Autophagy-lysosome inhibitor chloroquine prevents CTLA-4 degradation of T cells and attenuates acute rejection in murine skin and heart transplantation
| Autor: | Lang Jiang, Hao Zhang, Jikai Cui, Yanqiang Zou, Jiahong Xia, Jing Zhao, Shanshan Chen, Jie Wu, Jizhang Yu, Sheng Le, Heng Xu |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Graft Rejection
Male 0301 basic medicine T cell medicine.medical_treatment T cells Medicine (miscellaneous) Mice Transgenic chemical and pharmacologic phenomena 030230 surgery Protein degradation Lymphocyte Activation Cell Line Interferon-gamma Mice 03 medical and health sciences 0302 clinical medicine Autophagy medicine Animals Humans Cytotoxic T cell CTLA-4 Antigen Pharmacology Toxicology and Pharmaceutics (miscellaneous) Heart transplantation business.industry Cytotoxic T lymphocyte antigen-4 Graft Survival Chloroquine Skin Transplantation medicine.disease Immune checkpoint Transplant rejection Disease Models Animal 030104 developmental biology medicine.anatomical_structure CTLA-4 Proteolysis Cancer research Heart Transplantation Lymphocyte Culture Test Mixed Lysosomes business CD8 Research Paper |
| Zdroj: | Theranostics |
| ISSN: | 1838-7640 |
| Popis: | Background: The immune checkpoint cytotoxic T lymphocyte antigen-4 (CTLA-4), induced upon T cell activation but degraded quickly, has been targeted in the clinical therapy of advanced cancers and autoimmune diseases. However, whether inhibiting CTLA-4 degradation ameliorates transplant rejection remains unknown. Methods: The CTLA-4 expression in activated murine T cells treated with the inhibitors mediating protein degradation was detected by flow cytometry (FCM). CD45.1 mice, which received TEa T cells and underwent heart transplantation, were administrated with the inhibitor. Subsequently, CTLA-4 expression of TEa T cells was analyzed. Murine skin and heart transplantation models were built, then the survival and histopathology of the allografts, and T cell subsets in the spleens of each group were compared. Results: Chloroquine (CQ) was identified as an inhibitor of CTLA-4 degradation, which augmented both surface and total CTLA-4 expression in T cells. It considerably prolonged the skin and heart allograft survival time and reduced the infiltration of inflammatory cells in allografts. Besides decreasing the frequencies of the CD4+ and CD8+ effector T cells, especially IFN-γ producing T cells, CQ also increased the proportion of regulatory T cells in the spleen. The CTLA-4 blockade abrogated the benefits of CQ on the survival of heart allografts. Moreover, CQ enhanced CTLA-4 expression in activated human T cells and reduced the secretion of IFN-γ in human mixed lymphocyte reaction. Conclusion: Targeting CTLA-4 degradation provides a novel means to prevent transplant rejection and induce transplant tolerance. |
| Databáze: | OpenAIRE |
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