Th1 and Th17 Mediators in Experimental Emphysema

Summary

Principal Investigator: Farrah Kheradmand
Abstract: DESCRIPTION (provided by applicant): Lung-associated antigen presenting cells (APCs) detect innumerable toxins that enter the distal airspaces with each breath. Whether they quell or incite inflammation upon acute sensing of pollutants could be of important consequence. Specifically ineffective APC function results in immune tolerance, chronic infections, or cancer, whereas aberrant processing of antigen can induce autoimmunity. We have demonstrated that a subtype of smokers who develop emphysema harbor autoimmune inflammation, characterized by the presence of elastin- specific T helper type 1 (Th1) and Th17 cells. Antigen specific T cells induce matrix metalloproteinase (MMP) 12 secretion in the lung that inhibits alpha 1 anti-trypsin (A1AT), thereby unleashing the activity of neutrophil elastase that cleaves elastin and weakens lung parenchyma. However, the immune events leading to the activation of Th1 and Th17 cells and emphysema through cigarette smoke remain obscure. Further, even among smokers, there exists large phenotypic variability suggesting that modifier genes and environmental exposures together exert a combined effect. We have found that lung APCs isolated from mice with emphysema can induce inflammatory cytokines, and cause emphysema when transferred to na[unreadable]ve mice. Gene microarray analysis of lung APCs and our additional preliminary data suggest the presence of a regulatory relationship between the aryl hydrocarbon receptor (AhR), osteopontin (SPP1), and peroxisome proliferator- activated receptor gamma (PPAR-?), an anti-inflammatory transcription factor. Therefore, we hypothesize that tobacco smoke induces Th1 and Th17 cells through unique innate and adaptive immune mechanisms operative in lung APCs. We propose using a preclinical model of emphysema to i) Determine the sentinel role of the aryl hydrocarbon receptor in APC-induced pathogenic T cell activation in emphysema, and to ii) Determine the role of PPAR-?-osteopontin in cigarette smoke-dependent APC maturation and pathogenic Th1 and Th17 cell differentiation. This application captures some of the critical initiation events in smoke-induced inflammation and applies this knowledge to explore new therapeutic options in emphysema.
Funding Period: 2013-08-01 - 2017-06-30
more information: NIH RePORT

Top Publications

  1. pmc Essential role for autophagy in the maintenance of immunological memory against influenza infection
    Min Chen
    Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA
    Nat Med 20:503-10. 2014

Detail Information

Publications2

  1. pmc Essential role for autophagy in the maintenance of immunological memory against influenza infection
    Min Chen
    Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA
    Nat Med 20:503-10. 2014
    ..Our results suggest that autophagy is essential for the survival of virus-specific memory B cells in mice and the maintenance of protective antibody responses required to combat infections. ..

Research Grants30

  1. Mental Stress Ischemia: Prognosis and Genetic Influences
    Arshed A Quyyumi; Fiscal Year: 2013
    ....
  2. VASCULAR RELATIONS OF BLOOD CELLS AND PROTEINS
    Richard E Waugh; Fiscal Year: 2013
    ..The underlying mechanisms for these involve mechanical forces, molecular interactions and cellular properties acting synergistically in ways that are uniquely addressed by this program. ..
  3. Role of PPAR-gamma in Smoking-induced COPD Progression and Steroid Resistance
    Raju C Reddy; Fiscal Year: 2013
    ..It would also establish the feasibility of an innovative approach to restoring therapeutic glucocorticoid sensitivity, thereby promoting PPAR-g-glucocorticoid synergy, in COPD and potentially in other steroid-resistant diseases. ..
  4. Microbiome in COPD
    Rubin M Tuder; Fiscal Year: 2013
    ....
  5. Novel Anti-inflammatory Activities For ADAM8 In Pulmonary Emphysema
    Caroline A Owen; Fiscal Year: 2013
    ..Our studies may also identify ADAM8 as a novel target for developing therapeutic strategies to limit lung destruction and disease progression in patients with COPD. ..
  6. Dendritic cell directed T cell negative regulation for treating autoimmunity
    Chenthamarakshan Vasu; Fiscal Year: 2013
    ..Our study will have an immense impact on approaches to treat autoimmunity without risking opportunistic infections as well as by eliminating the need for a life-long treatment using general immunosuppressive agents. ..
  7. Oxidation in Inflammation and Cardiovascular Disease
    Stanley L Hazen; Fiscal Year: 2013
    ..It may also lead to important insights for atherosclerosis risk assessment, diagnosis and therapy. ..
  8. Immune-Based Interventions Against Infectious Diseases
    Alan L Rothman; Fiscal Year: 2013
    ..3. Recruit promising junior investigators and provide mentoring by established NIH-funded researchers. 4. Support a multidisciplinary research program led by junior investigators in translational infectious diseases immunology. ..
  9. PPAR gamma as a therapeutic target in COPD
    Thomas J Mariani; Fiscal Year: 2013
    ....
  10. Immunologic and Molecular Phenotypes in AATD and Sarcoidosis
    Lisa A Maier; Fiscal Year: 2013
    ..Finally, the data and information for the GRADS U01 that will be available in the public domain to be used by other investigators for future study of disease mechanisms and susceptibility. ..
  11. Distinct and Overlapping Pathways of Fibrosis and Emphysema in Cigarette Smokers
    Augustine M Choi; Fiscal Year: 2013
    ..4) Clinical Outcomes and Molecular Phenotypes in Smokers with Parenchymal Lung Disease Cores: 1) Administrative Core 2) Respiratory Computational Discovery Core 3) Clinical Biorepository Core 4) Murine Models and Molecular Analysis Core ..
  12. Biosynthesis and Function of Lactosaminyl Glycans in Hematopoiesis
    Robert Sackstein; Fiscal Year: 2013
    ..This research effort should yield new treatments to improve marrow function in such conditions. (End of Abstract) ..
  13. Cigarette Smoke-derived Electrophilic Aldehydes and Airway Inflammation
    Albert van Der Vliet; Fiscal Year: 2013
    ....
  14. Mucosal Immunity, Vaccines and Microbiota Interplay in Humans and Animal
    Marcelo B Sztein; Fiscal Year: 2013
    ..Given the shortcomings of available measures to successfully control this infection, and its bioterrorism potential, to develop a S. dysenteriae type 1 vaccine is of great importance. ..
  15. ADAPTATIONS TO HYPOXIA
    Kurt R Stenmark; Fiscal Year: 2013
    ..abstract_text> ..