Respiratory sensitization and allergy: current research approaches and needs.

There are currently no accepted regulatory models for assessing the potential of a substance to cause respiratory sensitization and allergy. In contrast, a number of models exist for the assessment of contact sensitization and allergic contact dermatitis (ACD). Research indicates that respiratory sensitizers may be identified through contact sensitization assays such as the local lymph node assay, although only a small subset of the compounds that yield positive results in these assays are actually respiratory sensitizers. Due to the increasing health concerns associated with occupational asthma and the impending directives on the regulation of respiratory sensitizers and allergens, an approach which can identify these compounds and distinguish them from contact sensitizers is required. This report discusses some of the important contrasts between respiratory allergy and ACD, and highlights several prominent in vivo, in vitro and in silico approaches that are being applied or could be further developed to identify compounds capable of causing respiratory allergy. Although a number of animal models have been used for researching respiratory sensitization and allergy, protocols and endpoints for these approaches are often inconsistent, costly and difficult to reproduce, thereby limiting meaningful comparisons of data between laboratories and development of a consensus approach. A number of emerging in vitro and in silico models show promise for use in the characterization of contact sensitization potential and should be further explored for their ability to identify and differentiate contact and respiratory sensitizers. Ultimately, the development of a consistent, accurate and cost-effective model will likely incorporate a number of these approaches and will require effective communication, collaboration and consensus among all stakeholders.

[1]  A. Hasan,et al.  Organisation for Economic Co-operation and Development , 2007 .

[2]  E. Gelfand,et al.  Migration and accumulation of eosinophils toward regional lymph nodes after airway allergen challenge. , 2004, The Journal of allergy and clinical immunology.

[3]  L. Skov,et al.  Gene transcripts as potential diagnostic markers for allergic contact dermatitis , 2005, Contact dermatitis.

[4]  I. Kimber,et al.  Induced changes in total serum IgE concentration in the Brown Norway rat: potential for identification of chemical respiratory allergens , 2002, Journal of applied toxicology : JAT.

[5]  J. Arts,et al.  Animal models to test respiratory allergy of low molecular weight chemicals: a guidance. , 2007, Methods.

[6]  M. Chan-yeung,et al.  Aetiological agents in occupational asthma. , 1994, The European respiratory journal.

[7]  M. Selgrade,et al.  A murine model for low molecular weight chemicals: differentiation of respiratory sensitizers (TMA) from contact sensitizers (DNFB). , 2003, Toxicology.

[8]  G Frank Gerberick,et al.  Interactions of contact allergens with dendritic cells: opportunities and challenges for the development of novel approaches to hazard assessment. , 2005, Toxicological sciences : an official journal of the Society of Toxicology.

[9]  C. Mapp Genetics and the occupational environment , 2005, Current opinion in allergy and clinical immunology.

[10]  G. Schuler,et al.  Generation of mature dendritic cells from human blood. An improved method with special regard to clinical applicability. , 1997, Advances in experimental medicine and biology.

[11]  M. Selgrade,et al.  Animal models for protein respiratory sensitizers. , 2007, Methods.

[12]  J. Pauluhn Brown Norway Rat Asthma Model of Diphenylmethane 4,4′-Diisocyanate , 2005, Inhalation toxicology.

[13]  I. Kimber,et al.  IgG and IgE antibody responses following exposure of Brown Norway rats to trimellitic anhydride: comparison of inhalation and topical exposure. , 2002, Toxicology.

[14]  C. Janeway,et al.  Allergy and Hypersensitivity , 2001 .

[15]  J. Mauderly,et al.  Effect of four‐week repeated inhalation exposure to unconjugated azodicarbonamide on specific and non‐specific airway sensitivity of the guinea pig , 1989, Journal of applied toxicology : JAT.

[16]  Ulrich Mohr,et al.  Experimental approaches to evaluate respiratory allergy in animal models. , 2005, Experimental and Toxicological Pathology.

[17]  Carl Westmoreland,et al.  A future approach to measuring relative skin sensitising potency: a proposal , 2006, Journal of applied toxicology : JAT.

[18]  W. Busse,et al.  Asthma and Rhinitis , 1995 .

[19]  Valérie Zuang,et al.  Dendritic Cells as a Tool for the Predictive Identification of Skin Sensitisation Hazard , 2005, Alternatives to laboratory animals : ATLA.

[20]  C. Borrebaeck,et al.  Functional and transcriptional profiling of MUTZ‐3, a myeloid cell line acting as a model for dendritic cells , 2006, Immunology.

