Difference between revisions of "Event:272"

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Recognizing the importance of the process of antigen presentation (i.e. T-cell priming), in vitro T-cell priming assays have been developed (see<ref name="Martin"></ref>). 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 T-cell proliferation would be detected <ref name="Vocanson"></ref>. 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
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Most protocols recognize the importance of the process of antigen-presentation, so in vitro T-cell-based assays are typically co-cultures of allergen-treated dendritic cells and modified T-lymphocytes with expression of selected biomarkers (e.g. interferon gamma), or T-cell proliferation being the reported outcome. Much of this work has been reviewed by Martin et al<ref name="Martin 2010"></ref>.
repertoire<ref>Kotturi MF, Scott I, Wolfe T, Peters B, Sidney J, Cheroutre H, et al. 2008. Naive precursor frequencies and MHC binding rather than the degree of epitope diversity shape CD8+ T cell immunodominance. J. Immunol. 181: 2124-2133.</ref. 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.
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It should be remembered that lymph node cell proliferation is the basis for the in vivo mouse Local Lymph Node Assay (LLNA). OECD TGs 429 is the validated test guideline for the Skin Sensitisation: Local Lymph Node Assay<ref name="OECD 2010a">OECD 2010. Test No.429: Skin sensitization: Local Lymph Node Assay. OECD Guidelines for the Testing of Chemicals, Section 4: Health effects. OECD Publishing. Doi: 10.1787/9789264071100-en.</ref> together with its two non-radioactive modifications (LLNA-DA TG442A<ref name="OECD 2010b">OECD 2010. Test No.442A: Skin sensitization: Local Lymph Node Assay:DA. OECD Guidelines for the Testing of Chemicals, Section 4: Health effects. OECD Publishing. Doi: 10.1787/9789264090972-en.</ref> and LLNA-BrdU ELISA TG 442B<ref name="OECD 2010c">OECD 2010. Test No.442B: Skin sensitization: Local Lymph Node Assay: BrdU-ELISA. OECD Guidelines for the Testing of Chemicals, Section 4: Health effects. OECD Publishing. Doi: 10.1787/9789264090996-en.</ref>).
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=== Overview table: How it is measured or detected ===
 
=== Overview table: How it is measured or detected ===

Revision as of 12:58, 24 September 2015



Event Title

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

Key Event Overview

Please follow link to widget page to edit this section.

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
human Homo sapiens Strong NCBI

Level of Biological Organization

Biological Organization
Cellular

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[1]). 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[2].

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?

Most protocols recognize the importance of the process of antigen-presentation, so in vitro T-cell-based assays are typically co-cultures of allergen-treated dendritic cells and modified T-lymphocytes with expression of selected biomarkers (e.g. interferon gamma), or T-cell proliferation being the reported outcome. Much of this work has been reviewed by Martin et al[1]. It should be remembered that lymph node cell proliferation is the basis for the in vivo mouse Local Lymph Node Assay (LLNA). OECD TGs 429 is the validated test guideline for the Skin Sensitisation: Local Lymph Node Assay[3] together with its two non-radioactive modifications (LLNA-DA TG442A[4] and LLNA-BrdU ELISA TG 442B[5]).


Overview table: How it is measured or detected

Overview
Method(s) Reference URL Regulatory

Acceptance

Validated Non

Validated

Local Lymph Node Assay (LLNA) TG 429 [1] X X
TG 442A LLNA:DA [2]
TG 442B LLNA: BrdU-ELISA [3]

Evidence Supporting Taxonomic Applicability

References

  1. 1.0 1.1 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.
  2. Vocanson M, Hennino A, Rozieres A, Poyet G, Nicolas JF 2009. Effector and regulatory mechanisms in allergic contact dermatitis. Allergy 64: 1699-1714.
  3. OECD 2010. Test No.429: Skin sensitization: Local Lymph Node Assay. OECD Guidelines for the Testing of Chemicals, Section 4: Health effects. OECD Publishing. Doi: 10.1787/9789264071100-en.
  4. OECD 2010. Test No.442A: Skin sensitization: Local Lymph Node Assay:DA. OECD Guidelines for the Testing of Chemicals, Section 4: Health effects. OECD Publishing. Doi: 10.1787/9789264090972-en.
  5. OECD 2010. Test No.442B: Skin sensitization: Local Lymph Node Assay: BrdU-ELISA. OECD Guidelines for the Testing of Chemicals, Section 4: Health effects. OECD Publishing. Doi: 10.1787/9789264090996-en.