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Event: 1719

Key Event Title

The KE title should describe a discrete biological change that can be measured. It should generally define the biological object or process being measured and whether it is increased, decreased, or otherwise definably altered relative to a control state. For example “enzyme activity, decreased”, “hormone concentration, increased”, or “growth rate, decreased”, where the specific enzyme or hormone being measured is defined. More help

Impairment of T-cell dependent antibody response

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. The short name should be less than 80 characters in length. More help
Impairment, TDAR

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. Note, KEs should be defined within a particular level of biological organization. Only KERs should be used to transition from one level of organization to another. Selection of the level of biological organization defines which structured terms will be available to select when defining the Event Components (below). More help

Key Event Components

Further information on Event Components and Biological Context may be viewed on the attached pdf.Because one of the aims of the AOP-KB is to facilitate de facto construction of AOP networks through the use of shared KE and KER elements, authors are also asked to define their KEs using a set of structured ontology terms (Event Components). In the absence of structured terms, the same KE can readily be defined using a number of synonymous titles (read by a computer as character strings). In order to make these synonymous KEs more machine-readable, KEs should also be defined by one or more “event components” consisting of a biological process, object, and action with each term originating from one of 22 biological ontologies (Ives, et al., 2017; See List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signalling by that receptor).Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. More help
Process Object Action
T cell activation involved in immune response decreased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
Immune dysfunction induced by JAK3 inhibition AdverseOutcome Yasuhiro Yoshida (send email) Under development: Not open for comment. Do not cite Under Development

Stressors

This is a structured field used to identify specific agents (generally chemicals) that can trigger the KE. Stressors identified in this field will be linked to the KE in a machine-readable manner, such that, for example, a stressor search would identify this as an event the stressor can trigger. NOTE: intermediate or downstream KEs in one AOP may function as MIEs in other AOPs, meaning that stressor information may be added to the KE description, even if it is a downstream KE in the pathway currently under development.Information concerning the stressors that may trigger an MIE can be defined using a combination of structured and unstructured (free-text) fields. For example, structured fields may be used to indicate specific chemicals for which there is evidence of an interaction relevant to this MIE. By linking the KE description to a structured chemical name, it will be increasingly possible to link the MIE to other sources of chemical data and information, enhancing searchability and inter-operability among different data-sources and knowledgebases. The free-text section “Evidence for perturbation of this MIE by stressor” can be used both to identify the supporting evidence for specific stressors triggering the MIE as well as to define broad chemical categories or other properties that classify the stressors able to trigger the MIE for which specific structured terms may not exist. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected from an ontology. In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
Homo sapiens Homo sapiens High NCBI
Mus musculus Mus musculus High NCBI

Life Stages

The structured ontology terms for life-stage are more comprehensive than those for taxa, but may still require further description/development and explanation in the free text section. More help
Life stage Evidence
All life stages High

Sex Applicability

No help message More help
Term Evidence
Unspecific High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. For example, the biological state being measured could be the activity of an enzyme, the expression of a gene or abundance of an mRNA transcript, the concentration of a hormone or protein, neuronal activity, heart rate, etc. The biological compartment may be a particular cell type, tissue, organ, fluid (e.g., plasma, cerebrospinal fluid), etc. The role in the biology could describe the reaction that an enzyme catalyses and the role of that reaction within a given metabolic pathway; the protein that a gene or mRNA transcript codes for and the function of that protein; the function of a hormone in a given target tissue, physiological function of an organ, etc. Careful attention should be taken to avoid reference to other KEs, KERs or AOPs. Only describe this KE as a single isolated measurable event/state. This will ensure that the KE is modular and can be used by other AOPs, thereby facilitating construction of AOP networks. More help

The production of antibodies to T cell-dependent antigens is a coordinated process involving B cells, antigen-presenting cells, and T cell derived cytokines. The B cells are stimulated to proliferate and differentiate. The TDAR might be altered if any of these cell populations are affected.

IL-2 and IL-4 are produced and secreted by helper T cells. Both are important in the development of TDAR. IL-4 affects maturation and class switching of B cells as well as proliferation. Both events induce and enhance TDAR. IL-2 promotes differentiation of B cells, which stimulates differentiation of activated T cells to Th2 cells. The suppressed production of IL-2 and IL-4 impairs TDAR (Justiz Vaillant and Qurie 2020).

