Aop: 313

Title

Each AOP should be given a descriptive title that takes the form “MIE leading to AO”. For example, “Aromatase inhibition [MIE] leading to reproductive dysfunction [AO]” or “Thyroperoxidase inhibition [MIE] leading to decreased cognitive function [AO]”. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE. More help

Stimulation of TLR7/8 in dendric cells leading to Psoriatic skin disease

Short name
A short name should also be provided that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
Skin disease by stimulation of TLR7/8

Graphical Representation

A graphical summary of the AOP listing all the KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs should be provided. This is easily achieved using the standard box and arrow AOP diagram (see this page for example). The graphical summary is prepared and uploaded by the user (templates are available) and is often included as part of the proposal when AOP development projects are submitted to the OECD AOP Development Workplan. The graphical representation or AOP diagram provides a useful and concise overview of the KEs that are included in the AOP, and the sequence in which they are linked together. This can aid both the process of development, as well as review and use of the AOP (for more information please see page 19 of the Users' Handbook).If you already have a graphical representation of your AOP in electronic format, simple save it in a standard image format (e.g. jpeg, png) then click ‘Choose File’ under the “Graphical Representation” heading, which is part of the Summary of the AOP section, to select the file that you have just edited. Files must be in jpeg, jpg, gif, png, or bmp format. Click ‘Upload’ to upload the file. You should see the AOP page with the image displayed under the “Graphical Representation” heading. To remove a graphical representation file, click 'Remove' and then click 'OK.'  Your graphic should no longer be displayed on the AOP page. If you do not have a graphical representation of your AOP in electronic format, a template is available to assist you.  Under “Summary of the AOP”, under the “Graphical Representation” heading click on the link “Click to download template for graphical representation.” A Powerpoint template file should download via the default download mechanism for your browser. Click to open this file; it contains a Powerpoint template for an AOP diagram and instructions for editing and saving the diagram. Be sure to save the diagram as jpeg, jpg, gif, png, or bmp format. Once the diagram is edited to its final state, upload the image file as described above. More help

Authors

List the name and affiliation information of the individual(s)/organisation(s) that created/developed the AOP. In the context of the OECD AOP Development Workplan, this would typically be the individuals and organisation that submitted an AOP development proposal to the EAGMST. Significant contributors to the AOP should also be listed. A corresponding author with contact information may be provided here. This author does not need an account on the AOP-KB and can be distinct from the point of contact below. The list of authors will be included in any snapshot made from an AOP. More help

Hiroyuki Komatsu (1) Takao Ashikaga (1) Tomoki Fukuyama (1) Ken Goto (1) Shinko Hata (1) Shigeru Hisada (1) Shiho Ito (1) Sumie Konishi (1) Tadashi Kosaka (1) Kiyoshi Kushima (1) Shogo Matsumura (1) Takumi Ohishi (1) Yasuharu Otsubo (1) Junichiro Sugimoto (1) Yasuhiro Yoshida (1)

(1) AOP Working Group, Testing Methodology Committee, The Japanese Society of Immunotoxicology

Corresponding author:  Komatsu (hiroyuki-komatsu@cmic.co.jp)

Point of Contact

Indicate the point of contact for the AOP-KB entry itself. This person is responsible for managing the AOP entry in the AOP-KB and controls write access to the page by defining the contributors as described below. Clicking on the name will allow any wiki user to correspond with the point of contact via the email address associated with their user profile in the AOP-KB. This person can be the same as the corresponding author listed in the authors section but isn’t required to be. In cases where the individuals are different, the corresponding author would be the appropriate person to contact for scientific issues whereas the point of contact would be the appropriate person to contact about technical issues with the AOP-KB entry itself. Corresponding authors and the point of contact are encouraged to monitor comments on their AOPs and develop or coordinate responses as appropriate.  More help
Hiroyuki Komatsu   (email point of contact)

Contributors

List user names of all  authors contributing to or revising pages in the AOP-KB that are linked to the AOP description. This information is mainly used to control write access to the AOP page and is controlled by the Point of Contact.  More help
  • Takumi Ohishi
  • Hiroyuki Komatsu

