Aop:154

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AOP Title

The Adverse Outcome Pathway on binding of FK506-binding protein 12 (FKBP12) by calcineurin inhibitors leading to immunosuppression
Short name: Immunosuppression

Authors

Hiroyuki Komatsu (1) Junichiro Sugimoto (1) Ken Goto (1) Kiyoshi Kushima (1) Naohisa Tsutsui (1) Shigeru Hisada (1) Shiho Ito (1) Tadashi Kosaka (1) Takumi Ohishi (1) Yasuharu Otsubo (1) Yoshihiro Takahashi (1)


(1) AOP Working Group, Testing Methodology Committee, The Japanese Society of Immunotoxicology

Status

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This AOP page was last modified on 12/11/2016.

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Abstract

FKBP12 is a receptor protein that binds with FK506 (Tacrolimus). FK506 is an immunosuppressant having a macrolide structure, that was first discovered in 1984 as a fermentation product of Streptomyces tsukubaensis. FK506 is similar to cyclosporin A or rapamycin in its inhibition of calcineurin activity, and it is used for its immunosuppressant effects after kidney, liver, and other organ transplants to lower the risk of organ rejection; after bone-marrow transplants to lower the risk of graft-versus-host disease (GVHD); or in the treatment of rheumatoid arthritis. It is also used in ointments for the treatment of atopic dermatitis. This case study describes the effects of FK506 on immune cells as a result of the formation of FKBP12-FK506 complexes. FKBP12 is expressed in T-cells, B-cells, Langerhans cells, and mast cells, and the pathway is complicated. In order to simplify the pathway of FKBP12-FK506, the AOP focus on the pathway through FKBP12 expressing on T cells.


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Summary of the AOP

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Molecular Initiating Event

Molecular Initiating Event Support for Essentiality
Binding of FK506 to FKBP12, Formation Strong

Key Events

Event Support for Essentiality
Binding of calcineurin with FK506-FKBP complexes, Binding, Formation Strong
Hampered NFAT activation and following nuclear localization, Activation Strong
Interference of NFAT complex formation at the site of nuclear cytokine promoters, Inhibition Strong
Suppression of cytokine production in the presence of T-cell activation, Suppression
Suppression of production of cytotoxic T-cells, Suppression Strong
Suppression of T-cell dependent antibody production, Suppression Strong

Adverse Outcome

Adverse Outcome
Suppression of transplant rejection, Suppression
Relief of atopic dermatitis, Relief
Increased susceptibility to infection, Increase

Relationships Among Key Events and the Adverse Outcome

Event Description Triggers Weight of Evidence Quantitative Understanding
Binding of FK506 to FKBP12, Formation Directly Leads to Binding of calcineurin with FK506-FKBP complexes, Binding, Formation Strong
Binding of calcineurin with FK506-FKBP complexes, Binding, Formation Directly Leads to Hampered NFAT activation and following nuclear localization, Activation Strong
Hampered NFAT activation and following nuclear localization, Activation Directly Leads to Interference of NFAT complex formation at the site of nuclear cytokine promoters, Inhibition Strong
Interference of NFAT complex formation at the site of nuclear cytokine promoters, Inhibition Directly Leads to Suppression of cytokine production in the presence of T-cell activation, Suppression Strong
Suppression of cytokine production in the presence of T-cell activation, Suppression Directly Leads to Suppression of production of cytotoxic T-cells, Suppression Strong
Suppression of cytokine production in the presence of T-cell activation, Suppression Indirectly Leads to Suppression of T-cell dependent antibody production, Suppression Moderate
Suppression of cytokine production in the presence of T-cell activation, Suppression Indirectly Leads to Relief of atopic dermatitis, Relief Moderate
Suppression of production of cytotoxic T-cells, Suppression Directly Leads to Suppression of transplant rejection, Suppression Strong
Suppression of T-cell dependent antibody production, Suppression Indirectly Leads to Increased susceptibility to infection, Increase Moderate
Suppression of cytokine production in the presence of T-cell activation, Suppression Indirectly Leads to Increased susceptibility to infection, Increase Moderate
Suppression of production of cytotoxic T-cells, Suppression Indirectly Leads to Increased susceptibility to infection, Increase Moderate

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Life Stage Applicability

Life Stage Evidence Links
all life stages Moderate

Taxonomic Applicability

Name Scientific Name Evidence Links
Since FK506-induced outcomes in humans are mimicked by similar responses in a variety of animal models, immunosuppression induced by FK506-FKPBP12 complexes are considered to be preserved across a variety of mammalian species.

Sex Applicability

Sex Evidence Links
Mixed Strong

Graphical Representation

FKBP Diagram 0929.jpg

Overall Assessment of the AOP

Domain of Applicability

The proposed AOP of FKBP12-FK506 complex-induced immunosuppression is not associated with life stage-, sex- or age-dependency. The relevant life stages for the AOP are through child to adult, since the ointment (Protopic) is approved for the pediatric atopic dermatitis; the MOA for immunosuppression deems to be applicable to all of the life stages. Since FK506-induced outcomes in humans are mimicked by similar responses in a variety of animal models, immunosuppression induced by FK506-FKPBP12 complexes are considered to be preserved across a variety of mammalian species.

Essentiality of the Key Events

Weight of Evidence Summary

Immunosuppression induced by FK506-FKBP12 complexes in T-cells is a known pharmacological effect of this drug, which has been well characterized and reported on extensively in related literature. The MIE of the immunosuppressive effects of FK506 have been clearly characterized as the formation of FKBP12-FK506 complexes. FK506-FKBP12 complex–induced immunosuppression is a known pharmacological effect of this drug; the outcomes of the immunosuppression are well known to lower tumor immunity and to increase susceptibility to infection are clear outcomes. FKBP12 is expressed in a plurality of immune cells; among them, involvement of T cells in the FK506-induced multiple immunosuppressive events deems to be clear and the MOA is explainable with clear relationships between each of the key events. FKBP12 and its downstream factors of calcineurin and NFAT are also expressed in B cells, dendritic cells and other immune cells as well as T cells; however, their involvement in the FK506-related immunosuppressive outcomes is unclear at present. FK506 was reported to increase the incidences of lymphoma or UV-induced skin tumors in the mouse carcinogenicity studies. FK506-induced immunosuppressive status might be related to the increased susceptibility to tumorigenesis; however, the precise MOA of the tumorigenesis remains unclear.

Quantitative Considerations

References


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