A mutant form of human IL-4, in which the tyrosine residue at position 124 is replaced by aspartic acid (hIL-4Y124D), was reported to specifically block IL-4 and IL-13-induced proliferation of B cells. In addition, hIL-4Y124D also strongly inhibited both IL-4- or IL-13-induced IgG4 and IgE synthesis in cultures of PBMCs, or highly purified sIgD+ B cells cultured in the presence of anti-CD40 monoclonal antibodies. IL-4 may be necessary to produce antibodies and to proliferate in B cells. The mutation of IL-4 may impair TDAR (Aversa, et al. 1993).

IL-4 stimulates B cells to proliferate, switch immunoglobulin classes, and differentiate to plasma and memory cells. Suppressing the production of these B cell related cytokines appears to impair TDAR, as evident from the results of FK506 treatment (Heidt, et al. 2010).

STAT5 is able to inhibit peroxisome proliferator activated receptor (PPAR)-regulated gene transcription. Conversely, ligand-activated PPAR can inhibit STAT5-regulated transcription. As a peroxisome proliferator, perfluorooctanoic acid (PFOA) induces PPARs. The suppression of TDAR has been observed with a no observable effect level (NOEL) of 1.88 mg/kg/d and lowest observed adverse effect level (LOEL) of 3.75 mg/kg/d for PFOA administered in drinking water over 15 days (Dewitt, et al. 2008). The increase in PPAR expression induced by PFOA may inhibit STAT5-regulated transcription, which is important for IL-4 production in TDAR.

How It Is Measured or Detected

One of the primary considerations in evaluating AOPs is the relevance and reliability of the methods with which the KEs can be measured. The aim of this section of the KE description is not to provide detailed protocols, but rather to capture, in a sentence or two, per method, the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements. Methods that can be used to detect or measure the biological state represented in the KE should be briefly described and/or cited. These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA).Key considerations regarding scientific confidence in the measurement approach include whether the assay is fit for purpose, whether it provides a direct or indirect measure of the biological state in question, whether it is repeatable and reproducible, and the extent to which it is accepted in the scientific and/or regulatory community. Information can be obtained from the OECD Test Guidelines website and the EURL ECVAM Database Service on Alternative Methods to Animal Experimentation (DB-ALM). ?

TDAR can be examined in vivo and in vitro. In vivo studies of antigen-specific antibodies are usually performed by measuring serum antibody levels with ELISA (Onda, et al. 2014) or with a plaque-forming cell (PFC) assay.

To assess keyhole limpet hemocyanin (KLH) antigen-specific T cell proliferation, 1 × 105 CD4+ T cells were co-cultured with 2 × 105 autologous PBMCs in 96-well plates in the presence of KLH. Cells were cultured for 5 or 7 days before being pulsed with 0.5 μCi 3[H]-thymidine (PerkinElmer) for 18 h. The cells were harvested using a 96-well cell FilterMate harvester. 3[H]-thymidine incorporation in CD4+ T cell response to biopharmaceuticals was measured by liquid scintillation counting using a TopCount NXT (Schultz, et al. 2017).

In another in vivo study, rats were repeatedly administered FK506 orally for 4 weeks and immunized with KLH. Rat serum was examined for T cell dependent, antigen-specific IgM and IgG levels by ELISA (Ulrich, et al. 2004).

Other authors repeatedly administered CNIs, including FK506 and CsA, to mice orally for 4 days and immunized with sheep red blood cells (SRBCs). Spleen cells were examined using a PFC assay (Kino, et al. 1987). Antigen-specific plaque-forming splenocytes were reduced at doses of 3.2, 10, 32, and 100 mg/kg of FK506 or 32 and 100 mg/kg CsA.

In another study, cynomolgus monkeys received 50 mg/kg CsA twice a day via oral gavage (10 h apart) for 23 days and were immunized with SRBCs. Serum was examined for anti-SRBC IgM and IgG levels using an ELISA specific for SRBC antigen (Gaida, et al. 2015).

In the final in vivo study cited here, mice were exposed to a single pharyngeal aspiration of 1,2:5,6-Dibenzanthracene, after which the supernatants of splenocytes were cultured for 24 h in the presence of lipopolysaccharide and assayed using a mouse IgM or IgG matched pairs antibody kit (Smith, et al. 2010).

For in vitro studies, total IgM and IgG levels in culture supernatants are often measured after polyclonal T cell activation rather than after antigen stimulation in immune cell cultures.