Status

The status section is used to provide AOP-KB users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. “Author Status” is an author defined field that is designated by selecting one of several options from a drop-down menu (Table 3). The “Author Status” field should be changed by the point of contact, as appropriate, as AOP development proceeds. See page 22 of the User Handbook for definitions of selection options. More help
Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite Under Development 1.75 Included in OECD Work Plan
This AOP was last modified on June 04, 2021 16:35
The date the AOP was last modified is automatically tracked by the AOP-KB. The date modified field can be used to evaluate how actively the page is under development and how recently the version within the AOP-Wiki has been updated compared to any snapshots that were generated. More help

Revision dates for related pages

Page Revision Date/Time
Stimulation, TLR7/8 November 21, 2020 07:14
Increase, IL-23 from matured dendritic cells November 23, 2020 06:44
Th17 cell migration and inflammation induction November 23, 2020 06:59
Psoriatic skin disease November 23, 2020 07:04
Maturation of TNF/iNOS-Producing Dendritic Cells November 23, 2020 06:38
Stimulation of TLR7/8 leads to Increase of IL-23 December 27, 2019 05:33
Increase of IL-23 leads to Th17 cell migration and inflammation induction December 27, 2019 05:35
Th17 cell migration and inflammation induction leads to Skin disease December 27, 2019 05:41
Imiquimod December 27, 2019 04:57
Resiquimod December 27, 2019 04:58

Abstract

In the abstract section, authors should provide a concise and informative summation of the AOP under development that can stand-alone from the AOP page. Abstracts should typically be 200-400 words in length (similar to an abstract for a journal article). Suggested content for the abstract includes the following: The background/purpose for initiation of the AOP’s development (if there was a specific intent) A brief description of the MIE, AO, and/or major KEs that define the pathway A short summation of the overall WoE supporting the AOP and identification of major knowledge gaps (if any) If a brief statement about how the AOP may be applied (optional). The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance More help

Toll-like receptor (TLR) 7 and TLR8 are pattern recognition receptors that are known to activate antiviral reaction of immune system, hyperactivation of which can lead to psoriatic skin disease when hyperactivation of them occurred. The relationship between TLR7/8 and immune functions is well understood, and antiviral compound that work by stimulating TLR7/8 have been developed. TLR7/8 agonists such as imidazoquinolin compounds stimulate these TLRs through the formation of homodimer. This signal activates the IL-23/IL-17 axis, which leads to  psoriasis and other related skin diseases.

Activation of the IL-23 / IL-17 axis and causes abnormal proliferation and inflammation of the epidermis, which is a pathological condition of psoriasis. This AOP shows an association between TLR7 / 8 stimulation and psoriatic skin disease.

TLR7-mediated signaling in plasmacytoid dendric cells (pDC) is mediated in a MyD88-dependent fashion, which initiates an IRF7, IRAK1, TRAF6, TRAF3, and IKKα-mediated response, secreting vast amounts of IFN type 1. Similarly, upon engagement of ligands in endosomes, TLR8 initiate the MyD88-dependent pathway culminating in synthesis and release of proinflammatory mediators, such as TNF-α via NF-κB activation. IFN-α and TNF-α cooperatively mature myeloid dendritic cells. TLR7/8 agonist stimulates a specific population of inflammatory dermal dendritic cells referred as TNF and inducible nitric oxide synthase–expressing DCs (Tip-DCs) to produce IL-23 after maturation by enhanced transcriptional activity.

IL-23R is mainly expressed in Th17 cells. In chronic psoriasis, the cytokines IL-12 and IL-23 produced by resident DC are the main causes. Not only does the expression of IL-23 increases in the skin tissue of the lesion, Th17 cells also increase.

