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Relationship: 1510

Title

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Suppression, IL-2 and IL-4 production leads to Impairment, T-cell dependent antibody response

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

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 Calcineurin Activity Leading to Impaired T-Cell Dependent Antibody Response adjacent High High Takumi Ohishi (send email) Open for comment. Do not cite WPHA/WNT Endorsed

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
cynomolgus monkey Macaca fascicularis High NCBI

Sex Applicability

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Sex Evidence
Unspecific High

Life Stage Applicability

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Term Evidence
All life stages High

Key Event Relationship Description

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Interleukin (IL)-2 and IL-4 are produced and secreted by helper T cells and play important roles in the development of T-cell dependent antibody response (TDAR), both of which induces/enhances T cell dependent antibody production. IL-4 affects maturation and class switching of B cells as well as proliferation, IL-2 promotes differentiation of B cells through IL-2 receptors and stimulates the activated T cell into T cell called Th2 cell. Therefore, suppressed production of IL-2 and IL-4 impairs T cell dependent antibody production (Alberts et al. 2008).

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

T cell-derived cytokines play important roles in the development of TDAR. Among them, IL-2 promotes proliferation of B cells, and IL-4 affects maturation and class switching of B cells as well as proliferation, both of which induces/enhances T cell dependent antibody production.

Thus, suppressing the production of IL-2, IL-4, and other cytokines in T cells reduces stimulation of B cells including proliferation, activation, and class switching, and leading to impairment of TDAR. Therefore, suppressing the production of these B-cell-related cytokines appears to be the main factor in impairment of TDAR by inhibitors of T-cell–dependent-antibody production.

Evidence Collection Strategy

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Evidence Supporting this KER

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Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

Cyclosporin A (CsA) is known to be one of the calcineurin inhibitiors. CsA-treatment is reported to suppress the productions of IL-2 and IL-4 and result in the reduction of the productions of antigen-specific IgM and IgG in cynomolgus monkeys (Gaida K. 2015).

It is established that IL-2 stimulates B cells to proliferate through the surface IL-2 receptors and that IL-4 stimulates B cells to proliferate, to induce class switch, and to differentiate into plasma and memory cells.

Dupilumab is known as anti-IL-4/13 receptor (IL-4/13R) antibody. Dupilumab (Dupixent) reduces productions of immunoglobulin (Ig) E and antigen specific IgG1 in mice (Sanofi K.K. 2018). It suggests that the blocking of IL-4 signaling by anti-IL-4/13R antibody results in the decrease in T cell dependent antibody production.

Th2 cell produces cytokines including IL-4. Suplatast tosilate (IPD) is known as an inhibitor of the production of IL-4 and IL-5 from Th2 cells and reduces the production of antigen specific IgE in human cell culture and mice (Taiho Pharmaceutical 2013). These findings suggests that the reduction of IL-4 production by the inhibitor of Th2 cell cytokines results in reduced production of IgE and/or IgG1 through inhibitions of maturation, proliferation and class switching of B cells.

IL-2 binds to IL-2 receptor (IL-2R) and acts on T cell. CD25 is one of IL-2R. Basiliximab (Simulect) is known as anti-CD25 antibody. Basiliximab binds to IL-2R and blocks IL-2 signaling. Clinical transplantation study of basiliximab reveals decreases in rejections. On the other hand, basiliximab inhibits the activation of antigen specific T cells (Novartis Pharma 2016). They suggest that the blocking of IL-2 signaling by anti-IL-2R antibody results in decreased rejection through the inhibition of the activation of antigen specific T cell with reduced antibody production.

FK506 and CsA suppress mRNA expression levels of cytokines in T cells including IL-2 and IL-4 that stimulate proliferation of B cells as well as B cell activation and class switching (Heidt et al, 2010).

Several in vivo studies in rodents showed decreased TDAR by the treatment of FK506 (Kino et al. 1987b, Ulrich et al. 2004). In in vitro tests examining antibody production in blood samples obtained from blood-bank donors, peripheral blood mononuclear cells (PBMC) treated with FK506 and CsA suppressed the production of IgM and IgG antibodies to T-cell dependent antigens (Heidt et al, 2009).

