments of Medicine and Microbiology and Immunology, Howard Hughes Medical Institute, University of California, San Francisco, California 94143, USA
    Annu Rev Immunol 31:317-43. 2013
    ....
  2. pmc Asthma: NHLBI Workshop on the Primary Prevention of Chronic Lung Diseases
    Daniel J Jackson
    1 Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
    Ann Am Thorac Soc 11:S139-45. 2014
    ....
  3. pmc Chitin activates parallel immune modules that direct distinct inflammatory responses via innate lymphoid type 2 and γδ T cells
    Steven J Van Dyken
    Howard Hughes Medical Institute and Departments of Medicine, Microbiology, and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA
    Immunity 40:414-24. 2014
    ....
  4. pmc MicroRNA regulation of the germinal center response
    Dirk Baumjohann
    Department of Microbiology and Immunology, Sandler Asthma Basic Research Center, University of California San Francisco, San Francisco, CA 94143, USA Electronic address
    Curr Opin Immunol 28:6-11. 2014
    ....
  5. pmc Measures of gene expression in sputum cells can identify TH2-high and TH2-low subtypes of asthma
    Michael C Peters
    Division of Pulmonary and Critical Care Medicine, University of California, San Francisco, Calif Cardiovascular Research Institute, University of California, San Francisco, Calif
    J Allergy Clin Immunol 133:388-94. 2014
    ..Little is known about the utility of gene profiling in sputum as a molecular phenotyping method...
  6. pmc Type 2 innate lymphoid cells control eosinophil homeostasis
    Jesse C Nussbaum
    Department of Medicine, University of California San Francisco, San Francisco, California 94143 0795, USA
    Nature 502:245-8. 2013
    ....
  7. pmc Type 2 innate lymphoid cells constitutively express arginase-I in the naive and inflamed lung
    Jennifer K Bando
    1 UCSF, 513 Parnassus Ave, S 1004, San Francisco, CA 94143, USA
    J Leukoc Biol 94:877-84. 2013
    ..brasiliensis infection. Thus, ILC2s are a novel source of Arg1 in resting tissue and during allergic inflammation. ..
  8. pmc MicroRNA-mediated regulation of T helper cell differentiation and plasticity
    Dirk Baumjohann
    Department of Microbiology and Immunology, Sandler Asthma Basic Research Center, University of California, San Francisco, California 94143, USA
    Nat Rev Immunol 13:666-78. 2013
    ....
  9. pmc The microRNA cluster miR-17∼92 promotes TFH cell differentiation and represses subset-inappropriate gene expression
    Dirk Baumjohann
    Department of Microbiology and Immunology, Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, California, USA
    Nat Immunol 14:840-8. 2013
    ..Our results identify the miR-17∼92 cluster as a critical regulator of T cell-dependent antibody responses, TFH cell differentiation and the fidelity of the TFH cell gene-expression program. ..
  10. pmc Regulation of miRNA biogenesis and turnover in the immune system
    Yelena Bronevetsky
    Department of Microbiology and Immunology, Sandler Asthma Basic Research Center, University of California San Francisco, San Francisco, CA, USA
    Immunol Rev 253:304-16. 2013
    ..A better understanding of these processes and their regulation by immunogenic stimuli is critical for integrating miRNAs into current models of gene expression networks that determine cell identity and immune function...
  11. pmc Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages
    Ari B Molofsky
    Howard Hughes Medical Institute, University of California, San Francisco, San Francisco 94143, USA
    J Exp Med 210:535-49. 2013
    ..Thus, ILC2s are resident in VAT and promote eosinophils and AAM implicated in metabolic homeostasis, and this axis is enhanced during Th2-associated immune stimulation...
  12. pmc Eri1: a conserved enzyme at the crossroads of multiple RNA-processing pathways
    Molly F Thomas
    Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA 94143, USA Sandler Asthma Basic Research Center, University of California San Francisco, San Francisco, CA 94143, USA
    Trends Genet 30:298-307. 2014
    ..This emerging view highlights the possibility for crosstalk and coregulation of diverse cellular processes regulated by RNA. ..

Research Grants30

  1. CHEMISTRY AND BIOLOGY OF HEPARAN SULFATE
    UMESH RAMANLAL DESAI; Fiscal Year: 2013
    ..End of Abstract) ..
  2. CENTER FOR BIOMEDICAL RESEARCH
    Timothy Turner; Fiscal Year: 2013
    ..abstract_text> ..
  3. Neuro-Circulatory Function in Chronic Heart Failure
    Irving H Zucker; Fiscal Year: 2013
    ..The role of exercise training in modulating ROS generation and antioxidant enzymes in animals with CHF will also be investigated in this project. ..
  4. Neutralizing Antibody &AAV FIX Gene Therapy
    Richard J Samulski; Fiscal Year: 2013
    ..The long-term objective of this PPG is to advance basic understanding of vector-cell-animal model interactions for safe gene delivery. ..
  5. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..
  6. INTEGRATED MECHANISMS OF CARDIAC MALADAPTATION
    R John Solaro; Fiscal Year: 2013
    ..Studies proposed here offer the potential for novel diagnostic procedures early in the progression of the disorders, and targets for novel therapies. (End of Abstract) ..
  7. UNMC EPPLEY CANCER CENTER SUPPORT GRANT
    Kenneth H Cowan; Fiscal Year: 2013
    ....
  8. Glycan Modulation of Inflammatory Responses
    Ajit P Varki; Fiscal Year: 2013
    ..abstract_text> ..
  9. Thrombus Formation and Antithrombotic Intervention
    John H Griffin; Fiscal Year: 2013
    ..New knowledge will contribute to improving prevention, diagnosis and treatment of relevant diseases related to thrombosis. ..