Modulation of T cell signaling threshold and T cell sensitivity to antigens

Patent metadata

Field	Value
Publication number	US-9598695-B2
Application number	US-201615165762-A
Country	US
Kind code	B2
Filing date	May 26, 2016
Priority date	Oct 24, 2006
Publication date	Mar 21, 2017
Grant date	Mar 21, 2017

Abstract

MicroRNAs (miRNAs) are a diverse and abundant class of ˜22-nucleotide (nt) endogenous regulatory RNAs that play a variety of roles in animal cells by controlling gene expression at the posttranscriptional level. Increased miR-181a expression in mature T cells is shown to cause a marked increase in T cell activation and augments T cell sensitivity to peptide antigens. Moreover, T cell blasts with higher miR-181a expression become reactive to antagonists. The effects of miR-181a on antigen discrimination are in part achieved by dampening the expression of multiple negative regulators in the T cell receptor (TCR) signaling pathway, including PTPN22 and the dual specificity phosphatases DUSP5 and DUSP6. This results in a reduction in the TCR signaling threshold, thus quantitatively and qualitatively enhancing T cell sensitDynaivity to antigens.

First claim

What is claimed is:

1. A method of decreasing T cell activity to an autoantigen, the method comprising:
reducing the activity of miR-181a in peripheral T cells of an individual with a T cell mediated autoimmune disease by administering a modified oligonucleotide that is complementary to miR-181a, wherein the oligonucleotide is at least 12 but not more than 25 nucleotides in length and has no more than 2 mismatches over its length compared to an equal length portion of miR-181a; and
thereby raising T cell receptor signaling threshold and decreasing T cell sensitivity to antigen.

2. The method of claim 1 , wherein said modified oligonucleotide comprises a cholesterol conjugate.

3. The method of claim 1 , wherein said modified oligonucleotide comprises one or more phosphorothioate linkages.

4. The method of claim 1 , wherein said modified oligonucleotide comprises one or more sugar modifications.

5. The method of claim 1 , wherein said modified oligonucleotide has no more than 1 mismatch over its length compared to an equal length portion of miR-181a.

6. The method of claim 1 , wherein said modified oligonucleotide is fully complementary over its length compared to an equal length portion of mi R-181a.

7. The method of claim 1 , wherein said modified oligonucleotide is at least 20 but not more than 25 nucleotides in length.

8. The method of claim 1 , wherein the contacting is performed ex vivo.

Assignees

• Univ Leland Stanford Junior

Inventors

• Li Qi-Jing
• Chen Chang-Zheng
• Davis Mark M
• Chau Jacqueline

Classifications

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/02

  Immunomodulators · CPC title

• C12N2310/3515

  Lipophilic moiety, e.g. cholesterol · CPC title

• C12N2310/321

  2'-O-R Modification · CPC title