Autoantibodies to apoptotic antigens, such as perlecan/LG3, are present pre-transplantation and contribute to organ rejection. We previously showed that during tissue injury, apoptotic endothelial cells (EC) secrete immunogenic apoptotic exosome-like vesicles (ApoExo), which are distinct from apoptotic bodies (ApoBodies) and carry active 20S proteasome (20Sprot) as well as LG3. Here, we aim to characterize the contribution of ApoExo to autoimmunity and rejection.

Apoptotic bodies (ApoBodies) and apoptotic exosome-like vesicles (ApoExo) released by apoptotic endothelial cells in vitro were purified by sequential centrifugation. Naïve WT and aortic allografted WT mice were injected every other day with ApoExo, Apo bodies or vehicle until sacrifice at 3 weeks. Serum cytokine 36plex assay was performed at sacrifice. Graft rejection and infiltration was evaluated by immunohistochemistry. In all models, anti-LG3, anti-vimentin, anti-angiotensin II type 1 receptor (AT1R), anti-fibronectin and anti-nuclear antibodies (ANA) IgG levels were monitored by ELISA.

In uninjured mice, injection of ApoExo (but not of ApoBodies) triggered an increase in circulating levels of IL-23, IL-17, CXCL-1 and TNF-alpha (p<0.01), hallmarks of the IL-23/IL-17 autoimmune axis. Strong anti-LG3 IgG (p<0.001) and ANA responses (p<0.001) were also noted while anti-vimentin, anti-AT1R and anti-fibronectin levels were not affected by ApoExo injection. Similarly, the injection of ApoExo (but not of ApoBodies) to allografted mice did not affect anti-vimentin, anti-AT1R and anti-fibronectin levels but increased anti-LG3 (p<0.01) and ANA (p<0.005) levels and heightened vascular remodelling (p<0.01) and allograft leucocyte infiltration (p<0.01).

Collectively, these results demonstrate the importance of apoptotic exosome-like vesicles in induction of the IL23/IL-17 autoimmune axis, production of ANA and anti-LG3 autoantibodies and acceleration of rejection.

CITATION INFORMATION: Dieudé M, Turgeon J, Karakeussian-Rimbault A, Pomerleau L, Robitaille A, Grandvaux N, Boilard É, Hébert M.-J. Apoptotic Exosome-Like Vesicles Released During Tissue Injury Trigger IL23/IL-17 Autoimmune Axis and Accelerate Rejection. Am J Transplant. 2017;17 (suppl 3).

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