Mature Th17 cells are activated by IL-23 stimulation. Signaling through IL-23 produces cytokines  IL-17 and IL-22 that mediate the psoriasis response and promote neutrophil migration into the epidermis, epidermal cell proliferation, and similar responses, which lead to the development of a psoriasis rash. In mice, psoriasis-like hyperplasia is induced by the application of IL-23 but does not occur in IL-17A and IL-22 KO mice, so IL-17A and IL-22 play an important role downstream of IL-23.

IL-17 receptor form heterodimers, and IL-17RA / IL-17RC appears in a variety of cells, including fibroblasts and epidermal cells. IL-17RE / IL-17RA expressed in epidermal cells and IL-17C binding  are also important in the pathology of psoriasis. Immunohistochemically, IL-17A is expressed only in cells of the dermal papilla layer, while IL-17C is widely expressed in cells such as hyperproliferative overexpressed keratinocytes, leukocytes, and vascular endothelial cells. IL-17C produces keratinocytes by bacterial stimulation and further stimulates keratinocytes to induce the production of various cytokines and chemokines. Keratinocytes are known to be self-activated by IL-17C.

IL-17 and IL-22 secreted from Th17 act on keratinocytes, causing abnormalities in keratinocytes through the secretion of inflammatory cytokines, chemokines, growth factors, and antimicrobial peptides, and thereby exacerbating  the skin symptoms of psoriasis.

The creation of this AOP began with an examination of important event relationships brought about by TLR7 / 8 activity due to environmental or genetic factors and resulting in abnormal differentiation of keratinocytes, which leads to thickening of the epidermis and its resultant autoimmune skin disease, psoriasis

Background (optional)

This optional subsection should be used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development. The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. Examples of potential uses of the optional background section are listed on pages 24-25 of the User Handbook. More help

Psoriasis is an chronic autoimmune disease characterized  by chronic epithelial inflammatory disease induced by environmental factors such as infection, stress, smoking or alcohol consumption as well as by genetic factors. The onset of psoriasis has been reported to be triggered by drugs and chemical substances use, including  beta-blockers, chloroquine, lithium, ACE inhibitors, indomethacin, terbinafine, and interferon alpha. Diagnosis is based on the type and distribution of the lesions.

Psoriasis occurs when abnormal differentiation (keratosis) of keratinocytes leads to thickening of the epidermis. Patients often exhibit an erythema with a clear border and epidermal hyperplasia, stratum corneum hyperplasia, heterocytosis in the stratum corneum, mixed skin moist cells of neutrophilic granulocytes and T cells in the epidermis. Dendritic cells (DC) and macrophages are associated with silver-white plaque. Neutrophilic effusion (Munro microabscesses) are observed in the epidermis, and CD8+ T cells (Tc17) increase the expression of angiogenesis related genes.

The main therapeutic agents are mild topical treatments such as emollients, salicylic acid, coal tar preparations, anthralin, corticosteroids, vitamin D3 derivatives, retinoids, calcineurin inhibitors or tazarotene. UV therapy is also used for moderate or severe psoriasis. Widespread psoriasis is treated with systemic therapies such as immunomodulators methotrexate, cyclosporin, retinoids and other immunosuppressants used alone or in combination.

Although there are stressors that are well known to induce psoriasis-like skin inflammation in mice, this AOP is based primarily on an understanding of stimulation caused by imiquimod, resiquimod or LL37-selfRNA complexes, for which a significant body of scientific literature has been published.

As a test model for psoriasis, an Autoimmune skin disease, mouse tests that induce skin inflammation like psoriasis are frequently conducted using the imidazoquinoline derivative imiquimod. This AOP is primarily based on an understanding of stimuli caused by imiquimod, resiquimod, or LL37-selfRNA complexes.

Imiquimod is derived from imidazoquinoline and is often used to create mouse models. It is our hope that this AOP will contribute to greater knowledge about the development of psoriatic skin diseases that start from stimulation of TLR as well as the development of new treatment targets for psoriasis.

