Schutz vor Autoimmunerkrankungen durch Expression von Autoantigenen in der Leber
Final Report Abstract
Background and Aim: Hepatic expression of an alternated peptide ligand (APL) of myelin basic protein (MBP) leads to protection from experimental autoimmune encephalomyelitis (EAE) in mice. EAE constitutes a mouse model for multiple sclerosis in which MBP is one of the major auto-antigens. Other auto-antigens are myelin oligodendrocyte glycoprotein (MOG) and proteolipid protein (PLP). The tolerance is mediated by MBP specific regulatory T cells after conversion of naïve T cells into the regulatory phenotype. Here we investigate the prophylactic and therapeutic potential of liver expressed APLs of MOG and PLP in EAE. Methods: EAE was analyzed in C57BL/6J and SJL/J mice after immunization with a MOG or PLP peptide, respectively. Native peptides and 15 different APLs were used for disease induction. All APLs were designed using the computer-based SMM-Align algorithm for screening and optimizing the native peptide sequence of MOG and PLP to gain higher MHCII affinity. In addition, plasmid vectors encoding for different APLs were cloned and hydrodynamically transferred into liver before or after EAE onset. EAE course was followed over 45 days after onset. Results: Two out of 15 tested APLs were able to induce EAE apart from the native peptides. No APL plasmid vector did protect C57BL/6J or SJL/J mice from EAE using hydrodynamics based gene transfer in a prophylactic or therapeutical approach. Conclusions: Hepatic expression of APLs with increased MHCII affinity by way of hydrodynamic gene transfer alone is not generally sufficient to induce immune tolerance. Other ways of gene transport might prove more effective, e.g. nanoparticles or liposomes. Algorithms analogous to the computer-based SMM-Align method should be tested and followed by in vivo evaluation of the calculated APLs.
Publications
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Nanoparticle-based autoantigen delivery to Treg-inducing liver sinusoidal endothelial cells enables control of autoimmunity in mice. Journal of Hepatology, Volume 62, Issue 6, June 2015, Pages 1349-1356
Carambia A, Freund B, Schwinge D, Bruns O, Salmen S, Ittrich H, Reimer R, Heine M, Huber S, Waurisch C, Eychmüller A, Wraith D, Korn T, Nielsen P, Weller H, Schramm C, Lüth S, Lohse AW, Heeren J und Herkel J
