Researchers identify apoptotic exosome-like vesicles as a central trigger for organ transplant rejection

Autoantibodies to components of apoptotic cells, such as anti-perlecan antibodies, contribute to rejection in organ transplant recipients. However, mechanisms of immunization to apoptotic components remain largely uncharacterized. Researcher at the Hospital of the University of Montreal used large-scale proteomics, with validation by electron microscopy and biochemical methods, to compare the protein profiles of apoptotic bodies and apoptotic exosome-like vesicles, smaller extracellular vesicles released by endothelial cells downstream of caspase-3 activation. They identified apoptotic exosome-like vesicles as a central trigger for production of anti-perlecan antibodies and acceleration of rejection. Unlike apoptotic bodies, apoptotic exosome-like vesicles triggered the production of anti-perlecan antibodies in naïve mice and enhanced anti-perlecan antibody production and allograft inflammation in mice transplanted with an MHC (major histocompatibility complex)–incompatible aortic graft. The 20S proteasome core was active within apoptotic exosome-like vesicles and controlled their immunogenic activity. Finally, the researcher showed that proteasome activity in circulating exosome-like vesicles increased after vascular injury in mice. These findings open new avenues for predicting and controlling maladaptive humoral responses to apoptotic cell components that enhance the risk of rejection after transplantation.

Apoptotic exosome-like vesicles aggravate vascular rejection.

(A) Anti-LG3 IgG titers in sera harvested 3 weeks after surgery from allografted mice injected with vehicle, exosome-like vesicles, or apoptotic bodies for 3 weeks after transplantation. (B) Hematoxylin and eosin (H&E), CD3, CD20, and C4d staining of aortic allograft sections from mice injected with vehicle, exosome-like vesicles, or apoptotic bodies for 3 weeks after transplantation (magnification: top panels, ×5; lower panels, ×20). (C) Intima/media ratio in allografts from mice injected with vehicle, exosome-like vesicles, or apoptotic bodies for 3 weeks after transplantation. (D) Mean number of CD3⁺ cells (T cells) per high-power field in allografts from mice injected with vehicle, exosome-like vesicles, or apoptotic bodies for 3 weeks after transplantation. (E) Mean number of CD20⁺ cells (B cells) per high-power field in allografts from mice injected with vehicle, exosome-like vesicles, or apoptotic bodies for 3 weeks after transplantation. (F) C4d deposition in allografts from mice injected with vehicle, exosome-like vesicles, or apoptotic bodies for 3 weeks after transplantation. (G) DSA levels in sera harvested 3 weeks after surgery from allografted mice injected with vehicle, exosome-like vesicles, or apoptotic bodies for 3 weeks after transplantation. n ≥ 8 for each condition. Data are pooled from three independent experiments; mean ± SEM; comparison with vehicle, t test.