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Relationship: 2027

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Suppression of IL-4 production leads to Impairment, TDAR

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Suppression of IL-4 production

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Impairment, TDAR

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name	Adjacency	Weight of Evidence	Quantitative Understanding	Point of Contact	Author Status	OECD Status
Inhibition of JAK3 leading to impairment of T-Cell Dependent Antibody Response	adjacent	High	High	Brendan Ferreri-Hanberry (send email)	Under development: Not open for comment. Do not cite	Under Development

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Term	Scientific Term	Evidence	Link
Homo sapiens	Homo sapiens	High	NCBI
Mus musculus	Mus musculus	High	NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Mixed	High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Term	Evidence
All life stages	High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

IL-2 induces T cell proliferation Therefore, the suppression of IL-2 production leads to the impairment of TDAR. The IL-2-JAK3-STAT5 axis regulates Th1 cell differentiation, suggesting that IL-2 mediated JAK3-STAT5 signaling may generically operate in the production of Th1-related cytokines (Shi, et al. 2008).

IL-2 is produced and secreted by helper T cells. IL-2 has important roles in the development of TDAR. IL-2 promotes differentiation of B cells by stimulating differentiation of activated T cells to Th2 T cells. Therefore, suppressed production of IL-2 impairs T cell dependent antibody production.

In T cells, binding of IL-4 to its receptor induces proliferation and differentiation into Th2 cells. Th2 cells assist B cells and promote class switching from IgM to IgG1 and IgE. Therefore, the suppression of IL-4 production leads to impairment of TDAR.

T cells, B cells, and antigen-presenting cells, such as dendritic cells, are involved in the induction and development of TDAR. Thus, changes in any of these immune cell populations can influence TDAR.

After treatment with FK506 or CsA, production of IL-2, IL-4, and other cytokines decreases in T cells (Dumont, et al. 1998, Dumont, et al. 1998). This reduces stimulation of B cells as well as proliferation, activation, and class switching, leading to impairment of TDAR. Therefore, FK506 and CsA are potent inhibitors of T cell dependent antibody production. Suppression of the production of these B cell related cytokines appears to be the main factor in the impairment of TDAR (Heidt, et al. 2010).

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Map 2.0

ID	Experimental Design	Species	Upstream Observation	Downstream Observation	Citation (first author, year)	Notes

Evidence Map

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Title	First Author	Biological Plausibility	Dose Concordance	Temporal Concordance	Incidence Concordance

Biological Plausibility

Dose Concordance Evidence

Temporal Concordance Evidence

Incidence Concordance Evidence

Uncertainties and Inconsistencies

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

IL-2 affects multiple populations of immune cells expressing IL-2 receptors, while IL-4 mainly acts on B cells. Additional suppression of other immune functions may also be possible.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Treatment with CsA (cyclosporin A) at 50 mg/kg BID (bis in die) resulted in reduction of IL-2, IL-4 cytokine production from PMA/ionomycin stimulation of whole blood in synomolgus monkey starting on Day 0 and continuing through the end of study on Day 16. In addition, Tacrolimus concentration was 1.0 ng/ml. Tacrolimus inhibited IL-2 and IL-4 mRNA levels. Glycosylation-inhibiting factor (GIF) secreted from CD4 cells suppressed IL-4 mRNA levels of the same cells during the initial 24 h of CD3/CD28 stimulation.

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

CsA treatment achieved 100% maximal inhibition of the ex vivo IL-2 response on Days 0, 9, and 16. CsA treatment achieved 82 [± 10]%, 68 [± 25]%, and 82 [± 9]% maximal inhibition of the ex vivo IL-4 response on Days 0, 9, and 16, respectively.

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

In a rat T cell proliferation assay, IL-2-induced T cell proliferation was inhibited by peficitinib in a concentration-dependent manner with an IC50 of 10 nM and by tofacitinib with a similar IC50 of 24 nM (Gianti and Zauhar 2015). In addition, cynomolgus monkeys treated with CsA showed suppression of IL-2 and TDAR using SRBCs in a dose-dependent manner (Gaida, et al. 2015).\

In the human T-B-cell co-culture stimulated with anti-CD3 monoclonal antibody, CNIs of FK506 and CsA lowered the mRNA levels of T cell cytokines at 8 h post-stimulation including IL-2 and IL-4 at 1.0 ng/mL (1.24 nM) FK506 or 100 ng/mL (90.7 nM) CsA, and inhibited IgM and IgG productions after 9 days at 0.3 and 1.0 ng/mL FK506 and 50 and 100 ng/mL CsA (Heidt, et al. 2010).

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

In human T cell culture, suplatast tosilate (an inhibitor of the production of cytokines by Th2 cells) inhibited IL-4 production after 3 days and antigen-specific IgE production after 10 days (Taiho 2013).

Other authors described that in human T-B-cell co-cultures, FK506 and CsA lowered the mRNA levels of IL-2 and IL-4 at 8 h post-stimulation and inhibited IgM and IgG production after 9 days (Heidt, et al. 2010).

Treatment with CsA (50 mg/kg) twice daily in cynomolgus monkeys resulted in reduction of IL-4 cytokine production from PMA/ionocycin stimulation of whole blood starting on day 0 and continuing through the end of the study on day 16. CsA treatment achieved 82 [±10]%, 68 [± 25]%, and 82 [± 9]% 100% maximal inhibition of ex vivo IL-4 response on days 0, 9, and 16. SRBC-specific IgM and IgG were significantly lower in animals dosed with CsA than in animals dosed with the vehicle control on days 9, 12, and 16 post-immunization. There was ≥80% or greater reduction in SRBC-specific IgM on days 9–16. SRBC-specific IgG was decreased by ≥95% on days 9–16 (Gaida, et al. 2015). This was similar to the degree of inhibition observed in rats using an KLH immunization model (Smith, et al. 2003).

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

B cells are required for the generation and / or maintenance of Th2 responses. Germinal center B cells regulate Th2 development through an IL-4 dependent process. Type 2 immunity and allergic responses are initiated by T cells and DCs, this response may be sustained and potentially amplified by an IL-4-driven feedback loop between Ag-specific T and B cells (Harris, et al. 2005).

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

The effects of FK506 on serum concentrations of anti-KLH antibodies IgM and IgG have been demonstrated in rats treated with FK506 for over 4 weeks and immunized with KLH (Ulrich, et al. 2004). The effects of FK506 and CsA on the levels of IgM and IgG in the culture supernatant have been demonstrated in human cells (Heidt, et al. 2010, Sakuma, et al. 2001). In thymectomized mice, the development of KLH-specific effector CD4 T cells was reportedly reduced and these cells were suppressed in their production of IL-4 (Bradley, et al. 1991). The effects of FK506 and CsA on the production of IL-2 have been demonstrated using mice and human cells. These facts suggest that there are no species differences between humans and rodents in the inhibition of IL-4 production and TDAR induction.