Mesencephalic Astrocyte-derived Neurotrophic Factor Supports Hepatitis B Virus-induced Immunotolerance.

BACKGROUND & AIMS: The immune tolerance induced by hepatitis B virus (HBV) is a major challenge for achieving effective viral clearance, and the mechanisms involved are not well-understood. One potential factor involved in modulating immune responses is mesencephalic astrocyte-derived neurotrophic factor (MANF), which has been reported to be increased in patients with chronic hepatitis B. In this study, our objective is to examine the role of MANF in regulating immune responses to HBV. METHODS: We utilized a commonly used HBV-harboring mouse model, where mice were hydrodynamically injected with the pAAV/HBV1.2 plasmid. We assessed the HBV load by measuring the levels of various markers including hepatitis B surface antigen, hepatitis B envelope antigen, hepatitis B core antigen, HBV DNA, and HBV RNA. RESULTS: Our study revealed that following HBV infection, both myeloid cells and hepatocytes exhibited increased expression of MANF. Moreover, we observed that mice with myeloid-specific MANF knockout (ManfMye-/-) displayed reduced HBV load and improved HBV-specific T cell responses. The decreased HBV-induced tolerance in ManfMye-/- mice was associated with reduced accumulation of myeloid-derived suppressor cells (MDSCs) in the liver. Restoring MDSC levels in ManfMye-/- mice through MDSC adoptive transfer reinstated HBV-induced tolerance. Mechanistically, we found that MANF promoted MDSC expansion by activating the IL-6/STAT3 pathway. Importantly, our study demonstrated the effectiveness of a combination therapy involving an hepatitis B surface antigen vaccine and nanoparticle-encapsulated MANF siRNA in effectively clearing HBV in HBV-carrier mice. CONCLUSION: The current study reveals that MANF plays a previously unrecognized regulatory role in liver tolerance by expanding MDSCs in the liver through IL-6/STAT3 signaling, leading to MDSC-mediated CD8+ T cell exhaustion.

Multimorbidity Patterns and Associations with Gait, Balance and Lower Extremity Muscle Function in the Elderly: A Cross-Sectional Study in Northwest China.

Purpose: Fall is a common geriatric syndrome leading to various adverse outcomes in the elderly. Gait and balance disorders and decreased lower extremity muscle function are the major intrinsic risk factors of falls, and studies suggested that they were closely related to the underlying chronic conditions. This study aimed to explore the patterns of multimorbidity and determine the associations of these multimorbidity patterns with gait, balance and lower extremity muscle function. Patients and Methods: A cross-sectional survey of 4803 participants aged ≥60 years in Shaanxi Province, China was conducted and the self-reported chronic conditions were investigated. The 6-m walk test, timed-up-and-go test (TUG) and 5-sit-to-stand test (5-STS) were conducted to evaluate gait, balance, and lower extremity muscle function respectively. Latent class analysis was used to explore patterns of multimorbidity, and multivariate regression analysis was used to determine the associations of multimorbidity patterns with gait, balance, and lower extremity muscle function. Results: Five multimorbidity patterns were identified: Degenerative Disease Class, Cardio-metabolic Class, Stroke-Respiratory-Depression Class, Gastrointestinal Class, and Very sick Class, and they were differently associated with gait and balance disorders and decreased lower extremity muscle function. In particular, the multimorbidity patterns of Degenerative Disease Class and Stroke-Respiratory-Depression Class were closely associated with all the three risk factors of falls. Conclusion: There are significant differences in the impact of different multimorbidity patterns on the major intrinsic risk factors of falls in the elderly population, and appropriate multimorbidity patterns are closely related to the prediction of falls and can help to develop fall prevention strategies in the elderly.

Chemotherapy induces immune checkpoint VISTA expression in tumor cells via HIF-2alpha.