[21]  I. Bernstein,et al.  Workshop overview. Identification of respiratory allergens. , 1996, Fundamental and Applied Toxicology.

[22]  T. Asquith,et al.  A proposed screen for evaluating low‐molecular‐weight chemicals as potential respiratory allergens , 1993, Journal of applied toxicology : JAT.

[23]  J. Pauluhn,et al.  Respiratory hypersensitivity to trimellitic anhydride in Brown Norway Rats: a comparison of endpoints , 2002, Journal of applied toxicology : JAT.

[24]  I Kimber,et al.  Alternative approaches to the identification and characterization of chemical allergens. , 2001, Toxicology in vitro : an international journal published in association with BIBRA.

[25]  In silico methods for evaluating human allergenicity to novel proteins: International Bioinformatics Workshop Meeting Report, 23-24 February 2005. , 2005, Toxicological sciences : an official journal of the Society of Toxicology.

[26]  Z. Berneman,et al.  Gene expression signatures in CD34+-progenitor-derived dendritic cells exposed to the chemical contact allergen nickel sulfate. , 2006, Toxicology and applied pharmacology.

[27]  Rosa García Couto Globally Harmonized System of Classification and Labelling of Chemicals (GHS) , 2009 .

[28]  G Frank Gerberick,et al.  Gene expression changes in peripheral blood-derived dendritic cells following exposure to a contact allergen. , 2004, Toxicology letters.

[29]  James G. Martin,et al.  Rat models of asthma and chronic obstructive lung disease. , 2006, Pulmonary pharmacology & therapeutics.

[30]  S. Aiba,et al.  Evaluation of CD86 expression and MHC class II molecule internalization in THP-1 human monocyte cells as predictive endpoints for contact sensitizers. , 2002, Toxicology in vitro : an international journal published in association with BIBRA.

[31]  S. Gibbs,et al.  Intrinsic characteristics of contact and respiratory allergens influence production of polarizing cytokines by dendritic cells , 2006, Contact dermatitis.

[32]  M. Karol,et al.  Animal models of occupational asthma. , 1994, The European respiratory journal.

[33]  J. Pauluhn,et al.  Respiratory hypersensitivity in guinea pigs sensitized to 1,6-hexamethylene diisocyanate (HDI): comparison of results obtained with the monomer and homopolymers of HDI. , 2002, Toxicology.

[34]  C. Janeway Immunobiology: The Immune System in Health and Disease , 1996 .

[35]  G Frank Gerberick,et al.  Development of a peptide reactivity assay for screening contact allergens. , 2004, Toxicological sciences : an official journal of the Society of Toxicology.

[36]  H. Rosenkranz,et al.  Structure-activity model of chemicals that cause human respiratory sensitization. , 1997, Regulatory toxicology and pharmacology : RTP.

[37]  G. Bannon,et al.  Evaluation of IP mouse models for assessing the allergenic potential of proteins , 2005 .

[38]  N. Kaminski,et al.  Allergic rhinitis induced by intranasal sensitization and challenge with trimellitic anhydride but not with dinitrochlorobenzene or oxazolone in A/J mice. , 2004, Toxicological sciences : an official journal of the Society of Toxicology.

[39]  B. Nemery,et al.  Validation of a mouse model of chemical-induced asthma using trimellitic anhydride, a respiratory sensitizer, and dinitrochlorobenzene, a dermal sensitizer. , 2006, The Journal of allergy and clinical immunology.

[40]  J. Pauluhn,et al.  Assessment of respiratory hypersensitivity in guinea-pigs sensitized to diphenylmethane-4,4'-diisocyanate (MDI) and challenged with MDI, acetylcholine or MDI-albumin conjugate. , 1994, Toxicology.

[41]  M. Epstein Are mouse models of allergic asthma useful for testing novel therapeutics? , 2006, Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie.

[42]  V. Palda,et al.  A systematic review of contact dermatitis treatment and prevention. , 2005, Journal of the American Academy of Dermatology.

[43]  N. Bloksma,et al.  Respiratory irritation by trimellitic anhydride in Brown Norway and Wistar rats. , 2001, Inhalation toxicology.

[44]  A. Iwasaki,et al.  Mucosal immunity and inflammation. I. Mucosal dendritic cells: their specialized role in initiating T cell responses. , 1999, The American journal of physiology.

[45]  N. Humphreys,et al.  Methods for the identification of chemical respiratory allergens in rodents: comparisons of cytokine profiling with induced changes in serum IgE , 2003, Journal of applied toxicology : JAT.

