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Autophagy-lysosome inhibitor chloroquine prevents CTLA-4 degradation of T cells and attenuates acute rejection in murine skin and heart transplantation
- Source :
- Theranostics
- Publication Year :
- 2020
- Publisher :
- Ivyspring International Publisher, 2020.
-
Abstract
- 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.
- Subjects :
- 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
Subjects
Details
- ISSN :
- 18387640
- Volume :
- 10
- Database :
- OpenAIRE
- Journal :
- Theranostics
- Accession number :
- edsair.doi.dedup.....f6e50c383ce8169a0feb967f1c1f8e95