To allow its use in humans and avoid side effects/risks or loss of potency, extracellular vesicles have to be tested to know more about their immunogenicity. As an example, the use of extracellular vesicles derived from HEK in humans would need to test their immunogenicity first, in particular for their use as camouflage of enzyme for enzyme replacement therapies that would require repeated injections. The subject of immunogenicity of such common cell lines is however rarely investigated, and this line seems not to be highly immunogenic [28]. On the contrary, stem cells like mesenchymal stem cells (MSC) are known to be lowly immunogenic, and extracellular vesicles derived from them are therefore expected not to be immunogenic, with little evidence for the moment [41].

On another side, if we make the comparison between extracellular vesicles injection and platelet transfusion (that do express ABO antigen system and HLA type 1), we see that most of the platelet transfusion are only matched with the ABO system, and that only around 7 % [83] of donors develop antibodies against HLA molecules. Therefore, we consider that if the extracellular vesicles express the ABO antigen, it will probably have to be matched with the donor. ABO is expressed by most epithelial and endothelial cells (https://www.proteinatlas.org/ENSG00000175164-ABO/tissue), and is able to be transferred to cells in the plasma where it is present in a soluble form in a low amount [84]. Therefore, any human blood derived extracellular vesicle probably express ABO markers. Interestingly, MSC derived extracellular vesicles do not express ABO antigens [85] and low amount of MHC class 1 and no 2 molecule [86]. 

Interestingly, Gabrielsson et al [87] described the use of dendritic cell derived extracellular vesicles to induce an immune response against a tumor, made a knock out of the MHC class 1 genes on the EV, and showed that the efficiency of the exosome therapy was not hampered by the absence of MHC class 1, meaning that MHC class 1 molecules maybe have not such an important role, and that allogenic use was rather more effective than autograft.

[28] X. Zhu, M. Badawi, S. Pomeroy, D.S. Sutaria, Z. Xie, A. Baek, J. Jiang, O.A. Elgamal, X. Mo, K.L. Perle, J. Chalmers, T.D. Schmittgen, M.A. Phelps, Comprehensive toxicity and immunogenicity studies reveal minimal effects in mice following sustained dosing of extracellular vesicles derived from HEK293T cells, Journal of Extracellular Vesicles, 6 (2017) 1324730.

[41] G. Zheng, R. Huang, G. Qiu, M. Ge, J. Wang, Q. Shu, J. Xu, Mesenchymal stromal cell-derived extracellular vesicles: regenerative and immunomodulatory effects and potential applications in sepsis, Cell and Tissue Research, (2018).

[83] P. Katerina, F. John, S.J. W., HLA alloimmunization against platelet transfusions: pathophysiology, significance, prevention and management, Tissue Antigens, 79 (2012) 237-245.

[84] C. Green, The ABO, Lewis and related blood group antigens; a review of structure and biosynthesis, FEMS microbiology immunology, 1 (1989) 321-330.

[85] G. Moll, A. Hult, L. von Bahr, J.J. Alm, N. Heldring, O.A. Hamad, L. Stenbeck-Funke, S. Larsson, Y. Teramura, H. Roelofs, B. Nilsson, W.E. Fibbe, M.L. Olsson, K. Le Blanc, Do ABO Blood Group Antigens Hamper the Therapeutic Efficacy of Mesenchymal Stromal Cells?, PLoS ONE, 9 (2014) e85040.

[86] J.M. Ryan, F.P. Barry, J.M. Murphy, B.P. Mahon, Mesenchymal stem cells avoid allogeneic rejection, in:  J Inflamm (Lond), 2005, pp. 8.

[87] S. Hiltbrunner, P. Larssen, M. Eldh, M.-J. Martinez-Bravo, A.K. Wagner, M.C.I. Karlsson, S. Gabrielsson, Exosomal cancer immunotherapy is independent of MHC molecules on exosomes, Oncotarget, 7 (2016) 38707-38717.

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