Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT82PDEY)

• DOT Name: Inducible T-cell costimulator (ICOS)
• Synonyms: Activation-inducible lymphocyte immunomediatory molecule; CD antigen CD278
• Gene Name: ICOS
• Related Disease:
  Common variable immunodeficiency
  Immunodeficiency, common variable, 1
• UniProt ID: ICOS_HUMAN
• PDB ID: 6X4G; 7JOO
• Pfam ID: PF15910
• Sequence:
  MKSGLWYFFLFCLRIKVLTGEINGSANYEMFIFHNGGVQILCKYPDIVQQFKMQLLKGGQ
  ILCDLTKTKGSGNTVSIKSLKFCHSQLSNNSVSFFLYNLDHSHANYYFCNLSIFDPPPFK
  VTLTGGYLHIYESQLCCQLKFWLPIGCAAFVVVCILGCILICWLTKKKYSSSVHDPNGEY
  MFMRAVNTAKKSRLTDVTL
• Function: Enhances all basic T-cell responses to a foreign antigen, namely proliferation, secretion of lymphokines, up-regulation of molecules that mediate cell-cell interaction, and effective help for antibody secretion by B-cells. Essential both for efficient interaction between T and B-cells and for normal antibody responses to T-cell dependent antigens. Does not up-regulate the production of interleukin-2, but superinduces the synthesis of interleukin-10. Prevents the apoptosis of pre-activated T-cells. Plays a critical role in CD40-mediated class switching of immunoglobin isotypes.
• Tissue Specificity: Activated T-cells. Highly expressed on tonsillar T-cells, which are closely associated with B-cells in the apical light zone of germinal centers, the site of terminal B-cell maturation. Expressed at lower levels in thymus, lung, lymph node and peripheral blood leukocytes. Expressed in the medulla of fetal and newborn thymus.
• KEGG Pathway:
  Cell adhesion molecules (hsa04514)
  T cell receptor sig.ling pathway (hsa04660)
  Intesti.l immune network for IgA production (hsa04672)
  Primary immunodeficiency (hsa05340)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Common variable immunodeficiency	DISHE7JQ	Definitive	Autosomal recessive	[1]
Immunodeficiency, common variable, 1	DIS4E6DF	Strong	Autosomal recessive	[2]

2 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Inducible T-cell costimulator (ICOS).	[3]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Inducible T-cell costimulator (ICOS).	[5]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Inducible T-cell costimulator (ICOS).	[4]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] ICOS is critical for CD40-mediated antibody class switching. Nature. 2001 Jan 4;409(6816):102-5. doi: 10.1038/35051107.
• [3] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [4] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [5] Inhibition of Super-Enhancer Activity in Autoinflammatory Site-Derived T Cells Reduces Disease-Associated Gene Expression. Cell Rep. 2015 Sep 29;12(12):1986-96. doi: 10.1016/j.celrep.2015.08.046. Epub 2015 Sep 17.