Difference between revisions of "Event:272"

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(How it is Measured or Detected)
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== Key Event Overview ==
 
== Key Event Overview ==
Please follow link to [//{{SERVERNAME}}/aopportal/events/{{PAGENAMEE}} widget page] to edit this section.
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Please follow link to [//{{SERVERNAME}}/events/{{PAGENAMEE}} widget page] to edit this section.
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<span style="color:#FF0000">'''If you manually enter text in this section, it will get automatically altered or deleted in subsequent edits using the widgets.'''</span>
  
 
=== AOPs Including This Key Event ===
 
=== AOPs Including This Key Event ===
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|[[Aop:40|Skin Sensitisation Initiated by Covalent Binding to Proteins]]||KE||[[Aop:40#Essentiality of the Key Events|Strong]]
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|[[Aop:40|Covalent Protein binding leading to Skin Sensitisation]]||KE||[[Aop:40#Essentiality of the Key Events|Strong]]
  
 
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| human || Homo sapiens || [[Event:272#Evidence Supporting Taxonomic Applicability|Strong]] || [http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606 NCBI]
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|human||Homo sapiens||[[Event:272#Evidence Supporting Taxonomic Applicability|Strong]]||[http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606 NCBI]
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|-
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|mouse||Mus musculus||[[Event:272#Evidence Supporting Taxonomic Applicability|Strong]]||[http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10090 NCBI]
  
 
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|Cellular
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|Organ
  
 
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== How this Key Event works ==
 
== How this Key Event works ==
Since the final stage in the sensitisation phase is the activation of naive T-lymphocytes in the local
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T-cells are typically affected by protein-hapten complexes presented by dendritic cells on Major Histocompatibility Complex (MHC) molecules. Molecular understanding of this process has improved in recent years (see<ref name="Martin 2010">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.</ref>). 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. If reactivated upon presentation by skin dendritic cells, these memory T-cells will induce allergic contact dermatitis<ref name="Vocanson 2009">Vocanson M, Hennino A, Rozieres A, Poyet G, Nicolas JF. 2009. Effector and regulatory mechanisms in allergic contact dermatitis. Allergy 64: 1699-1714.</ref>.
lymph node, an ''in vitro'' assay based on T-cells are useful in confirming the AOP as well as identifying
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sensitizers. As noted earlier, T-cells are typically activated to form a memory T-cell by protein-hapten
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complexes presented by dendritic cells on a MHC molecule. Molecular understanding of this process has
+
improved in recent years<ref name="Martin">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. [http://www.ncbi.nlm.nih.gov/pubmed/20717835]</ref>. 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 Tcell
+
proliferation being the reported outcome. Much of this work has been recently reviewed by Martin et
+
al. (<ref name="Martin"></ref>). It should be remembered that lymph node cell proliferation is the basis for the LLNA.
+
 
+
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 <ref name="Martin"></ref>).
+
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<ref name="Vocanson">Vocanson M, Hennino A, Rozieres A, Poyet G, Nicolas JF 2009. Effector and regulatory mechanisms in allergic contact dermatitis. Allergy 64: 1699-1714.</ref>.
+
 