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

However, as for the suppression of humoral immunity induced by the inhibition of calcineurin (CN) phosphatase activity, calcineurin inhibitors (CNIs) do not affect B cells directly but rather indirectly through T cells. That is, FK506 and CsA are capable of inhibiting immunoglobulin production when B cells are cultured with non-pre-activated T cells, but FK506 and CsA fail to inhibit immunoglobulin levels when pre-activated T cells are used to stimulate B cells. Hence, the inhibition of B cell response by FK506 and CsA appears due solely to inhibition of T helper cells (Heidt et al, 2010).

Therefore, it is concluded that decreased amounts of IL-2 and IL-4 secreted from helper T cells is the main factor for suppression of TDAR induced by CN phosphatase inhibition.

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. Therefore, reduced production of both IL-2 and IL-4 might certainly induce suppression of TDAR; however, there remains some possibility of additional suppression of other immune functions.

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

At present, no evidence is found.

Response-response Relationship
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Cynomolgus monkeys treated wth CsA at 50 mg/kg BID showed suppression of IL-2 and IL-4 production and inhibition of SRBC-specific IgM and IgG in TDAR (Gaida K. 2015).

In the blocking of IL-4 receptor in mice by dupilumab (anti-IL-4/13R antibody) at 25 mg/kg of twice weekly subcutaneous administration for 4weeks, IgE production was suppressed to about 1/100 and antigen specific IgG1 production was suppressed to about 1/200 (Sanofi K.K. 2018).

In the inhibition of IL-4 production in mice by suplatast tosilate at 10, 20, 50 and 100 mg/kg of oral administration for 5 days, antigen specific IgE production was suppressed from about 1/10 to 1/100 (Taiho Pharmaceutical 2013). In human T cell culture by suplatast tosilate at the concentration of 10 μg/mL, antigen specific IgE production after 10 days was suppressed from 56 to 72% and IL-4 production after 3 days was suppressed from 58 to 76% (Taiho Pharmaceutical 2013).

As for IL-2 and antibody production, in vitro T-cell-induced polyclonal B cell activation to produce antibody was inhibited with anti-IL-2 and anti-IL-2R antibodies. That is, murine small resting B cells, cultured with irradiated hapten-specific TH1 clone, were induced to enter cell cycle at 2 days and to secret antibody at 5 days. An anti-IL-2 and anti-IL-2R antibodies completely inhibited this T-cell dependent antibody production (Owens T, 1991).

In the human T-B cell co-culture stimulated with anti-CD3 monoclonal antibody, CNIs of FK506 and CsA lowered the m-RNA levels of T-cell cytokines at 8h post-stimulation including IL-2 and IL-4 at 1.0ng/mL (1.24nM) FK506 or 100ng/mL (90.7nM) CsA and inhibited IgM and IgG productions after 9 days at 0.3 and 1.0ng/mL FK506 and 50 and 100ng/mL CsA (Heidt S. 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 CsA-treatment for 24 days at 50 mg/kg BID, cynomolgus monkeys showed suppression of IL-2 and IL-4 production and inhibition of SRBC-specific IgM and IgG in TDAR (Gaida K. 2015).

In human T cell culture, suplatast tosilate inhibits IL-4 production after 3 days and antigen specific IgE production after 10 days (Taiho Pharmaceutical 2013).

In the human T-B cell co-culture, CNIs of FK506 and CsA lowered the m-RNA levels of IL-2 and IL-4 at 8h post-stimulation and inhibited IgM and IgG productions after 9 days (Heidt S. 2010).

Known Feedforward/Feedback loops influencing this KER
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At present, no evidence is found.

Domain of Applicability

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In cynomolgus monkeys, the effects of CsA on production of IL-2 and IL-4, and antigen-specific IgM and IgG in TDAR were demonstrated (Gaida K. 2015).

Suppressed IgE and antigen specific IgG1 productions by the blocking of IL-4 receptor were reported in mice using dupilumab (anti-IL-4/13R antibody) (Sanofi K.K. 2018).

Suppressed antigen specific IgE production by the inhibition of IL-4 production was reported in mice using suplatast tosilate (Taiho Pharmaceutical 2013).

Suppressed antigen specific IgE and IL-4 productions by the inhibition of IL-4 production were reported in human cell culture using suplatast tosilate(Taiho Pharmaceutical 2013).

The effects of FK506 on serum concentration of anti-KLH antibodies IgM and IgG have been demonstrated in rats treated with FK506 for over four weeks and immunized with KLH (Ulrich et al. 2004). The effects of FK506 and CsA on antigen-specific plaque-forming splenocytes have been demonstrated in mice treated with FK506 or CsA for 4 days and immunized with SRBC (Kino et al. 1987b).

