Session Time: 3:15pm-4:45pm
Presentation Time: 4:03pm-4:15pm
*Purpose: The immune checkpoint cytotoxic T lymphocyte antigen-4 (CTLA-4), which was induced upon T cell activation but degraded quickly, has been targeted in the clinical therapy of advanced cancer and autoimmune diseases. However, whether inhibiting CTLA-4 degradation ameliorates transplant rejection remains unknown.
*Methods: The CTLA-4 expression of activated murine T cells treated with the inhibitors mediating protein degradation was detected by flow cytometry. CD45.1 congenic mice, transferred with TEa T cells and received heart transplantation was administrated with the inhibitor, and then, CTLA-4 expression of TEa T cells was analyzed. Murine skin and heart transplantation models were built, and 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 the inhibitor of CTLA-4 degradation, which augmented both surface and total CTLA-4 expression of T cells upon activation in vitro and in vivo and considerably prolonged the skin and heart allograft survival time and reduced the infiltration of inflammatory cells in allografts. We found that CQ not only decreased the frequencies of the CD4+ and CD8+ effector T cells, particularly IFN-γ producing T cells but also increased the proportion of regulatory T cells in spleens. 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.
*Conclusions: Targeting CTLA-4 degradation provides a novel means to prevent transplant rejection and induce transplant tolerance.
To cite this abstract in AMA style:Wu J. Autophagy-Lysosome Inhibitor Chloroquine Prevents CTLA-4 Degradation of T Cells and Attenuates Acute Rejection in Murine Skin and Heart Transplantation [abstract]. Am J Transplant. 2020; 20 (suppl 3). https://atcmeetingabstracts.com/abstract/autophagy-lysosome-inhibitor-chloroquine-prevents-ctla-4-degradation-of-t-cells-and-attenuates-acute-rejection-in-murine-skin-and-heart-transplantation/. Accessed February 25, 2021.
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