Summary of the AOP

This section is for information that describes the overall AOP. The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help

Events:

Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a stressor and the biological system) of an AOP. More help
Key Events (KE)
This table summarises all of the KEs of the AOP. This table is populated in the AOP-Wiki as KEs are added to the AOP. Each table entry acts as a link to the individual KE description page.  More help
Adverse Outcomes (AO)
An AO is a specialised KE that represents the end (an adverse outcome of regulatory significance) of an AOP.  More help
Sequence Type Event ID Title Short name
1 MIE 1706 Stimulation, TLR7/8 Stimulation of TLR7/8
2 KE 1822 Maturation of TNF/iNOS-Producing Dendritic Cells Maturation, TNF/iNOS-Producing Dendritic Cells
3 KE 1707 Increase, IL-23 from matured dendritic cells Increase of IL-23
4 KE 1708 Th17 cell migration and inflammation induction Th17 cell migration and inflammation induction
5 AO 1709 Psoriatic skin disease Skin disease

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarises all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP. Each table entry acts as a link to the individual KER description page.To add a key event relationship click on either Add relationship: events adjacent in sequence or Add relationship: events non-adjacent in sequence.For example, if the intended sequence of KEs for the AOP is [KE1 > KE2 > KE3 > KE4]; relationships between KE1 and KE2; KE2 and KE3; and KE3 and KE4 would be defined using the add relationship: events adjacent in sequence button.  Relationships between KE1 and KE3; KE2 and KE4; or KE1 and KE4, for example, should be created using the add relationship: events non-adjacent button. This helps to both organize the table with regard to which KERs define the main sequence of KEs and those that provide additional supporting evidence and aids computational analysis of AOP networks, where non-adjacent KERs can result in artifacts (see Villeneuve et al. 2018; DOI: 10.1002/etc.4124).After clicking either option, the user will be brought to a new page entitled ‘Add Relationship to AOP.’ To create a new relationship, select an upstream event and a downstream event from the drop down menus. The KER will automatically be designated as either adjacent or non-adjacent depending on the button selected. The fields “Evidence” and “Quantitative understanding” can be selected from the drop-down options at the time of creation of the relationship, or can be added later. See the Users Handbook, page 52 (Assess Evidence Supporting All KERs for guiding questions, etc.).  Click ‘Create [adjacent/non-adjacent] relationship.’  The new relationship should be listed on the AOP page under the heading “Relationships Between Two Key Events (Including MIEs and AOs)”. To edit a key event relationship, click ‘Edit’ next to the name of the relationship you wish to edit. The user will be directed to an Editing Relationship page where they can edit the Evidence, and Quantitative Understanding fields using the drop down menus. Once finished editing, click ‘Update [adjacent/non-adjacent] relationship’ to update these fields and return to the AOP page.To remove a key event relationship to an AOP page, under Summary of the AOP, next to “Relationships Between Two Key Events (Including MIEs and AOs)” click ‘Remove’ The relationship should no longer be listed on the AOP page under the heading “Relationships Between Two Key Events (Including MIEs and AOs)”. More help

Network View

The AOP-Wiki automatically generates a network view of the AOP. This network graphic is based on the information provided in the MIE, KEs, AO, KERs and WoE summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Stressors

The stressor field is a structured data field that can be used to annotate an AOP with standardised terms identifying stressors known to trigger the MIE/AOP. Most often these are chemical names selected from established chemical ontologies. However, depending on the information available, this could also refer to chemical categories (i.e., groups of chemicals with defined structural features known to trigger the MIE). It can also include non-chemical stressors such as genetic or environmental factors. Although AOPs themselves are not chemical or stressor-specific, linking to stressor terms known to be relevant to different AOPs can aid users in searching for AOPs that may be relevant to a given stressor. More help
Name Evidence Term
Imiquimod High
Resiquimod High

Life Stage Applicability

Identify the life stage for which the KE is known to be applicable. More help
Life stage Evidence
All life stages Not Specified

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected. In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
Homo sapiens Homo sapiens High NCBI
Mus musculus Mus musculus Moderate NCBI

