Difference between revisions of "Event:272"

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Revision as of 09:27, 11 November 2014



Event Title

T-cells, Activation/Proliferation
Short name: T-cells, Activation/Proliferation

Key Event Overview

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AOPs Including This Key Event

AOP Name Event Type Essentiality
Skin Sensitisation Initiated by Covalent Binding to Proteins KE Strong

Taxonomic Applicability

Name Scientific Name Evidence Links

Level of Biological Organization

Biological Organization

How this Key Event works

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 Martin et al., 2010). 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 (Vocanson et al., 2009). Recognizing the importance of the process of antigen presentation (i.e. T-cell priming), in vitro T-cell priming assays have been developed (see Martin et al., 2010). While first generation assays could only detect strong or extreme sensitizers, more recent development using normal human peripheral blood depleted of regulatory cells that normally prevent the sensitisation phase increased the probability that Tcell proliferation would be detected (Vocanson et al., 2008). A related approach is based on the hypothesis that there is a correlation between the potency of contact allergens and T-cell frequency and T-cell receptor repertoire (Kotturi et al., 2008). It is plausible that sensitisation potency may correlate with the size of the contact allergen-specific effector and regulatory T-cell pools and their diversity, and this could form the basis of a new generation of in vitro T-cell priming assays. It should be remembered that lymph node cell proliferation is the basis for the LLNA. Perhaps the most interesting finding about lymphoid tissue, as related to the sensitisation is the selectivity of cytokine secretion. Hopkins et al. (2005), building on earlier work of Dearman and coworkers, reported that lymphoid tissue of mice exposed to classic electrophiles with conjugate proteins via ENV/JM/MONO(2012)10/PART1 36 nucleophilic substitution as halo-nitro-aromatic compounds (i.e. 1-chloro-2,4-dinitrobenzene and 1-fluoro- 2,4-dinitrobenzene) expresses high levels of the Th1 cytokine IFN-γ and low levels of the Th2 cytokines IL-5 and IL-10. Conversely, lymphoid tissue for mice exposed to 2,4-dinitrobenzene sulphonyl chloride, which conjugates with proteins via nucleophilic substitution as a sulphonyl halides, the acylating agent trimellitic anhydride, or fluorescein isothiocyanate, which conjugates with proteins via nucleophilic addition to the carbon atom of the isothiocyanate (-N=C=S) moiety, express high levels of the Th2 cytokines IL-5 and IL-10 and low levels of the Th1 cytokine IFN-γ (Hopkins et al., 2005). Based on differential binding to cellular and serum proteins Hopkins et al. (2005) showed that chemicals that stimulate a Th1 cytokine response bind selectively to cellular proteins, while chemicals that stimulate a Th2 cytokine response bind selectively to serum proteins. While it would be tempting to say electrophiles which preferentially bind to cysteine express a Th1 cytokine profile and electrophiles which preferentially bind to lysine express a Th2 cytokine profile, it is most likely not that simple.

How it is Measured or Detected

Methods that have been previously reviewed and approved by a recognized authority should be included in the Overview section above. All other methods, including those well established in the published literature, should be described here. Consider the following criteria when describing each method: 1. Is the assay fit for purpose? 2. Is the assay directly or indirectly (i.e. a surrogate) related to a key event relevant to the final adverse effect in question? 3. Is the assay repeatable? 4. Is the assay reproducible?

Evidence Supporting Taxonomic Applicability

References