In one study, T and B cells isolated from human PBMCs were co-cultured with CNIs for 9 days in the presence of polyclonal T cell stimulation. The supernatants were examined for IgM and IgG levels by ELISA. Treatment with FK506 or CsA reduced the levels of IgM and IgG at concentrations of 0.3 and 1.0 ng/mL (0.37 and 1.24 nM) or 50 and 100 ng/mL (41.6 and 83.2 nM), respectively (Heidt, et al. 2010).

In another study, SKW6.4 IL-6-dependent IgM-secreting human B cells were cultured for 4 days with anti-CD3/CD28 antibody-stimulated PBMC culture supernatant. IgM produced in the culture supernatants was measured by ELISA. FK506 or CsA reduced the levels of IgM at concentrations of 0.01 to 100 ng/mL or 0.1 to 1000 ng/mL (Sakuma, et al. 2001).

Domain of Applicability

This free text section should be used to elaborate on the scientific basis for the indicated domains of applicability and the WoE calls (if provided). While structured terms may be selected to define the taxonomic, life stage and sex applicability (see structured applicability terms, above) of the KE, the structured terms may not adequately reflect or capture the overall biological applicability domain (particularly with regard to taxa). Likewise, the structured terms do not provide an explanation or rationale for the selection. The free-text section on evidence for taxonomic, life stage, and sex applicability can be used to elaborate on why the specific structured terms were selected, and provide supporting references and background information.  More help

CNI-induced impairment of TDAR has been demonstrated in rodent studies. In one study, oral administration of FK506 or CsA to mice for 4 days impaired the response of PFC in splenocytes after intravenous immunization with sheep erythrocytes (Kino, et al. 1987). Likewise, oral administration of FK506 to rats over a 4-week period reduced the production of both anti-KLH-IgG and IgM after subcutaneous immunization with KLH (Ulrich, et al. 2004). Other authors described that treatment with CsA at 50 mg/kg BID via oral gavage in cynomolgus monkeys resulted in reduction of serum SRBC-specific IgM and IgG (Gaida, et al. 2015). As for humans, in vitro experiments showed that treatment with FK506 or CsA of PBMCs from blood bank donors suppressed the production of IgM and IgG specific to T cell dependent antigens (Heidt, et al. 2010). In SKW6.4 cells (IL-6 dependent, IgM-secreting, human B cell line) cultures, FK506 or CsA suppressed the production of IgM in the presence of T cell activation (Sakuma, et al. 2001). Considering that FK506 and CsA reduce T cell derived IL-2, these findings strongly suggest that impairment of TDAR following reduced production of IL-2 occurs at least in common among humans, monkeys, and rodents.

Yang et al. (2002b) exposed male C57BL/6 mice to a single concentration (0.02%) of PFOA in the diet for 16 days. TDAR was measured after inoculating PFOA-treated mice with horse red blood cells intravenously on day 10; serum levels of horse red blood cell-specific IgM and IgG in response to the immunization were significantly decreased (Yang, et al. 2002).

The suppression of TDAR in adult C57BL/6 female mice has been observed in several studies. NOEL of 1.88 mg/kg/d and LOEL of 3.75 mg/kg/d were identified for PFOA administered in drinking water for over 15 days (Dewitt, et al. 2008).

The suppression of TDAR in adrenalectomized or sham-operated C57BL/6N female mice was observed when PFOA was provided in drinking water for 10 days at doses of 0, 3.75, 7.5, or 15 mg/kg/d. TDAR was determined as the primary antibody response to the T cell dependent antigen in SRBCs. The day after exposure ended, SRBCs were introduced intravenously and SRBC-specific IgM was measured 5 days later (DeWitt, et al. 2009).

Evidence for Perturbation by Stressor

Regulatory Significance of the Adverse Outcome

An AO is a specialised KE that represents the end (an adverse outcome of regulatory significance) of an AOP. For KEs that are designated as an AO, one additional field of information (regulatory significance of the AO) should be completed, to the extent feasible. If the KE is being described is not an AO, simply indicate “not an AO” in this section.A key criterion for defining an AO is its relevance for regulatory decision-making (i.e., it corresponds to an accepted protection goal or common apical endpoint in an established regulatory guideline study). For example, in humans this may constitute increased risk of disease-related pathology in a particular organ or organ system in an individual or in either the entire or a specified subset of the population. In wildlife, this will most often be an outcome of demographic significance that has meaning in terms of estimates of population sustainability. Given this consideration, in addition to describing the biological state associated with the AO, how it can be measured, and its taxonomic, life stage, and sex applicability, it is useful to describe regulatory examples using this AO. More help

TDAR is considered to be the most important endpoint of immunotoxicity, because T cells, B cells, and antigen-presenting cells, such as dendritic cells, are involved in inducing and developing TDAR. Thus, changes in any of these immune cell populations can influence TDAR.