[46]  P. Paré,et al.  The use and misuse of Penh in animal models of lung disease. , 2004, American journal of respiratory cell and molecular biology.

[47]  P. Siegel,et al.  Dose‐response and time course of specific IgE and IgG after single and repeated topical skin exposure to dry trimellitic anhydride powder in a Brown Norway rat model , 2002, Allergy.

[48]  Y. Fukumori,et al.  Peptide-binding assessment using mass spectrometry as a new screening method for skin sensitization. , 2003, The Journal of toxicological sciences.

[49]  H. Volk,et al.  Reversal by interferon‐γ of inhibition of delay ed‐type hypersensitivity induction by anti‐CD4 or antiinterleukin 2 receptor (CD25) monoclonal antibodies. Evidence for the physiological role of the CD4+ TH1+ subset in mice , 1988 .

[50]  D. Basketter,et al.  Selectivity of IgE responses, mast cell sensitization, and cytokine expression in the immune response of Brown Norway rats to chemical allergens. , 1996, Cellular immunology.

[51]  P. Ulrich,et al.  Cytokine expression profiles during murine contact allergy: T helper 2 cytokines are expressed irrespective of the type of contact allergen , 2001, Archives of Toxicology.

[52]  P. Sly,et al.  Animal models of asthma , 2007, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[53]  I. Kimber,et al.  Cytokine fingerprinting: characterization of chemical allergens. , 1999, Methods.

[54]  I. Bernstein,et al.  Identification of Respiratory Allergens , 1996 .

[55]  H. van Loveren,et al.  Cytokine production induced by low-molecular-weight chemicals as a function of the stimulation index in a modified local lymph node assay: an approach to discriminate contact sensitizers from respiratory sensitizers. , 2002, Toxicology and applied pharmacology.

[56]  H. Sakaguchi,et al.  Evaluation of the skin sensitization potential of chemicals using expression of co-stimulatory molecules, CD54 and CD86, on the naive THP-1 cell line. , 2003, Toxicology in vitro : an international journal published in association with BIBRA.

[57]  J. Ceuppens,et al.  Respiratory response to toluene diisocyanate depends on prior frequency and concentration of dermal sensitization in mice. , 2004, Toxicological sciences : an official journal of the Society of Toxicology.

[58]  N. Bloksma,et al.  Respiratory Allergy to Trimellitic Anhydride in Rats: Concentration-Response Relationships During Elicitation , 2004, Inhalation toxicology.

[59]  A. Petersen,et al.  Mouse Strain Specificity of the IgE Response to the Major Allergens of Phleum pratense , 2005, International Archives of Allergy and Immunology.

[60]  P. Thorne,et al.  Assessment of airway reactivity in guinea pigs: comparison of methods employing whole body plethysmography. , 1988, Toxicology.

[61]  L. Bloemen,et al.  Repeated Inhalation Challenge with Diphenylmethane-4,4′-Diisocyanate in Brown Norway Rats Leads to a Time-Related Increase of Neutrophils in Bronchoalveolar Lavage After Topical Induction , 2005, Inhalation toxicology.

[62]  I Kimber,et al.  Investigation of induced changes in interleukin 1beta mRNA expression by cultured human dendritic cells as an in vitro approach to skin sensitization testing. , 2000, Toxicology in vitro : an international journal published in association with BIBRA.

[63]  B. Nemery,et al.  Validity of methods to predict the respiratory sensitizing potential of chemicals: A study with a piperidinyl chlorotriazine derivative that caused an outbreak of occupational asthma. , 2003, Toxicological sciences : an official journal of the Society of Toxicology.

[64]  I. Kimber,et al.  Assessing the potential to induce respiratory hypersensitivity. , 2006, Toxicological sciences : an official journal of the Society of Toxicology.

[65]  I. Kimber,et al.  What makes a chemical a respiratory sensitizer? , 2005, Current opinion in allergy and clinical immunology.

[66]  G Frank Gerberick,et al.  Elucidating changes in surface marker expression of dendritic cells following chemical allergen treatment. , 2002, Toxicology and applied pharmacology.

[67]  A. Kisselgof,et al.  Genetic variability in pulmonary physiological, cellular, and antibody responses to antigen in mice. , 1999, American journal of respiratory and critical care medicine.

[68]  J. Arts,et al.  Approaches to induce and elicit respiratory allergy: impact of route and intensity of exposure. , 2003, Toxicology letters.