Sex Applicability

The authors must select from one of the following: Male, female, mixed, asexual, third gender, hermaphrodite, or unspecific. More help
Sex Evidence
Mixed High

Overall Assessment of the AOP

This section addresses the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and WoE for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). The goal of the overall assessment is to provide a high level synthesis and overview of the relative confidence in the AOP and where the significant gaps or weaknesses are (if they exist). Users or readers can drill down into the finer details captured in the KE and KER descriptions, and/or associated summary tables, as appropriate to their needs.Assessment of the AOP is organised into a number of steps. Guidance on pages 59-62 of the User Handbook is available to facilitate assignment of categories of high, moderate, or low confidence for each consideration. While it is not necessary to repeat lengthy text that appears elsewhere in the AOP description (or related KE and KER descriptions), a brief explanation or rationale for the selection of high, moderate, or low confidence should be made. More help

TLR7/8 is stimulated when imidazoquinolin compounds or stimilar  agonists from  homodimers TLR7-mediated signaling in plasmacytoid dendritic cells (pDC) is mediated in a MyD88-dependent fashion, which initiates an IRF7, IRAK1, TRAF6, TRAF3, and IKKα-mediated response,thereby secreting large amounts of IFN-α. Similarly, the engagement of ligands in endosomescauses TLR8 initiate the MyD88-dependent pathway, culminating in synthesis and release of TNF-a and other proinflammatory mediators, via NF-κB activation.

IFN-α and TNF-α cooperatively mature myeloid dendritic cells. TLR7/8 agonist stimulates a  specific population of inflammatory dermal dendritic cells referred as Tip-DCs to produce IL-23 after maturation by enhanced transcriptional activity.

Naive T cells differentiate into Naive Th17 by both IL-6 and TGF-β cells that express the transcription factors ROR-γt, ROR-α, and STAT3. These naive Th17 cells are self-activated by IL-21 in an autocrine manner and mature into Th17 cells which express IL-23 receptor on cell surface. Mature Th17 cells are activated by IL-23 stimulation. IL-23-mediated signal transduction produces cytokines IL-17.

IL-17 mediates the psoriasis response, promoting such activities as neutrophil migration to the epidermis,and proliferation of epidermal cells, which leads to the outbreak of psoriasis rash. Thus, psoriatic skin is induced mainly by overproduction of IL-17, which leads to a variety of  adverse effects. We have identified a number of key events (KEs) along this pathway and created an AOP for stimulation of TLR7/8 that leads to psoriatic skin disease based on these key event relationships(KERs).

Domain of Applicability

The relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context are defined in this section. Biological domain of applicability is informed by the “Description” and “Biological Domain of Applicability” sections of each KE and KER description (see sections 2G and 3E for details). In essence the taxa/life-stage/sex applicability is defined based on the groups of organisms for which the measurements represented by the KEs can feasibly be measured and the functional and regulatory relationships represented by the KERs are operative.The relevant biological domain of applicability of the AOP as a whole will nearly always be defined based on the most narrowly restricted of its KEs and KERs. For example, if most of the KEs apply to either sex, but one is relevant to females only, the biological domain of applicability of the AOP as a whole would be limited to females. While much of the detail defining the domain of applicability may be found in the individual KE and KER descriptions, the rationale for defining the relevant biological domain of applicability of the overall AOP should be briefly summarised on the AOP page. More help

