I10 Acute innate immune responses to simulated transplantation surgery in two HD mouse models

Multiple studies provide proof-of-concept for the benefits of cell replacement therapy (CRT) in Huntington’s disease (HD), however attaining a high survival rate of the cells post-transplantation has remained a significant challenge. Neuroinflammation is crucial in the onset and progression of HD. We hypothesise that inflammatory response to CRT surgery might be exacerbated due to a primed intrinsic inflammatory environment, partly explaining cell death and graft failure. This study aims to define innate immune responses to simulated transplantation surgery in two HD mouse models (HDQ175 & HDR6/1). Mice (96 in total: 24 HDQ175, 24 HDR6/1 and 48 wild-type control) were either kept as Control (no surgery, time 0), or underwent bilateral stereotactic needle insertion to the striatum simulating CRT surgery and culled at 1hr, 24hrs or 72hrs post-surgery. A 3mm3 cube of tissue surrounding and including the injury site was collected for RNA sequencing and multiplex cytokine analysis. The introduction of a needle into mouse brain produced an amplified pro-inflammatory response in both HD models, compared with background controls. Cytokines including IL-1β, IL-6, TNF-α were raised at 1hr and 24hrs post-needle insertion ‘p The amplified pro-inflammatory response to needle injury in HD brain compared to wild-type, reveals a state of enhanced basal pro-inflammatory activation. Thus the HD brain appears to be ‘primed’ to produce an enhanced immune response. The inflammatory reaction to surgical trauma post-CRT is likely to contribute to neural graft site hostility. Simultaneous modulation of these pro-inflammatory pathways during graft delivery may improve graft survival in CRT and advance the translation of direct intraparenchymal delivery of cells into clinical practice.