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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 Do not cite | Under Development |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
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
Evidence Supporting this KER
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.
Biological Plausibility
FK506 and rapamycin suppress the mRNA expression levels of IL-2 and IL-4 in T cells, which stimulate the proliferation of B cells (Heidt, et al. 2010).
Several in vivo studies in rodents have shown decreased TDAR following treatment with FK506 (Kino, et al. 1987, Ulrich, et al. 2004). In vitro tests examined antibody production in blood samples obtained from blood bank donors and PBMCs treated with FK506 and CsA. The suppressed production of immunoglobulin (Ig) M and G antibodies to T cell dependent antigens was demonstrated (Heidt, et al. 2010).
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. However, concerning the suppression of humoral immunity induced by the inhibition of CN phosphatase activity, CNIs do not affect B cells directly. Rather, the effect is indirect via T cells. 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 solely due to inhibition of T helper cells (Heidt, et al. 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 in the suppression of TDAR.
Empirical Evidence
Empirical support for the suppression of IL-4 production leads to impairment, and the T cell dependent antibody response is strong.
Rationale:
In CD3/PMA activated human T cells, FK506 suppressed the production of IL-2, IL-4, and IFN-γ at concentrations of 1.2 to 12.5 nM and inhibited the expression of IL-2, IL-4, and IFN-γ mRNA at concentrations of 10 nM (Dumont, et al. 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. The FK506 levels were 0.3 and 1.0 ng/mL (0.37 and 1.24 nM) and the CsA levels were 50 and 100 ng/mL (41 and 83 nM) (Heidt, et al. 2010).
After a 4-day culture of SKW6.4 IL-6-dependent IgM-secreting human B cells and anti-CD3/CD28 stimulation of the PBMC culture supernatant with FK506 or CsA, the level of IgM in the culture supernatant was reduced at concentrations of 0.01 to 100 ng/mL (0.01 to 124 nM) of FK506 and 0.1 to 1000 ng/mL (0.08 to 832 nM) of CsA (Sakuma, et al. 2001).
Rats were treated with FK506 for over 4 weeks and immunized with KLH. The serum concentrations of anti-KLH IgM and IgG were reduced at a dose of 3 mg/kg/day (Ulrich, et al. 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 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. Additional suppression of other immune functions may also be possible.
Known modulating factors
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
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
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
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
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
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.
References
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Dumont FJ, Staruch MJ, Fischer P, DaSilva C, 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.
Gaida K, Salimi-Moosavi H, Subramanian R, Almon V, Knize A, Zhang M, Lin FF, Nguyen HQ, Zhou L, Sullivan JK, Wong M, McBride HJ. 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. DOI: 10.3109/1547691X.2014.915897.
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Heidt S, Roelen DL, Eijsink C, Eikmans M, van Kooten C, Claas FH, Mulder A. 2010. Calcineurin inhibitors affect B cell antibody responses indirectly by interfering with T cell help. Clin Exp Immunol 159:199-207. DOI: 10.1111/j.1365-2249.2009.04051.x.
Kino T, Hatanaka H, Hashimoto M, Nishiyama M, Goto T, Okuhara M, Kohsaka M, Aoki H, Imanaka H. 1987. FK-506, a novel immunosuppressant isolated from a Streptomyces. I. Fermentation, isolation, and physico-chemical and biological characteristics. J Antibiot (Tokyo) 40:1249-1255. DOI: 10.7164/antibiotics.40.1249.
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