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Relationship: 2027
Title
Suppression of IL-4 production leads to Impairment, TDAR
Upstream event
Downstream event
Key Event Relationship Overview
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 | Yasuhiro Yoshida (send email) | Under development: Not open for comment. Do not cite | Under Development |
Taxonomic Applicability
Sex Applicability
Sex | Evidence |
---|---|
Mixed | High |
Life Stage Applicability
Term | Evidence |
---|---|
All life stages | High |
Key Event Relationship Description
Interleukin (IL)-2 induced T cell proliferation. Therefore, the suppression of IL-2 production leads to the impairment of T cell dependent antibody responses (TDAR). IL-2-JAK3-STAT5 axis has been demonstrated to regulate Th1 cell differentiation, suggesting that IL-2-mediated JAK3-STAT5 signaling may generically operate in the production of Th1-related cytokines (107-Shi-2008)
IL-2 are produced and secreted by helper T cells and play important roles in the development of TDAR. IL-2 promotes differentiation of B cells through IL-2 stimulates differentiation of the activated T cell into T cell called Th2 cell. 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 provide help for B cells and promote class switching from IgM to IgG1 and IgE. Therefore, the suppression of IL-4 production leads to the impairment of TDAR.
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.
After treatment with FK506 or cyclosporin A (CsA), production of IL-2, IL-4, and other cytokines decreases in T cells (61-Dumont-1998,108-Dumont-1998), reducing stimulation of B cells as well as proliferation, activation, and class switching, and leading to impairment of TDAR. Therefore, FK506 and CsA are potent inhibitors of T-cell–dependent-antibody production and suppressing the production of these B-cell-related cytokines appears to be the main factor in impairment of TDAR (39-Heidt-2010).
Evidence Supporting this KER
non
Biological Plausibility
FK506 and Rapamycin suppress mRNA expression levels of IL-2 and IL-4 in T cells that stimulate proliferation of B cells (39-Heidt-2010).
Several in vivo studies in rodents showed decreased TDAR by the treatment of FK506 (69-Ulrich-2004,70-Kino-1987). In in vitro tests examining antibody production in blood samples obtained from blood-bank donors, peripheral blood mononuclear cell (PBMC) treated with FK506 and CsA suppressed the production of immunoglobulin (Ig) M and G antibodies to T-cell dependent antigens (39-Heidt-2010).
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 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 (39-Heidt-2010).
Therefore, it is concluded that decreased amounts of IL-4, in addition to IL-2, secreted from helper T cells is the main factor for suppression of TDAR.
Empirical Evidence
Empirical support of the suppression, IL-4 production leads to impairment, T-cell dependent antibody response is strong.
Rationale:
- In CD3/phorbol 12-myristate 13-acetate (PMA)-activated human T cells, FK506 suppressed production of IL-2, IL-4, and IFN-γ at the concentrations of 1.2 to 12.5 nM as well as inhibited expression of IL-2, IL-4, and IFN-γ mRNA at the concentrations of 10 nM (61-Dumont-1998).
- After 9-day culture of B cells and non-pre-activated T cell stimulation with FK506 or CsA, the levels of IgM and IgG in the culture supernatant were reduced at 0.3 and 1.0 ng/mL (0.37 and 1.24 nM) of FK506 or 50 and 100 ng/mL (41 and 83nM) of CsA (39-Heidt-2010).
- After 4-day culture of SKW6.4 cells (IL-6-dependent IgM-secreting human B-cell line) and anti-CD3/CD28 stimulated PBMC culture supernatant with FK506 or CsA, the level of IgM in the culture supernatant was reduced at the concentrations of 0.01 to 100 ng/mL (0.01 to 124 nM) of FK506 or 0.1 to 1000 ng/mL (0.08 to 832 nM) of CsA (73-Sakuma-2001).
- Rats were treated with FK506 for over four weeks and immunized with KLH, after which serum concentration of anti-KLH IgM and IgG reduced at the dose levels of 3 mg/kg/day (69-Ulrich-2004).
In vitro suppression of T-cell–derived cytokines and T-cell-dependent antibody production or antibody production after polyclonal T-cell stimulation showed similar dose responses to CNIs. Time gaps were found, however, between these two KEs, which showed earlier onset of cytokine production and delayed onset of antibody production.
Uncertainties and Inconsistencies
IL-2 affects multiple populations of immune cells expressing IL-2 receptors, while IL-4 mainly acts on B cells. There remains some possibility of additional suppression of other immune functions.
