Comments for Aop:154
Nathalie Delrue
On August 25, 2021 12:40
The attached document is a snapshot of AOP 154 showing in track changes the authors' revisions to address the comments made by Germany during the WNT and WHPA endorsement phase (10 May – 22 July 2021).
Uploaded file:
Nathalie Delrue
On August 24, 2021 11:21
The AOP was submitted to the WNT and WPHA for endorsement on 10 May 2021. During this phase, Germany submitted comments which were addressed by the AOP authors to the satisfaction of Germany, who confirmed the endorsement of the AOP on 22 July 2021.
The attached document includes the comments sent by Germany to the authors of AOP 154 and, in red, the responses from the authors.
Uploaded file:
Nathalie Delrue
On November 04, 2020 09:59
Outcome of the verification of AOP readiness for WNT and WPHA submission
Uploaded file:
Nathalie Delrue
On December 11, 2019 07:42
At the EAGMST June meeting in 2018, this AOP was released for external review. It was brought to the attention of the group though that this AOP may not be an ‘adverse’ outcome pathway but a ‘therapeutic’ outcome pathway (i.e. immunotoxicity vs immunosuppression). Further discussion bringing the expertise of an immunotoxicologist was subsequently organised. The outcome of the discussion was the following:
Expert recommendation:
First of all I want to thank you and your colleagues. You did a great job by developing this very useful AOP154. It is just a minor concern that I have and maybe the integration of the following points could help to prevent scientific discussion in the process of the external review.
#1: Abstract/Applicability Domain/MIE
As the regulatory use of AOPs and the methods related is an important issue, it would be very important to distinguish the therapeutic effect of drugs from the adverse effect of chemicals. The “wanted” drug effects of CNIs such as
FK506 and FKBP12 that could help to overcome health problems that are related to inflammation (organ rejection etc.). On the other site are the “unwanted” adverse effects of chemicals. These chemicals´ effects on immunosuppression and the specific participation of CN are less well understood than the drug effects. However, from my understanding the chemicals´ effects are the crucial in the adverse outcome pathways. I would propose to focus in the abstract and applicability domain in AOPWiki on adverse and not therapeutic effects and give examples from the literature. It could be helpful to integrate here examples for chemicals/drugs that exhibit immunosuppression by CN inhibition as an adverse effect for instance as mentioned in tab. 1 of the excellent review of Luster and Rosenthal in Environmental Health Perspectives Vol. 100, pp. 219-236, 1993.
#2: Populations of T cells
I understand the idea to keep an AOP as complex as necessary but I would suggest to specify the T cell populations mentioned in the AOP. In immunology research the family of T cells is becoming rather complex and cells such as T helper (Th1, Th2, Th17), cytotoxic and regulatory T cells are all T cells but show by inflammatory and immunosuppressive potential opposite effects. If you focus in the AOP on T helper cells that produce IL-2 and IL-4, I would recommend to specify T helper cells, if possible IFN-g producing Th1 and IL-4 producing Th2.
#3: Literature 2015-2018
Of course the AOP was originally developed some years ago, it could be helpful to perform a scientific literature review also including new publications of the years 2015-2018.
-------------------------
Authors responses:
We appreciate your careful review and helpful comments for the development of the AOP154.
Your comments will help us for an external review.
We will compete the update of AOP154 on the AOP-wiki by the end of January 2019. Below is our idea about the update.
#1: Abstract/Applicability Domain/MIE
First, we thank you for sharing the review paper.
Although "wanted" immunosuppression by CNIs is the therapeutic effect as you say, the effect can also be "unwanted" adverse effects. For example, unexpected immunosuppression such as increased susceptibility to infection is an "unwanted" effect of CNIs. Accordingly, we have focused on the effects on TDAR as one of the most important endpoint affecting protective immunity in the AOP154.
However, as you say, the present AOP154 does not fully describe the differences between the “wanted” and “unwanted” pharmacology. We will amend the description referencing the paper provided from you.
#2: Populations of T cells
As you pointed out, AOP154 lacks the description about T cell populations. We will amend the AOP about IL-2 and IL-4 produced by Th1 and Th2 cells and refer the effects on other T cell subsets.
#3: Literature 2015-2018
We understand that AOP is living document. Therefore, we will continue our efforts to search new literature including new publications of the years 2015-2018.
Kiyoshi Kushima
On May 31, 2018 01:23
According to the reviewers’ comments, we revised the AOP. Please find enclosed file decribed reply to comment.
Uploaded file:
Ye Lin Jun
On April 11, 2018 11:59
Review_summary_with SR2 comments_11.04.2018
Uploaded file:
Ye Lin Jun
On April 11, 2018 03:39
Review_K. Goyak_11.04.2018
Uploaded file:
Brigitte Landesmann
On April 10, 2018 04:08
Review_summary_10.04.2018
Uploaded file:
Brigitte Landesmann
On April 03, 2018 11:01
Review_E.Perkins_03.04.2018
Uploaded file:
edited - April 03, 2018 11:02
Brigitte Landesmann
On March 22, 2018 09:34
Review_B.Landesmann_22.03.2018
Uploaded file:
Ye Lin Jun
On February 02, 2018 05:33
AOP 154 Internal Review Charge Questions Template (Q1 2018)
The results from previous internal review(including reviewers' comments and authors' responses) took place in Q1 2017 have been included in the template as in blue boxes.
Uploaded file:
edited - February 02, 2018 05:34
Nathalie Delrue
On May 22, 2017 05:39
Internal review:
The revision of AOP:154 has been completed, and the responses against each comments are avaialble in the attached review file.
Uploaded file:
Cataia Ives
On March 22, 2017 10:06
This AOP underwent OECD review prior to the launch of this version of the Wiki. To see those prior reviews, follow this link: https://aopwiki.org/wiki/index.php/Talk:Aop:154#tab=Formal_Reviews_Managed_by_the_OECD