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, 2009, Sakuma et al, 2001).

The effects of FK506 and CsA on production of IL-2 and IL-4 have been demonstrated using mice and human cells (Kino et al. 1987a, Dumont et al. 1998).

These facts suggest that there are no species differences between humans, monkeys and rodents in inhibitions of IL-2 and IL-4 production and TDAR induction.

References

List of the literature that was cited for this KER description. More help
  1. Alberts, B., Johnson, A., Lewis, L., Raff, M., Roberts, K. and Walter, P. (2008). Molecular Biology of the Cell. 5th ed., Garland Science, New York. 1539-1601
  2. Sanofi K.K. (2018) Drug interview form Dupixent subcutaneous injection 300 mg syringe. 2nd edition.
  3. Taiho Pharmaceutical Co.,Ltd. (2013) Drug interview form IPD capsule 50 and 100. Revised 5th edition.
  4. Novartis Pharma K.K. (2016). Drug interview form Simulect i.v. injection 20 mg. 10th edition.
  5. Dumont, F.J., Staruch, M.J., Fischer, P., DaSilva, C. and Camacho, R. (1998). Inhibition of T cell activation by pharmacologic disruption of the MEK1/ERK MAP kinase or calcineurin signaling pathways results in differential modulation of cytokine production. Journal of immunology 160 (6): 2579-89.
  6. Heidt, S., Roelen, D. L., Eijsink, C., Eikmans, M., van Kooten, C., Claas, F. H. and Mulder, A. (2010). Calcineurin inhibitors affect B cell antibody responses indirectly by interfering with T cell help. Clinical and experimental immunology. 159(2): 199-207.
  7. Gaida K., Salimi-Moosavi H., Subramanian R., Almon V., Knize A., Zhang M., Lin F.F., Nguyen H.Q., Zhou L., Sullivan J.K., Wong M., McBride H.J. (2015). Inhibition of CRAC with a human anti-ORAI1 monoclonal antibody inhibits T-cell-derived cytokine production but fails to inhibit a T-cell-dependent antibody response in the cynomolgus monkey. J Immunotoxicol 12:164-173.
  8. Kino, T., Hatanaka, H., Miyata, S., Inamura, N., Nishiyama, M., Yajima, T., Goto, T., Okuhara, M., Kohsaka, M. and Aoki, H. (1987a). FK-506, a novel immunosuppressant isolated from a Streptomyces. II. Immunosuppressive effect of FK-506 in vitro. Journal of antibiotics. 40(9): 1256-1265.
  9. Kino, T., Hatanaka, H., Hashimoto, M., Nishiyama, M., Goto, T., Okuhara, M., Kohsaka, M., Aoki, H. and Imanaka, H. (1987b). FK-506, a novel immunosuppressant isolated from a Streptomyces. I. Fermentation, isolation, and physico-chemical and biological characteristics. Journal of antibiotics. 40(9): 1249-1255.
  10. Owens T.(1991). Requirement for noncognate interaction with T cells for the activation of B cell  immunoglobulin secretion by IL-2. Cell Immunol 133:352-366.
  11. Sakuma, S., Kato, Y., Nishigaki, F., Magari, K., Miyata, S., Ohkubo, Y., and Goto, T. (2001b). Effects of FK506 and other immunosuppressive anti-rheumatic agents on T cell activation mediated IL-6 and IgM production in vitro. International Immunopharmacology 1(4): 749-57.
  12. Ulrich, P., Paul, G., Perentes, E., Mahl, A., and Roman D. (2004). Validation of immune function testing during a 4-week oral toxicity study with FK506. Toxicology Letters 149(1-3): 123-31.
  13. Alessandro B, Paola S, Alberto E. Paneraic, Tiziana P,Paola Palanzaa and Stefano P(2003). Chronic psychosocial stress-induced down-regulation of immunity depends upon individual factors Journal of Neuroimmunology 141: 58–64
  14. Donna C. S, Matthew J. S and Kimber L. W Jr. (2010) Systemic immunosuppression following a single pharyngeal aspiration of 1,2:5,6-dibenzanthracene in female B6C3F1 mice, Journal of Immunotoxicology, 7:3, 219-231