Enhancement of the Tolerogenic Phenotype in the Liver by ImmTOR Nanoparticles
| العنوان: | Enhancement of the Tolerogenic Phenotype in the Liver by ImmTOR Nanoparticles |
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| المؤلفون: | Christopher J. Roy, Takashi Kishimoto, Petr O. Ilyinskii, Gina L. Rizzo, Julie LePrevost |
| المصدر: | Frontiers in Immunology, Vol 12 (2021) Frontiers in Immunology |
| بيانات النشر: | Frontiers Media SA, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, immune tolerance, Programmed Cell Death 1 Receptor, CD8-Positive T-Lymphocytes, Lymphocyte Activation, T-Lymphocytes, Regulatory, regulatory T cells, B7-H1 Antigen, Hepatitis, Immune tolerance, Mice, 0302 clinical medicine, Immunology and Allergy, CTLA-4 Antigen, Cells, Cultured, Original Research, B-Lymphocytes, biology, Chemistry, ImmTOR, double-negative T cells, Tolerance induction, medicine.anatomical_structure, Female, Kupffer Cells, Ovalbumin, Polyesters, T cell, LSECs, Immunology, liver, 03 medical and health sciences, Immune system, Downregulation and upregulation, Hepatic Stellate Cells, medicine, Animals, Sirolimus, MHC class II, rapamycin, Histocompatibility Antigens Class II, Endothelial Cells, Dendritic Cells, RC581-607, Mice, Inbred C57BL, 030104 developmental biology, Hepatocytes, Hepatic stellate cell, Cancer research, biology.protein, Nanoparticles, Immunologic diseases. Allergy, CD8, 030215 immunology |
| الوصف: | ImmTOR biodegradable nanoparticles encapsulating rapamycin have been shown to induce a durable tolerogenic immune response to co-administered biologics and gene therapy vectors. Prior mechanism of action studies have demonstrated selective biodistribution of ImmTOR to the spleen and liver following intravenous (IV) administration. In the spleen, ImmTOR has been shown to induce tolerogenic dendritic cells and antigen-specific regulatory T cells and inhibit antigen-specific B cell activation. Splenectomy of mice resulted in partial but incomplete abrogation of the tolerogenic immune response induced by ImmTOR. Here we investigated the ability of ImmTOR to enhance the tolerogenic environment in the liver. All the major resident populations of liver cells, including liver sinusoidal endothelial cells (LSECs), Kupffer cells (KC), stellate cells (SC), and hepatocytes, actively took up fluorescent-labeled ImmTOR particles, which resulted in downregulation of MHC class II and co-stimulatory molecules and upregulation of the PD-L1 checkpoint molecule. The LSEC, known to play an important role in hepatic tolerance induction, emerged as a key target cell for ImmTOR. LSEC isolated from ImmTOR treated mice inhibited antigen-specific activation of ovalbumin-specific OT-II T cells. The tolerogenic environment led to a multi-pronged modulation of hepatic T cell populations, resulting in an increase in T cells with a regulatory phenotype, upregulation of PD-1 on CD4+ and CD8+ T cells, and the emergence of a large population of CD4–CD8– (double negative) T cells. ImmTOR treatment protected mice in a concanavalin A-induced model of acute hepatitis, as evidenced by reduced production of inflammatory cytokines, infiltrate of activated leukocytes, and tissue necrosis. Modulation of T cell phenotype was seen to a lesser extent after administration by empty nanoparticles, but not free rapamycin. The upregulation of PD-1, but not the appearance of double negative T cells, was inhibited by antibodies against PD-L1 or CTLA-4. These results suggest that the liver may contribute to the tolerogenic properties of ImmTOR treatment. |
| تدمد: | 1664-3224 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::45c4937bc1fdc0ac1ddcad09685a933e https://doi.org/10.3389/fimmu.2021.637469 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....45c4937bc1fdc0ac1ddcad09685a933e |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 16643224 |
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