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Application of substances capable of inhibiting activity of Treg cells and promoting differentiation of Tfh cells in treating HBV infection

A technology of cell activity and cell differentiation, applied in the direction of medical raw materials derived from mammals, introduction of foreign genetic material using vectors, analysis of materials, etc., can solve the problems of lack of HBV infection models in small animals infected by hepatitis B virus

Pending Publication Date: 2018-01-23
INST OF RADIATION MEDICINE ACAD OF MILITARY MEDICAL SCI OF THE PLA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The study of HBV infection is largely limited by the lack of small animal HBV infection models

Method used

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  • Application of substances capable of inhibiting activity of Treg cells and promoting differentiation of Tfh cells in treating HBV infection
  • Application of substances capable of inhibiting activity of Treg cells and promoting differentiation of Tfh cells in treating HBV infection
  • Application of substances capable of inhibiting activity of Treg cells and promoting differentiation of Tfh cells in treating HBV infection

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0083] Embodiment 1, establishment of acute and chronic HBV mouse model

[0084] 1. Model building

[0085] The pAAV / HBV1.2 plasmid (diluted with normal saline) was injected into male C57BL / 6N mice aged 6-8 weeks by tail vein high pressure injection. The injection dose is 10 μg pAAV / HBV1.2 plasmid per mouse, the injection volume is 8%-12% of the mouse body weight, and all the injection volumes are pushed in at a uniform speed within 5-7 seconds, and a total of 9 pAAV / HBV1.2 plasmids are obtained Plasmid transfection mouse model (hereinafter referred to as acute HBV mouse model). To facilitate tail vein injection, the tip of the 2ml syringe can be replaced with the tip of the 1ml syringe.

[0086] According to the above method, the pAAV / HBV1.2 plasmid was replaced with the pAAV empty plasmid, and other steps remained unchanged, and a control mouse of the acute HBV mouse model was obtained, which was named control mouse N.

[0087] According to the above method, male C57BL / 6N...

Embodiment 2

[0097] Example 2, Analysis of HBV-induced differentiation of germinal center B cells and Tfh cells in acute and chronic HBV mouse models

[0098] In the 3rd week of plasmid injection, according to the following steps 1-3, respectively isolate the liver lymphocytes and liver draining lymph nodes of the acute HBV mouse model and control mouse N and the chronic HBV mouse model and control mouse J in Example 1 For lymphocytes and splenic lymphocytes, the proportion of germinal center B cells and follicular helper T cells (Follicular helper CD4 + T cells, Tfh cells) ratio, according to the method of step 6, using Q-PCR to analyze CD4 + The mRNA expression levels of the mater transcription factor Bcl6 and the main effector cytokine IL-21 in T cells differentiated from Tfh cells. The experiment was repeated three times, and each experiment was set in triplicate.

[0099] 1. Liver Lymphocyte Isolation

[0100] (1) Dissection of mice: the mice were deeply anesthetized by intraperiton...

Embodiment 3

[0135] Example 3 Germinal center B cell differentiation and surface antibody response disappear in acute HBV model mice lacking Tfh cell differentiation

[0136] CD4-Cre Bcl6 fl / fl mouse CD4 + The transcription factor Bcl6 responsible for Tfh cell differentiation is specifically deleted in T cells, so the CD4 of this mouse + T cells cannot differentiate into Tfh cells after activation, while CD4 of other subsets + T cell effector differentiation was not affected. CD4-Cre Bcl6 of C57BL / 6 background fl / fl The mice were mated with C57BL / 6N mice to obtain CD4-Cre Bcl6 of the F1 generation wt / fl mice, and then the F1 generation of CD4-Cre Bcl6 wt / fl The mice were mated with C57BL / 6N mice to obtain CD4-Cre Bcl6 of the F2 generation wt / fl For mice, repeat this operation until the CD4-Cre Bcl6 of the F4 generation is obtained wt / fl Mice, which have acquired an acute HBV background (C57BL / 6N background). Then from the female CD4-Cre Bcl6 of the F4 generation wt / fl Mouse and ma...

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Abstract

The invention discloses an application of substances capable of inhibiting activity of Treg cells and promoting differentiation of Tfh cells in treating HBV infection. The application provided by theinvention includes applications of a substance which is capable of inhibiting activity of regulatory T cells, a substance which is capable of scavenging the regulatory T cells and a reagent kit whichis composed of either the substance which is capable of inhibiting activity of the regulatory T cells or the substance which is capable of scavenging the regulatory T cells and an HBV vaccine as wellas applications of T follicular helper cells and germinal center B cells in preparing products for treating and / or preventing and / or diagnosing the HBV infection. Experiments prove that humoral immuneresponse disorder in a chronic HBV model mouse can be repaired by scavenging the Treg cells in vivo, and HBV scavenging can be promoted; by inhibiting functions of the Treg cells through intraperitoneal injection of a CTLA4 blocking antibody, so that the humoral immune response disorder in the chronic HBV model mouse can be repaired and HBV scavenging can be promoted. Therefore, by targeting to the regulatory T cells, functions of the regulatory T cells can be inhibited, the differentiation of HBV specific Tfh cells can be enhanced and HBV virus scavenging can be accelerated.

Description

technical field [0001] The invention relates to the application of substances for inhibiting Treg cell activity and promoting Tfh cell differentiation in the treatment of HBV infection in the field of biotechnology. Background technique [0002] Hepatitis B Virus (HBV) is a DNA virus that can be transmitted by mother to child, sexual contact and close contact in daily life. According to statistics, there are currently nearly 350 million HBV carriers in the world, of which about 100 million people are carriers of HBV in my country. HBV infection may cause acute or chronic hepatitis and develop into a series of severe chronic liver diseases. About 1 million people worldwide die each year from cirrhosis, liver failure and hepatocellular carcinoma induced by chronic HBV infection. [0003] Cure chronic hepatitis virus infection to prevent the occurrence of liver diseases such as cirrhosis or hepatocellular carcinoma has been the goal that people have been pursuing for the past...

Claims

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Application Information

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IPC IPC(8): A61K45/00A61K39/395A61K39/29A61K35/17A61P31/20G01N33/569C12N15/85A01K67/02
Inventor 唐丽贺福初王晓文董庆洋李倩
Owner INST OF RADIATION MEDICINE ACAD OF MILITARY MEDICAL SCI OF THE PLA
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