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Human innate immune responses to hexamethylene diisocyanate (HDI) and HDI-albumin conjugates.

Authors
Wisnewski-AV; Liu-Q; Liu-J; Redlich-CA
Source
Clin Exp Allergy 2008 Jun; 38(6):957-967
NIOSHTIC No.
20034227
Abstract
BACKGROUND: Isocyanates, a leading cause of occupational asthma, are known to induce adaptive immune responses; however, innate immune responses, which generally precede and regulate adaptive immunity, remain largely uncharacterized. OBJECTIVE: The aim of the study was to identify and characterize the cellular, molecular and systemic innate immune responses induced by hexamethylene diisocyanate (HDI). METHODS: Human peripheral blood mononuclear cells (PBMCs) were stimulated in vitro with HDI-albumin conjugates or control antigen, and changes in phenotype, gene and protein expression were characterized by flow cytometry, microarray, Western blot and ELISA. Cell uptake of isocyanate was visualized microscopically using HDI-albumin conjugates prepared with fluorescently labelled albumin. In vivo, human HDI exposure was performed via a specific inhalation challenge, and subsequent changes in PBMCs and serum proteins were measured by flow cytometry and ELISA. Genotypes were determined by PCR. RESULTS: Human monocytes take up HDI-albumin conjugates and undergo marked changes in morphology and gene/protein expression in vitro. The most significant (P-values 0.007-0.05) changes in microarray gene expression were noted in lysosomal genes, especially peptidases and proton pumps involved in antigen processing. Chemokines that regulate monocyte/macrophage trafficking (MIF, MCP-1) and pattern-recognition receptors that bind chitin (chitinases) and oxidized low-density lipoprotein (CD68) were also increased following isocyanate-albumin exposure. In vivo, HDI-exposed subjects exhibited a drastic increase in the percentage of PBMCs with the same HDI-albumin responsive phenotype characterized in vitro (HLA-DR(+)/CD11c(+) with altered light scatter properties). An exposure-dependent decrease (46+/-11%; P<0.015) in serum concentrations of chitinase 3-like-1 was also observed in individuals who lack the major (type 1) human chitinase (due to genetic polymorphism), but not in individuals possessing at least one functional chitinase-1 allele. CONCLUSIONS: Previously unrecognized innate immune responses to HDI and HDI-albumin conjugates could influence the clinical spectrum of exposure reactions.
Keywords
Isocyanates; Models; Occupational-diseases; Mathematical-models; Occupational-exposure; Pulmonary-system-disorders; Vapors; Work-environment; Work-practices; Quantitative-analysis; Airborne-fibers; Airborne-particles; Allergic-disorders; Allergic-reactions; Particle-aerodynamics; Particulate-dust; Particulate-sampling-methods
Contact
Adam V. Wisnewski, Department of Internal Medicine, Yale School of Medicine, 1 Gilbert Street, TAC-S415, New Haven, CT 06520
CODEN
CLEAEN
Publication Date
20080601
Document Type
Journal Article
Email Address
adam.wisnewski@yale.edu
Funding Amount
2634676
Funding Type
Grant
Fiscal Year
2008
NTIS Accession No.
NTIS Price
Identifying No.
Grant-Number-R01-OH-003457
Issue of Publication
6
ISSN
0954-7894
Priority Area
Disease and Injury: Asthma and Chronic Obstructive Pulmonary Disease
Source Name
Clinical and Experimental Allergy
State
CT; MA; CA; KY
Performing Organization
Yale University, New Haven, Connecticut
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