Upstream eventActivation/Proliferation, T-cells
N/A, Allergic contact dermatitis on challenge
Key Event Relationship Overview
AOPs Referencing Relationship
|guinea pig||Cavia porcellus||High||NCBI|
Life Stage Applicability
Key Event Relationship Description
T-cells are typically affected by protein-hapten complexes presented by dendritic cells on MHC molecules. Molecular understanding of this process has improved in recent years (see ). Briefly, MHC molecules are membrane proteins which present the small peptide antigens placed in a “groove” of the MHC molecule during its intracellular synthesis and transport to the cell surface. In the context of the MHC molecular on the cell surface, the small peptide antigen is recognized via the T-cell receptors as self or non-self (e.g. foreign). If this peptide is a foreign peptide, such as part of a proteinhapten complex, the T-cell will be activated to form a memory T-cell, which subsequently proliferates. If reactivated upon hapten presentation by skin dendritic cells, these memory T-cells will induce allergic contact dermatitis.
Evidence Supporting this KER
Uncertainties and Inconsistencies
Quantitative Understanding of the Linkage
Is it known how much change in the first event is needed to impact the second? Are there known modulators of the response-response relationships? Are there models or extrapolation approaches that help describe those relationships?
While quantitative models have been developed with guinea-pig data, the LLNA assay was designed to allow for a direct quantitative assessment of skin sensitisation potency. Briefly, the relative potency of a skin-sensitizing chemical is measured by derivation of an ECx value, which is the concentration of a test chemical necessary to produce a X-fold increase in lymph node cell proliferation compared with concurrent vehicle controls (i.e. a threshold positive response). Since the LLNA does not include the challenge phase of sensitisation, it may be considered an incomplete in vivo sensitisation assay. Using LLNA data, sensitizers can be grouped into potency groups (e.g. extreme, strong, moderate, weak, and non-sensitizers). However, as noted by Basketter et al., the LLNA is not without limitations, including variability between EC3 values or any other value (i.e. ECx) within isoreactive mechanistic classes. There are increased efforts to look at in vivo skin sensitisation potential or lack of potential as concordance between LLNA and guinea-pig data, and human evidence.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
- Martin SF, Esser PR, Schmucker S, Dietz L, Naisbitt DJ, Park BK, Vocanson M, Nicolas JF, Keller M, Pichler WJ, Peiser M, Luch A, Wanner R, Maggi E, Cavani A, Rustemeyer T, Richter A, Thierse HJ, Sallusto F. 2010. T-cell recognition of chemical, protein allergens and drugs; toward the development of in vitro assays. Cell. Mol. Life Sci. 67: 4171-4184.
- Vocanson M, Hennino A, Rozieres A, Poyet G, Nicolas JF. 2009. Effector and regulatory mechanisms in allergic contact dermatitis. Allergy 64: 1699-1714
- Basketter DA, Lea LJ, Cooper KJ, Dickens A, Stocks J, Pate I. 1999. Thresholds for classification as a skin sensitiser in the local lymph node assay: a statistical evaluation. Food Chem. Toxicol. 37:1167-1174.
- Basketter DA, McFadden JF, Gerberick F, Cochshott A, Kimber I. 2009. Nothing is perfect, not even the local lymph node assay: a commentary and the implications for REACH. Contact Dermatitis 60: 65-69.