Using Murine Models to Understand the Immunologic Basis of Toluene Diisocyanate Asthma

Details

• Personal Author:
  Johnson VJ ; Luster MI
• Description:
  Diisocyanates are the leading cause of occupational asthma afflicting between 5 and 15% of exposed workers. Despite this prevalence, the immunological basis for this disease remains poorly understood. Whether toluene diisocyanate (TDI) asthma is driven by TH2 responses, if TH1 responses are important, and the role of specific antibodies in disease pathogenesis are a few of the unanswered questions. We have developed a murine model in which mice become sensitized following long-term, low level inhalation exposure to TDI vapor. Sensitized mice display characteristic asthma symptoms upon challenge, including airway hyperreactivity (AHR), airway inflammation and antibody production. In addition, mice show elevated lung expression of TH2 and TH1 cytokines. Genetically modified mouse models and antibody neutralization approaches have suggested important roles for TH2 and TH1 responses as well as antibody production. All disease symptoms were reduced in CD4 and CD8 deficient mice. IL-4 and IL-13 neutralization showed moderate effects on all disease endpoints whereas combined depletion of both cytokines ablated disease. Mice deficient in IFNy showed a marked decrease in AHR but only minor effects on lung pathology, cytokine production and antibody levels. These findings show that both TH2 and TH1 responses are important. The ability of serum to transfer disease and attenuation of disease in Fc receptor deficient mice underscore the importance of antibodies in TDI asthma. This model also demonstrated an important role for pro-inflammatory cytokines. Prevention of TNF or IL-1 signalling reduced inflammation and AHR. Importantly, inhibition of IL-1 prevented TDIinduced increases in adhesion molecules required for recruitment of inflammatory cells to the lung. Therefore, it is likely that pro-inflammatory cytokines are early mediators of disease and may be involved in the initial recruitment of inflammatory cells to the lung during the effector phase of the disease. In summary, these studies demonstrate distinct and overlapping roles for TH1, TH2 and antibody responses and pro-inflammatory cytokines in TDI asthma. [Description provided by NIOSH]
• Subjects:
  Mining Occupational Health Safety
• Keywords:
  Airway-obstruction Animal-studies Animals Antibody-response Bronchial-asthma Diseases Exposure-assessment Exposure-levels Laboratory-animals Lung-disease Lung-disorders Models Occupational-diseases Occupational-exposure Toluenes

  More +
• ISSN:
  1096-6080
• Document Type:
  Text
• Genre:
  Abstract or Summary
• Place as Subject:
  OSHA Region 3 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  306-307
• Volume:
  90
• Issue:
  1
• NIOSHTIC Number:
  nn:20029900
• Citation:
  Toxicologist 2006 Mar; 90(1):306-307
• CAS Registry Number:
  Toluene (CAS RN 108-88-3) ; Toluene 2,4-diisocyanate (CAS RN 584-84-9)
• Federal Fiscal Year:
  2006
• NORA Priority Area:
  Disease and Injury: Asthma and Chronic Obstructive Pulmonary Disease
• Peer Reviewed:
  False
• Source Full Name:
  The Toxicologist. Society of Toxicology 45th Annual Meeting and ToxExpo, March 5-9, 2006, San Diego, California
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:29a9ed80c5646815a9d413384dd56add30cac86df0737584d434ee2ebb6b472d6f7c9da5f6e83fb6fecf99950d81af7f860ef76a2d50bc7ba74c6845510ab2b0
• Download URL:
  https://stacks.cdc.gov/view/cdc/190793/cdc_190793_DS1.pdf
• File Type:
  [PDF - 145.69 KB ]