The 20S Proteasome, Active within Exosome-Like Vesicles Released by Apoptotic Cells Accelerates Rejection.

M. Dieudé,^1,4,5 C. Bell,^2,5 J. Turgeon,^1,5 D. Beillevaire,^1,4,5 S. Qi,^1,5 E. Boilard,^3,5 P. Thibault,^2,5 M.-J. Hébert.^1,4,5

¹Research Centre Centre hospitalier de l'Université
de Montréal (CRCHUM), Montréal, Canada
²Institute for research in immunology and cancer (IRIC), Montreal, Canada
³Centre de Recherche du CHU de Québec, Québec, Canada
⁴Université
de Montréal, Montréal, Canada
⁵Canadian National Transplant Research Program, Edmonton, Canada.

Meeting: 2016 American Transplant Congress

Abstract number: 350

Keywords: Apoptosis, Autoimmunity, Endothelial cells, Vascular disease

Session Information

Session Name: Concurrent Session: Pathways of Allograft Rejection: Animal Models

Session Type: Concurrent Session

Date: Monday, June 13, 2016

Session Time: 4:30pm-6:00pm

Presentation Time: 5:18pm-5:30pm

Location: Room 310

Apoptotic bodies (ApoBodies) and apoptotic exosome-like MV (ApoExo) released by apoptotic endothelial cells in vitro were purified by sequential centrifugation and analysed by electron microscopy and comparative proteomics. C57Bl/6 mice transplanted with an aortic graft from a MHC-mismatched BALB/c donor or non-transplanted C57Bl/6 mice were injected intravenously with apoptotic MV for up to 3 weeks.

Injection of ApoBodies failed to induce an immunogenic response. Injection of ApoExo induced a strong anti-LG3 IgG response, both in non-transplanted (p<0.001) and transplanted (p<0.05) mice. Donor specific antibodies were detected in allografted mice but their levels were not affected by the injection of MVs. The injection of ApoExo to transplanted mice, but not of ApoBodies, heightened the severity of rejection as shown by increased neointima formation (n=6, p<0.01), infiltration by CD3+ T cells (p<0.01) and CD20+ B cells (p<0.01) and C4d deposition (p<0.001).

Proteomic analyses identified perlecan/LG3 and the 20S proteasome specifically in ApoExo. The proteolytic activity of the 20S proteasome was significantly increased in ApoExo (p<0.01) compared to ApoBodies or cell extracts. Proteasome inhibition in endothelial cells with bortezomib, did not reduce the production of ApoExo but significantly impeded their proteolytic activity (p<0.001). Injection of proteasome-inhibited ApoExo led to reduced recruitment of both B (p<0.01) and T (p<0.05) cells to the allograft in association with decreased C4d deposition (p<0.05) and reduced circulating levels of anti-LG3 IgG (p<0.05).

These results identify apoptotic exosome-like vesicles as novel accelerators of rejection and the 20S proteasome, active within these MV, as an important determinant of immune responses to the graft.

CITATION INFORMATION: Dieudé M, Bell C, Turgeon J, Beillevaire D, Qi S, Boilard E, Thibault P, Hébert M.-J. The 20S Proteasome, Active within Exosome-Like Vesicles Released by Apoptotic Cells Accelerates Rejection. Am J Transplant. 2016;16 (suppl 3).

To cite this abstract in AMA style:

Dieudé M, Bell C, Turgeon J, Beillevaire D, Qi S, Boilard E, Thibault P, Hébert M-J. The 20S Proteasome, Active within Exosome-Like Vesicles Released by Apoptotic Cells Accelerates Rejection. [abstract]. Am J Transplant. 2016; 16 (suppl 3). https://atcmeetingabstracts.com/abstract/the-20s-proteasome-active-within-exosome-like-vesicles-released-by-apoptotic-cells-accelerates-rejection/. Accessed November 21, 2024.

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