The proposed AOP for psoriasis-like skin thickening resulting from abnormal differentiation of keratinocytes, starting with Toll-like receptor (TLR) 7/8 activity, is independent of life stage, gender, or age (Lowes et al. 2007). The pathogenesis of psoriasis, an autoimmune disease, is genetically predisposed (3), but the autoantigen that causes psoriasis has not been identified (Zaba et al. 2008). Other causes of psoriasis are caused by external and internal triggers such as mild trauma, sunburn, infection, systemic drugs, and stress (Hansel et al. 2011). Stimulation of TLR7 / 8 releases INF-α and TNF-α in large amounts to produce IL-23, and Th17 cells mature by the stimulation to produce IL-17 and IL-22. In psoriasis skin formation, cytokines such as TNF-α, IL-23, and IL-17 work continuously. Since TNF-α inhibitors significantly suppressed IL-17A and IL-23p19 expression in psoriatic eruptions (Leonardi et al. 2012), by suppressing self-activation of Tip-DC by TNF-α, It can be seen that IL-23 and IL-17A production was suppressed. Anti-IL-17 and anti-IL-17RA antibodies suppress IL-17A and IL-17C, which are highly expressed in psoriatic eruptions. In particular, anti-IL-17RA antibody has been shown to normalize the expression of keratinocyte-related genes and IL-17C production two weeks after administration, followed by normalization of IL-17A production from leukocytes.

In mice, subcutaneous administration of IL-23 induced psoriatic eruption and IL-17A expression (K. A. et al. 2013), and IL-17C transgenic mice overexpressing IL-17C in keratinocytes showed psoriatic eruption. As shown in (8), the reaction of psoriasis-like eruption occurs in mice due to the chain of stimulation to T cells and epidermal cells starting from TLR.

Essentiality of the Key Events

An important aspect of assessing an AOP is evaluating the essentiality of its KEs. The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence.The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs.When assembling the support for essentiality of the KEs, authors should organise relevant data in a tabular format. The objective is to summarise briefly the nature and numbers of investigations in which the essentiality of KEs has been experimentally explored either directly or indirectly. See pages 50-51 in the User Handbook for further definitions and clarifications.  More help

Stressor, MIE and later events:MyD88 knock out(KO) mice

TLR7 (TLR7 / 8 in human) recognizes the imidazoquinoline derivative, binds to the adapter molecule MyD88, activates IRAKs (IL-1 receptor associated kinases), interacts with TRAF6 (TNF receptor associated factor 6) and IKK (Activates the IκB kinase complex). It phosphorylates IκB, induces its degradation, and transfers the transcription factor NF-κB to the nucleus. This pathway is called MyD88-dependent pathway and is essential for the production of inflammatory cytokines such as TNF-α (Akira S, Takeda K .: Nat Rev Immunol. Jul; 4: 499-511, 2004). When pDC is stimulated with a TLR7 / 8 ligand, the transcription factor IRF7 constitutively expressing pDC and MyD88 associate directly. IRF7 activity does not occur when pDCs of MyD88 KO mice are stimulated with TLR7 / 8 ligand. IRF7 is also activated by binding to TRAF6, leading to IFN-α production, which requires the Myd88 / TRAF6 / IRF7 complex. (Satoshi U, Shizuo A: Virus 54; 2: 145-152,2004)

Imiquimod 5% cream was applied to the left flank of female SKH-1 hairless mice (25 g body weight). The IFN-α and TNF-α concentrations in the skin after 1 and 2 hours of application increased these concentrations compared to the untreated skin.

In C57BL / 6 mice (8-12 weeks old) sensitized with 0.5% dinitrofluorobenzene (DNFB) as an antigen, imiquimod 5% cream was applied to the auricle once a day for 3 days. The application of imiquimod 5% cream promoted edema of the ears of mice (promoted DTH) compared to the base cream group. Imiquimod activates antigen-specific T cells by topical application to the skin. (Beserna Cream Interview Form Mochida Pharmaceutical Co., Ltd.)

 

KE-1 and later event:IL-17, IL-22 KO mice

In mice, psoriasis-like hyperplasia is induced by the application of IL-23, but this effect does not occur in IL-17A and IL-22 KO mice. IL-17A deficient mice show little epidermal hyperplasia after intradermal administration of IL-23. WT mice treated with anti-IL-17A Ab did not show IL-23-induced epidermal hyperplasia. IL-17 KO mice treated with IL-23 do not induce TNF-α mRNA and do not cause epidermal thickening. IL-22 did not increase in IL-17-/-mice after IL-23 administration, and IL-17 clearly increased in IL-22-/-mice. In IL-17-/-, IL-22-/-and WT mice treated with IL-23, immunohistochemically CD3 + T cells, CD11c (dendritic cells), F4 / 80 (macrophages), Gr-1 (Neutrophils) were analyzed. There was no difference in F4 / 80 and Gr-1 + cells in IL-17A-/-compared to WT mice, and CD3 + T cells decreased, but there was no obvious difference in IL-22-/-mice .