Tumor cells can evade the innate and adaptive immune systems, which play important roles in tumor recurrence and metastasis. Malignant tumors that recur after chemotherapy are more aggressiveciscis, suggesting an increased ability of the surviving tumor cells to evade innate and adaptive immunity. Therefore, in order to reduce patient mortality, it is important to discover the mechanisms by which tumor cells develop resistance to chemotherapeutics. In the present study we focused on the tumor cells that survived chemotherapy. We found that chemotherapy could promote the expression of VISTA in tumor cells, and that this change was mediated by HIF-2α. In addition, VISTA overexpression on melanoma cells promoted immune evasion, and the application of the VISTA-blocking antibody 13F3 enhanced the therapeutic effect of carboplatin. These results offer an insight into the immune evasion of chemotherapy-resistant tumors, and provide a theoretical basis for the combined application of chemotherapy drugs and VISTA inhibitors to treat tumors.

The study of immune checkpoint inhibitors in chronic hepatitis B virus infection.

Chronic hepatitis B (CHB) is a contagious disease caused by the hepatitis B virus, which can damage the liver via cirrhosis or cancer. Existing CHB treatments are not completely effective; immune checkpoint inhibitors show potential hope for treating CHB, but their safety and efficacy need to be further validated. In this review, we introduce the mechanisms of CHB virus infection, the expression of immune checkpoints during CHB, and the treatments that are currently available. Finally, we discuss the possibilities for using immune checkpoint inhibitors to treat CHB.

Adverse and unconventional reactions related to immune checkpoint inhibitor therapy for cancer.

Immunotherapy is an emerging method for the treatment of cancer. Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that block immune checkpoint pathways and release the body's anti-tumor immunity. They consist mainly of antibodies against cytotoxic T lymphocyte associated antigen-4 (CTLA-4), programmed death receptor 1 (PD-1), and programmed death ligand 1 (PD-L1). Although ICI therapy has been shown to be effective at treating cancer, it can also destroy immune tolerance and lead to organ toxicity. These unwanted side effects are known as immune related adverse events (irAEs). ICI treatment can also cause unconventional reactions such as pseudoprogression and hyperprogression. Pseudoprogression looks like an increase in the tumor parenchyma but is actually a temporary inflammation in the tumor; hyperprogression refers to the acceleration of tumor growth after the start of immunotherapy. Understanding the mechanisms of these two phenomena and distinguishing their differences are necessary for the effective prevention and treatment of unconventional reactions.

Biomarkers related to immune checkpoint inhibitors therapy.

Immune checkpoint inhibitors (ICIs) therapy is an emerging cancer treatment. During treatment it is necessary to monitor the patient at all times and respond to any adverse reactions that may occur, such as immune-related adverse events and unconventional reactions. Biomarkers, the biochemical indicators that mark changes in the structure or function of systems, organs, tissues, and cells, may be used to predict and design treatment for such reactions. Anti-tumor immunotherapy biomarkers can be derived from the tumors themselves (e.g. negative regulatory molecules and dynamic changes in genome sequence) or from the immune system (e.g. peripheral blood cell population counts, various cytokines, tumor-infiltrating lymphocytes, and intestinal microbes). The development of biomarkers is important for monitoring the effect of treatment, assessing the patient's response to ICIs, determining adverse reactions, and predicting the direction of disease development. In addition, organ toxicity and systemic events also have an impact on the therapeutic effect of ICIs.

The expression and immunoregulation of immune checkpoint molecule VISTA in autoimmune diseases and cancers.

Immune checkpoint inhibitors (ICIs) and immunotherapy have proven to be a transformative therapy for many forms of cancer treatment. While many antibodies targeting the PD-1, PD-L1, and CTLA-4 pathways have been approved for clinical use by the FDA, it is clear that a single ICI is not sufficient to eradicate disease. ICI combination strategies are being extensively investigated to advance cancer treatment to next curative stage. Among the immune checkpoint inhibitors being actively investigated, the potential of VISTA (V-domain Ig suppressor of T cell activation), a unique B7 family member that functions as both ligand and receptor, is being actively pursued. This article summarizes the expression and immunomodulatory effects of VISTA in autoimmune diseases and cancer, and assesses its potential as an additional component of immune checkpoint cancer therapy.