John Stratigis1, Nicholas Ahn1, Kendall Lawrence1, Haiying Li1, Andre Dias2, Camila Fachin2, Barbara Coons1, Paolo De Coppi3, Darrell Irvine4, Stavros Loukogeorgakis3,1, Alan Flake1
1Center for Fetal Research, The Children's Hospital of Philadelphia, Philadelphia, USA. 2Federal University of Parana, Curitiba, Brazil. 3Stem Cells and Regenerative Medicine, UCL Great Ormond Street Institute of Child Health, London, United Kingdom. 4Massachusetts Institute of Technology, Cambridge, USA


Aim of Study:

Autoimmune disease (AD) occurs when there is breakdown in immunological self-tolerance. In utero transplantation (IUT) of allogenic cells results in presentation of antigen to the thymus with development of central tolerance. Thymic presentation of antigen can also be achieved by IUT of nanoparticle (NP) encapsulated peptides. Our aim was to determine whether prenatal antigen presentation using a NP-based  platform can maintain/boost self-tolerance and prevent AD in a model of experimental autoimmune encephalopathy (EAE; murine multiple sclerosis).



EAE was generated in C57BL/6 mice by administering myelin oligodendrocyte glycoprotein (MOG) at 8 weeks of age to induce adaptive autoimmune response-mediated central nervous system (CNS) demyelination. To prevent EAE, IUT of MOG-loaded NP (NP-MOG) was performed at embryonic day 14 (E14), and was followed by postnatal NP-MOG booster injections at up to the age of 12 weeks. Mice were monitored using a 5-point EAE scoring system for 4 weeks after EAE induction.


Main Results:

Administration of MOG at 8 weeks of age resulted in EAE in most f animals [disease free survival (DFS): 17.6%; positive control]. Remarkably, IUT of NP-MOG+postnatal boosters prevented EAE [Group A; DFS: 100%; p<0.001 vs. positive control). This was in contrast to what was observed when mice received E14 NP-MOG only without boosters (Group B; DFS: 0%) or postnatal NP-MOG without IUT (Group C; DFS: 12.5%), which did as poorly as positive controls (p<0.001 vs. Group A). CNS analysis in Group A animals demonstrated prevention of the EAE-inducing autoimmune response, as evident by the lack of infiltration by MOG-specific/myelin-destroying T-cells.



Our study demonstrates that EAE can be prevented by a novel strategy based on induction/maintenance of central tolerance by prenatal delivery of NP-encapsulated peptides and may lead to a paradigm shift in the management of AD.