These data suggest that cytokines alone are not sufficient to mediate IL-23-induced epidermal changes, and that IL-17 and IL-22 are downstream mediators of mouse skin IL-23-induced changes. Therefore, Th17 cytokines are required for the generation of IL-23-mediated skin lesions.

KE-2 and later events: Mouse psoriasis-like dermatitis model

When TPA (12-O-tetradecanoy1phorbol-13-acetate) on the dorsal skin of K14 / mIL-1F6 gene-modified mice overexpress mouse IL-1F6 (IL-36a) selectively under the keratin 14 promoter was applied, skin pathological findings specific to psoriasis were observed, such as epidermal hyperplasia, epidermal exfoliation and micro-abscess formation, and wet inflammatory cells in the dermis. Quantitative RT-PCR measures mRNA expression levels of inflammatory chemokines and cytokines in skin tissues, and includes inflammatory chemokines: CCL3, CCL4, CXCL10, CXCL1, and cytokines: IL-23, IL-12, IL-1β, etc. These expressions were elevated. (Kyowa Hakko Kirin Co., Ltd.)

Evidence Assessment

The biological plausibility, empirical support, and quantitative understanding from each KER in an AOP are assessed together.  Biological plausibility of each of the KERs in the AOP is the most influential consideration in assessing WoE or degree of confidence in an overall hypothesised AOP for potential regulatory application (Meek et al., 2014; 2014a). Empirical support entails consideration of experimental data in terms of the associations between KEs – namely dose-response concordance and temporal relationships between and across multiple KEs. It is examined most often in studies of dose-response/incidence and temporal relationships for stressors that impact the pathway. While less influential than biological plausibility of the KERs and essentiality of the KEs, empirical support can increase confidence in the relationships included in an AOP. For clarification on how to rate the given empirical support for a KER, as well as examples, see pages 53- 55 of the User Handbook.  More help

Quantitative Understanding

Some proof of concept examples to address the WoE considerations for AOPs quantitatively have recently been developed, based on the rank ordering of the relevant Bradford Hill considerations (i.e., biological plausibility, essentiality and empirical support) (Becker et al., 2017; Becker et al, 2015; Collier et al., 2016). Suggested quantitation of the various elements is expert derived, without collective consideration currently of appropriate reporting templates or formal expert engagement. Though not essential, developers may wish to assign comparative quantitative values to the extent of the supporting data based on the three critical Bradford Hill considerations for AOPs, as a basis to contribute to collective experience.Specific attention is also given to how precisely and accurately one can potentially predict an impact on KEdownstream based on some measurement of KEupstream. This is captured in the form of quantitative understanding calls for each KER. See pages 55-56 of the User Handbook for a review of quantitative understanding for KER's. More help

Considerations for Potential Applications of the AOP (optional)

At their discretion, the developer may include in this section discussion of the potential applications of an AOP to support regulatory decision-making. This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. While it is challenging to foresee all potential regulatory application of AOPs and any application will ultimately lie within the purview of regulatory agencies, potential applications may be apparent as the AOP is being developed, particularly if it was initiated with a particular application in mind. This optional section is intended to provide the developer with an opportunity to suggest potential regulatory applications and describe his or her rationale.To edit the “Considerations for Potential Applications of the AOP” section, on an AOP page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing AOP.” Scroll down to the “Considerations for Potential Applications of the AOP” section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update AOP’ to save your changes and return to the AOP page or 'Update and continue' to continue editing AOP text sections.  The new text should appear under the “Considerations for Potential Applications of the AOP” section on the AOP page. More help

References

List the bibliographic references to original papers, books or other documents used to support the AOP. More help