The ICH S8 immunotoxicity testing guideline on pharmaceuticals recommends that TDAR can be evaluated whenever the target cells of immunotoxicity are not clear based on pharmacology and findings in standard toxicity studies. For the assessment of pesticides, the United States Environmental Protection Agency Office of Prevention, Pesticides and Toxic Substances  870.7800 immunotoxicity testing guideline recommends TDAR using SRBC.

Finally, the draft Food and Drug Administration guidance of nonclinical safety evaluation for immunotoxicology recommends the TDAR assay.

References

List of the literature that was cited for this KE description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide (https://www.oecd.org/about/publishing/OECD-Style-Guide-Third-Edition.pdf) (OECD, 2015). More help

Aversa G, Punnonen J, Cocks BG, de Waal Malefyt R, Vega F, Jr., Zurawski SM, Zurawski G, de Vries JE. 1993. An interleukin 4 (IL-4) mutant protein inhibits both IL-4 or IL-13-induced human immunoglobulin G4 (IgG4) and IgE synthesis and B cell proliferation: support for a common component shared by IL-4 and IL-13 receptors. J Exp Med 178:2213-2218. DOI: 10.1084/jem.178.6.2213.

Dewitt JC, Copeland CB, Strynar MJ, Luebke RW. 2008. Perfluorooctanoic acid-induced immunomodulation in adult C57BL/6J or C57BL/6N female mice. Environ Health Perspect 116:644-650. DOI: 10.1289/ehp.10896.

DeWitt JC, Shnyra A, Badr MZ, Loveless SE, Hoban D, Frame SR, Cunard R, Anderson SE, Meade BJ, Peden-Adams MM, Luebke RW, Luster MI. 2009. Immunotoxicity of perfluorooctanoic acid and perfluorooctane sulfonate and the role of peroxisome proliferator-activated receptor alpha. Crit Rev Toxicol 39:76-94. DOI: 10.1080/10408440802209804.

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.

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.

Justiz Vaillant AA, Qurie A. 2020. Interleukin. In StatPearls: Treasure Island (FL)

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.

Onda M, Ghoreschi K, Steward-Tharp S, Thomas C, O'Shea JJ, Pastan IH, FitzGerald DJ. 2014. Tofacitinib suppresses antibody responses to protein therapeutics in murine hosts. J Immunol 193:48-55. DOI: 10.4049/jimmunol.1400063.

Sakuma S, Kato Y, Nishigaki F, Magari K, Miyata S, Ohkubo Y, Goto T. 2001. Effects of FK506 and other immunosuppressive anti-rheumatic agents on T cell activation mediated IL-6 and IgM production in vitro. Int Immunopharmacol 1:749-757.

Schultz HS, Reedtz-Runge SL, Backstrom BT, Lamberth K, Pedersen CR, Kvarnhammar AM, consortium A. 2017. Quantitative analysis of the CD4+ T cell response to therapeutic antibodies in healthy donors using a novel T cell:PBMC assay. PLoS One 12:e0178544. DOI: 10.1371/journal.pone.0178544.

Smith DC, Smith MJ, White KL. 2010. Systemic immunosuppression following a single pharyngeal aspiration of 1,2:5,6-dibenzanthracene in female B6C3F1 mice. J Immunotoxicol 7:219-231. DOI: 10.3109/1547691X.2010.487193.

Ulrich P, Paul G, Perentes E, Mahl A, Roman D. 2004. Validation of immune function testing during a 4-week oral toxicity study with FK506. Toxicol Lett 149:123-131. DOI: 10.1016/j.toxlet.2003.12.069.

Yang Q, Abedi-Valugerdi M, Xie Y, Zhao XY, Moller G, Nelson BD, DePierre JW. 2002. Potent suppression of the adaptive immune response in mice upon dietary exposure to the potent peroxisome proliferator, perfluorooctanoic acid. Int Immunopharmacol 2:389-397. DOI: 10.1016/s1567-5769(01)00164-3.