+
Perhaps the most interesting finding about lymphoid tissue, as related to the sensitisation is the
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selectivity of cytokine secretion. Hopkins et al.<ref name="Hopkins">Hopkins JE, Naisbitt DJ, Kitteringham NR, Dearman RJ, Kimber I, Park BK. 2005. Selective
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haptenation of cellular or extracellular proteins by chemical allergens: Association with cytokine polarization. Chem. Res. Toxicol. 18: 375-381.</ref>), building on earlier work of Dearman and coworkers, reported that lymphoid tissue of mice exposed to classic electrophiles with conjugate proteins via
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36 nucleophilic substitution as halo-nitro-aromatic compounds (i.e. 1-chloro-2,4-dinitrobenzene and 1-fluoro-
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2,4-dinitrobenzene) expresses high levels of the Th1 cytokine IFN-γ and low levels of the Th2 cytokines
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IL-5 and IL-10. Conversely, lymphoid tissue for mice exposed to 2,4-dinitrobenzene sulphonyl chloride,
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which conjugates with proteins via nucleophilic substitution as a sulphonyl halides, the acylating agent
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trimellitic anhydride, or fluorescein isothiocyanate, which conjugates with proteins via nucleophilic
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addition to the carbon atom of the isothiocyanate (-N=C=S) moiety, express high levels of the Th2
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cytokines IL-5 and IL-10 and low levels of the Th1 cytokine IFN-γ. Based on
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differential binding to cellular and serum proteins Hopkins et al. (<ref name="Hopkins"></ref>) showed that chemicals that
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stimulate a Th1 cytokine response bind selectively to cellular proteins, while chemicals that stimulate a
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Th2 cytokine response bind selectively to serum proteins. While it would be tempting to say electrophiles
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which preferentially bind to cysteine express a Th1 cytokine profile and electrophiles which preferentially
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bind to lysine express a Th2 cytokine profile, it is most likely not that simple.
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== How it is Measured or Detected ==
 
== How it is Measured or Detected ==
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</em>
 
</em>
  
Recognizing the importance of the process of antigen presentation (i.e. T-cell priming), ''in vitro'' T-cell
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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>.
priming assays have been developed (see<ref name="Martin"></ref>). While first generation assays could only
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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 TG 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 No442A: 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>).
detect strong or extreme sensitizers, more recent development using normal human peripheral blood
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depleted of regulatory cells that normally prevent the sensitisation phase increased the probability that T-cell
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proliferation would be detected <ref name="Vocanson"></ref>). A related approach is based on the hypothesis
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that there is a correlation between the potency of contact allergens and T-cell frequency and T-cell receptor
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repertoire (<ref>Kotturi MF, Scott I, Wolfe T, Peters B, Sidney J, Cheroutre H, et al. 2008. Naive precursor
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frequencies and MHC binding rather than the degree of epitope diversity shape CD8+ T cell
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immunodominance. J. Immunol. 181: 2124-2133.</ref>). It is plausible that sensitisation potency may correlate with the size of the
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contact allergen-specific effector and regulatory T-cell pools and their diversity, and this could form the
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basis of a new generation of ''in vitro'' T-cell priming assays. It should be remembered that lymph node cell
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proliferation is the basis for the LLNA.
+
  
 
=== Overview table: How it is measured or detected ===
 
=== Overview table: How it is measured or detected ===
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{| cellspacing="0" cellpadding = "3" border="1"
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{| class="wikitable" id="Event272"
 
|+ '''Overview'''
 
|+ '''Overview'''
 
! Method(s)
 
! Method(s)
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== Evidence Supporting Taxonomic Applicability ==
 
== Evidence Supporting Taxonomic Applicability ==
 
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Some ''in vitro'' assays have been developed using human T cells<ref name="Martin 2010"></ref>.
 
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Lymph node proliferation is the basis for the ''in vivo'' mouse LLNA.
  
 
== References ==
 
== References ==
  
 
<references />
 
<references />

Latest revision as of 12:07, 27 May 2016



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.

If you manually enter text in this section, it will get automatically altered or deleted in subsequent edits using the widgets.

AOPs Including This Key Event

AOP Name Event Type Essentiality
Covalent Protein binding leading to Skin Sensitisation KE Strong

Taxonomic Applicability

Name Scientific Name Evidence Links
human Homo sapiens Strong NCBI
mouse Mus musculus Strong NCBI

Level of Biological Organization

Biological Organization
Organ

How this Key Event works

T-cells are typically affected by protein-hapten complexes presented by dendritic cells on Major Histocompatibility Complex (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. If reactivated upon presentation by skin dendritic cells, these memory T-cells will induce allergic contact dermatitis[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 TG 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

Some in vitro assays have been developed using human T cells[1]. Lymph node proliferation is the basis for the in vivo mouse LLNA.

References

  1. 1.0 1.1 1.2 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 No442A: 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.