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Relationship: 379


A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Activation, Dendritic Cells leads to Activation/Proliferation, T-cells

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes. Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Covalent Protein binding leading to Skin Sensitisation adjacent High Agnes Aggy (send email) Open for citation & comment WPHA/WNT Endorsed
Covalent Binding, Protein, leading to Increase, Allergic Respiratory Hypersensitivity Response adjacent High Not Specified Arthur Author (send email) Under Development: Contributions and Comments Welcome Under Development

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help

Sex Applicability

An indication of the the relevant sex for this KER. More help

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Under the influence of fibroblast- blood endothelial- and lymph endothelial-chemokines (e.g. CCL19, CCL21) and epidermal cytokines (e.g. interleukin (IL), IL-1 α, IL-1β, IL-18, tumour necrosis factor alpha (TNF-α)) maturing dendritic cells migrate from the epidermis to the dermis of the skin and then to the proximal lymph nodes, where they can present the hapten-protein complex to T-cells via a major histocompatibility complex molecule ([1];[2]). 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 ([3]). 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 protein-hapten complex, the T-cell will be activated to form a memory T-cell, which subsequently proliferates ([4]). These observations are consistent with the immunological mechanism presented with this AOP, where it is assumed that for an adverse outcome to commence, a certain number of dendritic cells is required to be activated and to migrate to the nearest lymph node in order to instigate the further cascade of biological events (see[5]).

This KER description is based only on the OECD document 2012 and needs updating.

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER.  For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

It is well accepted and experimentally proved that in the local lymph node, mature dendritic cells present the hapten-protein complex to T-cells via a major histocompatibility complex molecule (MHC)[2];[1]. T-cells are typically affected by protein-hapten complexes presented by dendritic cells on MHC molecules. The T-cell will be then activated to form a memory T-cell, which subsequently proliferates[4].

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help
Modulating Factor (MF) MF Specification Effect(s) on the KER Reference(s)

Taylor et al. (2020) found single nucleotide polymorphisms (SNPs) associated with differences in biomarker levels following occupational exposure to 1,6-hexamethylene diisocyanate isocyanurate and 1,6-hexamethylene diisocyanate implicate the TGF-beta pathway regulating endothelial migration and proliferation as well as genes regulating chemokine-induced lymphocyte migration. 

Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help
Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help


List of the literature that was cited for this KER description. More help
  1. 1.0 1.1 Antonopoulos C, Cumberbatch M, Mee JB, Dearman RJ, Wei XQ, Liew FY, Kimber I, Groves RW. 2008. IL-18 is a key proximal mediator of contact hypersensitivity and allergen induced Langerhans cell migration in murine epidermis. J. Leukoc. Biol. 83: 361-367.
  2. 2.0 2.1 Ouwehand K, Santegoets SJAM, Bruynzeel DP, Scheper RJ, de Gruijl TD, Gibbs S. 2008. CXCL12 is essential for migration of activated Langerhans cells for epidermis to dermis. Eur. J. Immunol. 38: 3050-3059.
  3. 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.
  4. 4.0 4.1 Vocanson M, Hennino A, Rozieres A, Poyet G, Nicolas JF 2009. Effector and regulatory mechanisms in allergic contact dermatitis. Allergy 64: 1699-1714.
  5. Api AM, Basketter DA, Cadby PA, Cano MF, Ellis G, Gerberick GF, Griem P, McNamee PM, Ryan CA and Safford B. 2008. Dermal sensitisation quantitative risk assessment (QRA) for fragrance ingredients. Reg. Toxicol. Pharmcol. 52: 3-23.
  6. Zou T, Caton AJ, Koretzky GA, Kambayashi T. 2010. Dendritic cells induce regulatory T cell proliferation through antigen-dependent and –independent interactions. J. Immunol. 185:2790-2799.

TAYLOR, L. W., FRENCH, J. E., ROBBINS, Z. G., BOYER, J. C. & NYLANDER-FRENCH, L. A. 2020. Influence of Genetic Variance on Biomarker Levels After Occupational Exposure to 1,6-Hexamethylene Diisocyanate Monomer and 1,6-Hexamethylene Diisocyanate Isocyanurate. Front Genet, 11, 836.