UC Irvine

Abstract: Multiple Sclerosis (MS) is a chronic inflammatory autoimmune disease affecting the central nervous system (CNS) and for which there is no cure. Current treatments focus on suppression of the immune system but fail to repair the resulting damage to the CNS. Neural stem cell (NSC) transplantation is a promising therapeutic strategy for treating neurodegenerative diseases through cell replacement and repair however it is unclear how these cells would mediate repair in MS. We report that human NSCs promote CNS specific T regulatory cells (Tregs) which activate endogenous repair pathways and promote remyelination in a murine model of MS. We observed remyelination, decreased inflammation and an increase in (CNS)-infiltrating CD4+CD25+FoxP3+ Tregs in EAE mice receiving an intra-spinal transplant of NSCs. Recovery was not a result of cell replacement, as NSCs underwent xenograft rejection, and was Treg dependent, as ablation of Tregs abrogated histopathological improvement. RAG2−/−2D2 (R2D2) mice, which bear a TCR repertoire restricted to myelin oligodendrocyte glycoprotein (MOG) and neurofilament, lack CD25+FoxP3+ Tregs under homeostatic conditions; however, upon exposure to MOG, R2D2 mice developed CD25+FoxP3+ Tregs in cervical lymph nodes and the spinal cord. hNSCs also promoted Tregs in vitro in co-cultures with wild type B6 and R2D2 splenocytes, but not with RAG2−/− OT-II+ splenocytes. Additionally, hNSC-Tregs also appear to derive from the exTreg pool suggesting both antigen specific expansion and antigen dependent maintenance of FOXP3 in CNS-specific Tregs. hNSC Tregs also have a unique expression profile and express transglutimase-2 which is implicated in oligodendrocyte dependent repair in the CNS.