[69]  N. Kaminski,et al.  Topical application versus intranasal instillation: a qualitative comparison of the effect of the route of sensitization on trimellitic anhydride-induced allergic rhinitis in A/J mice. , 2006, Toxicological sciences : an official journal of the Society of Toxicology.

[70]  N. Bloksma,et al.  Respiratory allergy and pulmonary irritation to trimellitic anhydride in Brown Norway rats. , 2003, Toxicology and applied pharmacology.

[71]  N. Bloksma,et al.  Local lymph node activation in rats after dermal application of the sensitizers 2,4-dinitrochlorobenzene and trimellitic anhydride. , 1996, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[72]  J. Saloga,et al.  Flow-cytometric screening for the modulation of receptor-mediated endocytosis in human dendritic cells: implications for the development of an in vitro technique for predictive testing of contact sensitizers. , 1997, Journal of immunological methods.

[73]  J. Seagrave,et al.  Animal models of asthma: potential usefulness for studying health effects of inhaled particles. , 2000, Inhalation toxicology.

[74]  Neil Humphreys,et al.  Chemical allergy: considerations for the practical application of cytokine profiling. , 2003, Toxicological sciences : an official journal of the Society of Toxicology.

[75]  S. Galli,et al.  Systemic anaphylaxis in the mouse can be mediated largely through IgG1 and Fc gammaRIII. Assessment of the cardiopulmonary changes, mast cell degranulation, and death associated with active or IgE- or IgG1-dependent passive anaphylaxis. , 1997, The Journal of clinical investigation.

[76]  N. Kaminski,et al.  Immune Responses in the Lung and Local Lymph Node of A/J Mice to Intranasal Sensitization and Challenge with Adjuvant-Free Ovalbumin , 2003, Toxicologic pathology.

[77]  A. Enk,et al.  Contact sensitizers specifically increase MHC class II expression on murine immature dendritic cells. , 2000, In vitro & molecular toxicology.

[78]  J. Pauluhn,et al.  Respiratory allergy: hazard identification and risk assessment. , 1994, Fundamental and applied toxicology : official journal of the Society of Toxicology.

[79]  S. Aiba,et al.  Dendritic cells differently respond to haptens and irritants by their production of cytokines and expression of co‐stimulatory molecules , 1997, European journal of immunology.

[80]  Cees de Heer,et al.  Dose-Response Relationships and Threshold Levels in Skin and Respiratory Allergy , 2006, Critical reviews in toxicology.

[81]  N. Bloksma,et al.  Local lymph node activation and IgE responses in brown Norway and Wistar rats after dermal application of sensitizing and non-sensitizing chemicals. , 1997, Toxicology.

[82]  W. D. de Jong,et al.  Assessment of preferential T-helper 1 or T-helper 2 induction by low molecular weight compounds using the local lymph node assay in conjunction with RT-PCR and ELISA for interferon-gamma and interleukin-4. , 2000, Toxicology and applied pharmacology.

[83]  Harshinder Singh,et al.  Structure-activity models for contact sensitization. , 2005, Chemical research in toxicology.

[84]  P. Horn,et al.  Use of the mouse intranasal test (MINT) to determine the allergenic potency of detergent enzymes: comparison to the guinea pig intratracheal (GPIT) test. , 1998, Toxicological sciences : an official journal of the Society of Toxicology.

[85]  M. Selgrade,et al.  Inconsistencies between cytokine profiles, antibody responses, and respiratory hyperresponsiveness following dermal exposure to isocyanates. , 2006, Toxicological sciences : an official journal of the Society of Toxicology.

[86]  J. Pauluhn,et al.  Assessment of respiratory hypersensitivity in guinea pigs sensitized to toluene diisocyanate: improvements on analysis of respiratory response. , 1997, Fundamental and applied toxicology : official journal of the Society of Toxicology.

[87]  J. Pauluhn Validation of an improved nose‐only exposure system for rodents , 1994, Journal of applied toxicology : JAT.

[88]  H. Ritz,et al.  Respiratory and immunological responses of guinea pigs to enzyme-containing detergents: a comparison of intratracheal and inhalation modes of exposure. , 1993, Fundamental and applied toxicology : official journal of the Society of Toxicology.

[89]  Petra S Kern,et al.  TIMES-SS--a promising tool for the assessment of skin sensitization hazard. A characterization with respect to the OECD validation principles for (Q)SARs and an external evaluation for predictivity. , 2007, Regulatory toxicology and pharmacology : RTP.