Smith, Paul (2015) MSc Project Report - University submission: Investigating the pathological significance of Sppl2a in a pre-clinical model of multiple sclerosis. University of Freiburg - MSc projects electronically available through library.

Abstract

This is a MSc project report to the University of Freiburg (Germany) - the project was agreed in advance with the Sppl2a project team within ATI. Other MSc student reports (Carla Winter) using the same knockout mice have already been reported. No compounds were used.

This thesis describes a highly beneficial effect of Sppl2a knockout in a B-cell dependent and independent mouse MS model called Experimental Autoimmune Encephalomyelitis (EAE). The collected data from Sppl2a knockout mice confirmed published severe mature B-cell depletion and revealed for the first time a complete prevention of B-cell dependent EAE induction (with human derived myelin oligodendrocyte glycoprotein (humanMOG)). This observation was consistent with the postulated crucial role of B-cells for humanMOG presentation in this EAE model variant. Furthermore, it was shown that SPPL2a deficiency ameliorated a B-cell independent EAE model (with ratMOG) independent of regulatory T-cell (Treg) immuno-suppression. This reduced EAE phenotype could be explained by insufficient (auto)immune cell priming, impaired pathogenic T-helper 17 cell (TH17) subset responses, myeloid derived suppressor cells (MDSCs) expansion in lymphoid organs and disrupted macrophage migration inhibitory factor (MIF) signaling due to disturbed CD74 cell surface homeostasis in Sppl2a knockout animals.
Taken together, this altered immune phenotype resulted in a reduced inflammatory environment in the Sppl2a knockout animals. These data shed light on B-cell independent pathological mechanisms during central nervous system (CNS) neuro-inflammation and emphasize the role of SPPL2a as an essential immunological link and potential innovative target in MS therapy.

Item Type:	Article
Date Deposited:	26 Apr 2016 23:45
Last Modified:	26 Apr 2016 23:45
URI:	https://oak.novartis.com/id/eprint/25892