PMID- 19422874
OWN - NLM
STAT- MEDLINE
DCOM- 20090709
LR  - 20151119
IS  - 1879-3185 (Electronic)
IS  - 0300-483X (Linking)
VI  - 261
IP  - 3
DP  - 2009 Jul 10
TI  - Contact and respiratory sensitizers can be identified by cytokine profiles 
      following inhalation exposure.
PG  - 103-11
LID - 10.1016/j.tox.2009.04.057 [doi]
AB  - There are currently no validated animal models that can identify low molecular 
      weight (LMW) respiratory sensitizers. The Local Lymph Node Assay (LLNA) is a 
      validated animal model developed to detect contact sensitizers using skin 
      exposure, but all LMW respiratory sensitizers tested so far were also positive in 
      this assay. Discrimination between contact and respiratory sensitizers can be 
      achieved by the assessment of cytokine profiles. In a LLNA using the inhalation 
      route, both contact and respiratory sensitizers enhanced proliferation in the 
      draining lymph nodes. The question was if their cytokine profiles were affected 
      by the route of exposure. Male BALB/c mice were exposed head/nose-only during 3 
      consecutive days to the respiratory sensitizers trimellitic anhydride, phthalic 
      anhydride, toluene diisocyanate, hexamethylene diisocyanate (HDI), and isophorone 
      diisocyanate; the contact sensitizers dinitrochlorobenzene (DNCB), oxazolone 
      (OXA) and formaldehyde (FA), and the irritant methyl salicylate (MS). Three days 
      after the last exposure the draining lymph nodes were excised and cytokine 
      production was measured after ex vivo stimulation with Concanavalin A. Skin 
      application was used as a positive control. After inhalation exposure the 
      respiratory sensitizers induced more interleukin-4 (IL-4) and interleukin (IL-10) 
      compared to the contact sensitizers, whereas the contact sensitizers, except 
      formaldehyde, induced relatively more interferon-gamma (IFN-gamma) production. 
      When IL-4 and IFN-gamma were plotted as a function of the proliferative response, 
      it was shown that IL-4 could be used to identify respiratory sensitizers, except 
      HDI, at concentration levels inducing intermediate stimulation indices. HDI could 
      be distinguished from DNCB and OXA at high SI values. In contrast, contact 
      sensitizers could only be identified when IFN-gamma was measured at high 
      stimulation indices. The skin positive control, tested at high concentrations, 
      showed comparable results for IL-4 and IL-10, whereas IFN-gamma levels could not 
      be used to discriminate between respiratory and contact sensitizers. The contact 
      sensitizer FA and the irritant MS did not induce significant cytokine production 
      after inhalation and skin exposure. In conclusion, the respiratory LLNA is able 
      to identify and distinguish strong contact and respiratory sensitizers when 
      simultaneously proliferation and cytokine production are assessed in the upper 
      respiratory tract draining LNs.
FAU - De Jong, Wim H
AU  - De Jong WH
AD  - Laboratory for Health Protection Research, National Institute for Public Health 
      and the Environment, P.O. Box 1, 3720 BA Bilthoven, The Netherlands.
FAU - Arts, Josje H E
AU  - Arts JH
FAU - De Klerk, Arja
AU  - De Klerk A
FAU - Schijf, Marcel A
AU  - Schijf MA
FAU - Ezendam, Janine
AU  - Ezendam J
FAU - Kuper, C Frieke
AU  - Kuper CF
FAU - Van Loveren, Henk
AU  - Van Loveren H
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20090505
PL  - Ireland
TA  - Toxicology
JT  - Toxicology
JID - 0361055
RN  - 0 (Allergens)
RN  - 0 (Biomarkers)
RN  - 0 (Cytokines)
RN  - 130068-27-8 (Interleukin-10)
RN  - 207137-56-2 (Interleukin-4)
RN  - 82115-62-6 (Interferon-gamma)
SB  - IM
MH  - Administration, Cutaneous
MH  - Allergens/administration & dosage/*toxicity
MH  - Animals
MH  - Biomarkers/metabolism
MH  - Cell Proliferation/drug effects
MH  - Cells, Cultured
MH  - Cytokines/*metabolism
MH  - Dermatitis, Allergic Contact/*etiology/immunology/pathology
MH  - Dose-Response Relationship, Drug
MH  - *Inhalation Exposure
MH  - Interferon-gamma/metabolism
MH  - Interleukin-10/metabolism
MH  - Interleukin-4/metabolism
MH  - *Local Lymph Node Assay
MH  - Lymph Nodes/*drug effects/immunology/pathology
MH  - Male
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Models, Animal
MH  - Respiratory Hypersensitivity/*chemically induced/immunology/pathology
EDAT- 2009/05/09 09:00
MHDA- 2009/07/10 09:00
CRDT- 2009/05/09 09:00
PHST- 2009/02/17 00:00 [received]
PHST- 2009/04/07 00:00 [revised]
PHST- 2009/04/28 00:00 [accepted]
PHST- 2009/05/09 09:00 [entrez]
PHST- 2009/05/09 09:00 [pubmed]
PHST- 2009/07/10 09:00 [medline]
AID - S0300-483X(09)00233-9 [pii]
AID - 10.1016/j.tox.2009.04.057 [doi]
PST - ppublish
SO  - Toxicology. 2009 Jul 10;261(3):103-11. doi: 10.1016/j.tox.2009.04.057. Epub 2009 
      May 5.