Quantitative Understanding of the Linkage
Response-response Relationship
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 (42-Gianti-2015).
In addition, cynomolgus monkeys treated wth CsA showed suppression of IL-2 and TDAR using sheep red blood cells with a dose dependent manner (71-Gaida-2015).
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 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 (39-Heidt-2010).
Time-scale
In human T cell culture, suplatast tosilate (an inhibitor of the production of cytokines on Th2 cell) inhibits IL-4 production after 3 days and antigen specific IgE production after 10 days (109-Taiho-2013).
In the human T-B cell co-culture, FK506 and CsA lowered the m-RNA levels of IL-2 and IL-4 at 8 h post-stimulation and inhibited IgM and IgG productions after 9 days (39-Heidt-2010).
Treatment with CsA at 50 mg/kg twice daily in cynomolgus monkey 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 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 compared to animals dosed with the vehicle control on Days 9, 12, and 16 post-immunization. There was an 80% or greater reduction in SRBC-specific IgM on Days9-16. SRBC-specific IgG was decreased by ≥95% on Days 9-16 (71-Gaida-2015). This similar to the degree of inhibition observed in rats using a KLH immunization model (110-Smith-2003).
Known modulating factors
At present, no evidence is found.
Known Feedforward/Feedback loops influencing this KER
At present, no evidence is found.
Domain of Applicability
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 (69-Ulrich-2004).
The effects of FK506 and CsA on the levels of IgM and IgG in the culture supernatant have been demonstrated in human cells (39-Heidt-2010,73-Sakuma-2001).
In thymectomized mice, development of KLH-specific effector CD4 T cells is reduced and these cells were suppressed in production of IL-4 (111-Bradley-1991). The effects of FK506 and CsA on 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 inhibitions of IL-4 production and TDAR induction.
References
39. 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. Clin Exp Immunol 159, 199-207
42. Gianti, E., and Zauhar, R. J. (2015) An SH2 domain model of STAT5 in complex with phospho-peptides define "STAT5 Binding Signatures". J Comput Aided Mol Des 29, 451-470
61. 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. J Immunol 160, 2579-2589
69. 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, 123-131
70. Kino, T., Hatanaka, H., Hashimoto, M., Nishiyama, M., Goto, T., Okuhara, M., Kohsaka, M., Aoki, H., and Imanaka, H. (1987) FK-506, a novel immunosuppressant isolated from a Streptomyces. I. Fermentation, isolation, and physico-chemical and biological characteristics. The Journal of antibiotics 40, 1249-1255
71. 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., and 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. Journal of immunotoxicology 12, 164-173
73. Sakuma, S., Kato, Y., Nishigaki, F., Magari, K., Miyata, S., Ohkubo, Y., and Goto, T. (2001) Effects of FK506 and other immunosuppressive anti-rheumatic agents on T cell activation mediated IL-6 and IgM production in vitro. International immunopharmacology 1, 749-757
107. Shi, M., Lin, T. H., Appell, K. C., and Berg, L. J. (2008) Janus-kinase-3-dependent signals induce chromatin remodeling at the Ifng locus during T helper 1 cell differentiation. Immunity 28, 763-773
108. Dumont, F. J., Koprak, S., Staruch, M. J., Talento, A., Koo, G., DaSilva, C., Sinclair, P. J., Wong, F., Woods, J., Barker, J., Pivnichny, J., Singer, I., Sigal, N. H., Williamson, A. R., Parsons, W. H., and Wyvratt, M. (1998) A tacrolimus-related immunosuppressant with reduced toxicity. Transplantation 65, 18-26
109. Taiho, P. C., Ltd. (2013) Drug interview form IPD capsule 50 and 100. . Revised 5th edition.
110. Smith, H. W., Winstead, C. J., Stank, K. K., Halstead, B. W., and Wierda, D. (2003) A predictive F344 rat immunotoxicology model: cellular parameters combined with humoral response to NP-CgammaG and KLH. Toxicology 194, 129-145
111. Bradley, L. M., Duncan, D. D., Tonkonogy, S., and Swain, S. L. (1991) Characterization of antigen-specific CD4+ effector T cells in vivo: immunization results in a transient population of MEL-14-, CD45RB- helper cells that secretes interleukin 2 (IL-2), IL-3, IL-4, and interferon gamma. J Exp Med 174, 547-559