- Patent Number:
12064,405
- Appl. No:
17/520499
- Application Filed:
November 05, 2021
- نبذة مختصرة :
The present invention relates to an immunosuppressant comprising TSAHC or a pharmaceutically acceptable salt thereof as an active ingredient. TSAHC treatment suppressed the expression and secretion of cytokines/chemokines such as IL6, IL1β, TNFα, CXCL1, CXCL2, CXCL3, CXCL6, CXCL8, CCL2, CCL5, CCL20, CXCL10 and CCR10 according to the expression of TM4SF5 gene and protein, and the cytokines or chemokines mediated by the expression of TM4SF5 induced abnormalities in the inflammatory response and metabolic function of liver tissues, hepatic epithelial cells and macrophages, and correlated with liver tissue damage and immune cell recruit in TM4SF5 transgenic animals. Therefore, a composition comprising TSAHC or a pharmaceutically acceptable salt thereof as an active ingredient can be effectively used as an immunosuppressant.
- Inventors:
Seoul National University R&DB Foundation (Seoul, KR)
- Assignees:
SEOUL NATIONAL UNIVERSITY R&DB FOUNDATION (Seoul, KR)
- Claim:
1. An immunosuppressive method, comprising: administering 4′-(p-toluenesulfonylamido)-4-hydroxychalcone (TSAHC) to a subject in an amount effective for the TSAHC to inhibit: (i) secretion of inflammatory cytokines or chemokines dependent on the expression of TM4SF5; (ii) activation of M1 type macrophages by inhibiting (a) binding of TM4SF5 and GLUT1, (b) sensitivity of glycolysis to extracellular glucose, or (c) glycolysis in macrophages; (iii) conversion of M1 type macrophages to M2 type macrophages; and (iv) chronic activation of M2 type macrophages by inhibiting the expression of mannose receptor C-type 1 (MRC1, CD206), fibronectin (FN1), arginase I (Arg1), and peroxisome proliferator-activated receptor gamma (Pparγ) in macrophages, in the subject, thereby suppressing immunity in the subject, wherein the subject has excessive inflammatory response caused by liver resection or liver tissue resection, abnormality in metabolic function of liver or liver tissue, liver transplant rejection or liver tissue transplant rejection, or exposure to substance(s) toxic to the liver or liver tissue.
- Claim:
2. The immunosuppressive method according to claim 1 , wherein the TSAHC further inhibits the differentiation and activation of hepatic epithelial cells or macrophages, glucose uptake, and glycolytic function activation.
- Claim:
3. The immunosuppressive method according to claim 1 , wherein the cytokine or chemokine inhibits the increase of the expression of TM4SF5 or SIRT1 or the increase of the phosphorylation of FAK (Tyrosine 397), c-Src (Tyrosine 416), and STAT3 (Tyrosine 705) in hepatic epithelial cells.
- Claim:
4. The immunosuppressive method according to claim 1 , wherein the cytokine or chemokine inhibits the recruit of immune cells into the liver tissue or the increase of the phosphorylation of FAK (Tyrosine 397), c-Src (Tyrosine 416), and STAT3 (Tyrosine 705) in hepatic epithelial cells, or the expression of collagen I alpha 1 or laminin γ2.
- Claim:
5. The immunosuppressive method according to claim 1 , wherein the cytokine or chemokine interacts with macrophages to inhibit the expression of TM4SF5 in macrophages.
- Claim:
6. The immunosuppressive method according to claim 1 , wherein the cytokine or chemokine is at least one selected from the group consisting of F4/80, IL1β, IL6, TNFα, CCR10, CXCL6, CCL2, CCL5, CCL20, CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL8, and CXCL10.
- Claim:
7. The immunosuppressive method according to claim 1 , wherein the cytokine or chemokine is at least one selected from the group consisting of CCL2, CCL5, CCL20, CXCL1, CXCL6, CXCL8, and CXCL10, that are increased by the TM4SF5 expression dependently or decreased by the Kelch Like ECH Associated Protein 1 (KEAP1) expression.
- Claim:
8. The immunosuppressive method according to claim 1 , wherein the TSAHC reduces the secretion of at least one selected from the group consisting of IL-6, CCL2, IL1 ß and TNFα in macrophages.
- Claim:
9. The immunosuppressive method according to claim 1 , wherein the TSAHC inhibits the binding of TM4SF5 and IL6Rα in hepatic epithelial cells.
- Claim:
10. The immunosuppressive method according to claim 1 , wherein the TSAHC further inhibits the increase of oxygen consumption caused by mitochondrial respiration.
- Claim:
11. The immunosuppressive method according to claim 1 , wherein the immunosuppressive method is effective for preventing or treating excess inflammatory response of the liver or the liver tissue due to the fat accumulation, hepatic epithelial cell damage, α-SMA (α-smooth muscle actin) expression increase, immune cell activation and concentration, Ccl20 or Cxcl10 expression, or collagen accumulation caused by high-fat diet, methionine-choline deficient diet, or CCl 4 treatment.
- Claim:
12. The immunosuppressive method according to claim 1 , wherein the immunosuppressive method inhibits the increase of the expression of Tm4sf5, Trem2, Clec4f or Tim4 in Kupffer macrophages or bone marrow-derived macrophages caused by high-fat diet or methionine-choline-deficient diet.
- Patent References Cited:
10-0751899 August 2007
10-2008-0052391 June 2008
10-2012-0023524 March 2012
10-2019-0046705 May 2019
WO2019124608 June 2019
- Other References:
Min-Gyu Jeon et al. Inflammation, vol. 40, No. 6, Dec. 2017. cited by examiner
- Primary Examiner:
Ward, Paul V
- Attorney, Agent or Firm:
Fredrikson & Byron, P.A.
- الرقم المعرف:
edspgr.12064405
Processing Request
No Comments.