Chronic Hepatitis B
Conditions
Keywords
Chronic Hepatitis B, CD8+ T Cell Exhaustion, ANKRD11, Epigenetic Regulation, TCR-T Cell Therapy
Brief summary
Achieving a functional cure for chronic hepatitis B (CHB) is largely hindered by the irreversible functional exhaustion and immune tolerance of hepatitis B virus (HBV)-specific CD8 positive T (CD8+ T) cells. In investigators previous studies, an in vivo Clustered Regularly Interspaced Short Palindromic Repeat(CRISPR) screen identified ANKRD11 for the first time as an "epigenetic brake" on CD8+ T-cell effector function. Loss of ANKRD11 markedly enhanced the expansion, effector function, and viral clearance capacity of HBV-specific T cells. Based on these findings, investigators hypothesize that ANKRD11 regulates the epigenetic program of T-cell exhaustion by restricting the activity of AP-1 family transcription factors, and that targeting ANKRD11 can reverse T-cell dysfunction and overcome immune tolerance. This project will: (1) elucidate the epigenetic mechanisms by which ANKRD11 regulates T-cell exhaustion using conditional knockout mouse models and multi-omics approaches; (2) evaluate how ANKRD11 deficiency reshapes the differentiation trajectory and antiviral function of HBV-specific T cells in models of chronic HBV infection; and (3) develop a combinatorial gene-editing strategy integrating "release of the brake" with "stepping on the accelerator" to generate enhanced T Cell Receptor-T cell Therapy(TCR-T) cells and evaluate their efficacy and safety in humanized mouse models. The study is expected to define a novel mechanism by which ANKRD11 regulates T-cell exhaustion, establish an enhanced TCR-T therapeutic strategy, and provide a potential approach toward achieving a functional cure for chronic HBV infection.
Detailed description
The human participant component of this study is limited to prospective collection of peripheral blood samples from patients with chronic hepatitis B and healthy volunteers for preclinical laboratory investigations. No therapeutic intervention is assigned to human participants. The major experimental components of the overall research project are conducted in vitro and in animal models.
Interventions
None listed
Sponsors
Beijing Municipal Administration of Hospitals
Study design
Observational model
OTHER
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* (1) Inclusion criteria for healthy donors: Age 18-60 years; Voluntary participation in this study and signing a written informed consent form; HLA-A11 positive; Generally in good health condition; No infection with hepatitis B virus, hepatitis C virus, HIV, syphilis, etc.; No severe liver, kidney, heart, lung, or blood system diseases; No recent immunosuppressive agents, cell therapy, or other treatments that may significantly affect immune function. (2) Inclusion criteria for chronic HBV patients: Age 18-65 years; Voluntary participation in this study and signing a written informed consent form; HLA-A11 positive; Meeting the diagnostic criteria for chronic HBV infection or chronic hepatitis B; HBsAg positive for ≥6 months; Able to provide basic clinical data, including HBsAg, HBeAg, HBV DNA, ALT, AST, etc.
Exclusion criteria
(1)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Antigen-Specific Cytotoxic Activity of HBV-Specific TCR-T Cells | After 4 hours of co-culture | Antigen-specific cytotoxic activity of HBV-specific TCR-T cells will be assessed using HBc141-151 peptide-loaded T2-A11 target cells at effector-to-target ratios of 1:1, 2.5:1, 5:1, and 10:1 by LDH release assay and flow cytometry-based cytotoxicity assay. |
Contacts
CONTACTMinghui Li
Outcome results
None listed