Isocyanates are a group of highly reactive widely used low-molecular weight chemicals, and are the most commonly reported cause of occupation asthma in developed countries. Yet, the mechanisms by which isocyanates cause asthma are not well defined. Based on our preliminary data and that reported in the literature, we hypothesize that isocyanate-induced asthma is dependent on isocyanate antigen-driven T-cell mediated, airway inflammation. To address this hypothesis, we propose to investigate isocyanate-induced asthma is dependent on isocyanate antigen-driven T-cell mediated, airway inflammation. To address this hypothesis, we propose to investigate isocyanate antigen-driven T-cell responses in vitro-, following in vivo exposure. Our investigations will identify and characterize isocyanate antigens and reactive human T-cells. We will compare isocyanate antigen-reactive T-cells from primary exposure sites (skin/lung), with those from blood, to evaluate potential routes of sensitization and identify diagnostic indicators of isocyanate sensitivity/susceptibility. The studies will be performed in a population of hexamethylene diisocyanate (HDI) exposed autobody shop workers. Patient samples will be acquired through collaboration with ongoing field epidemiological and clinical studies. The findings of this proposal will provide evidence to support or refute our hypothesis that isocyanate asthma is mediated by isocyanate antigen-specific T-cells and will also serve as a model for other types of occupational asthma. Specifically, we propose to:
Aim 1) Generate and characterize HDI antigens including; isocyanate metabolites, and isocyanate conjugated t normal human and foreign proteins.
Aim 2) Evaluate the T-cell antigenicity of the HDI antigens, based on blood and lung lymphocyte proliferation. Evaluate the T-cell antigenicity of the HDI antigens, based on blood and lung lymphocyte proliferation, cytokine production, and phenotype in order to identify the molecular form of HDI that initiates airway cytokine production, and phenotype in order to identify the molecular form of HDI that initiates airway inflammation in asthma patients.
Aim 3) Establish T- cell lines from the skin, lung and peripheral blood of HDI asthma patients and characterize the phenotype, antigen specificity, cytokine production and TCR expression of isocyanate responsive T-cells in these different compartments.
Aim 4) Compare isocyanate responsive T-cells found in the skin, lung and blood and correlate with clinical sensitivity to determine characteristics associated with exposure and sensitization leading to clinical asthma. These studies should enable identification of the biologically relevant HDI antigen(s) and greatly enhance our understanding of how isocyanates initiate specific T-cell responses that lead to isocyanate sensitivity and asthma. Characterization of isocyanate antigens and isocyanate-responsive T-cells will identify targets for the diagnosis, prevention and treatment of isocyanate asthma.
|Wisnewski, Adam V; Xu, Lan; Robinson, Eve et al. (2011) Immune sensitization to methylene diphenyl diisocyanate (MDI) resulting from skin exposure: albumin as a carrier protein connecting skin exposure to subsequent respiratory responses. J Occup Med Toxicol 6:6|
|Wisnewski, A V; Liu, Q; Liu, J et al. (2008) Human innate immune responses to hexamethylene diisocyanate (HDI) and HDI-albumin conjugates. Clin Exp Allergy 38:957-67|
|Pronk, Anjoeka; Preller, Liesbeth; Raulf-Heimsoth, Monika et al. (2007) Respiratory symptoms, sensitization, and exposure response relationships in spray painters exposed to isocyanates. Am J Respir Crit Care Med 176:1090-7|
|Campo, P; Wisnewski, A V; Lummus, Z et al. (2007) Diisocyanate conjugate and immunoassay characteristics influence detection of specific antibodies in HDI-exposed workers. Clin Exp Allergy 37:1095-102|
|Wisnewski, Adam V (2007) Developments in laboratory diagnostics for isocyanate asthma. Curr Opin Allergy Clin Immunol 7:138-45|
|Ye, Young-Min; Kim, Cheol-Woo; Kim, Hyung-Ryul et al. (2006) Biophysical determinants of toluene diisocyanate antigenicity associated with exposure and asthma. J Allergy Clin Immunol 118:885-91|
|Wisnewski, A V; Liu, Q; Liu, J et al. (2005) Glutathione protects human airway proteins and epithelial cells from isocyanates. Clin Exp Allergy 35:352-7|
|Wisnewski, Adam V; Stowe, Meredith H; Cartier, Andre et al. (2004) Isocyanate vapor-induced antigenicity of human albumin. J Allergy Clin Immunol 113:1178-84|
|Liu, Qing; Wisnewski, Adam V (2003) Recent developments in diisocyanate asthma. Ann Allergy Asthma Immunol 90:35-41|
|Herrick, Christina A; Das, Jyoti; Xu, Lan et al. (2003) Differential roles for CD4 and CD8 T cells after diisocyanate sensitization: genetic control of TH2-induced lung inflammation. J Allergy Clin Immunol 111:1087-94|
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