Aop:154
Status
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AOP Title
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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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 |
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Binding of FK506 to FKBP12, Formation | Strong |
Key Events
Adverse Outcome
Adverse Outcome |
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Suppression of transplant rejection, Suppression |
Relief of atopic dermatitis, Relief |
Increased susceptibility to infection, Increase |
Relationships Among Key Events and the Adverse Outcome
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Life Stage Applicability
Life Stage | Evidence | Links |
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all life stages | Moderate |
Taxonomic Applicability
Name | Scientific Name | Evidence | Links |
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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 |
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Mixed | Strong |
Graphical Representation
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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