Figure 1
NRP-1 inhibition reduces central nervous system (CNS) vascular permeability, microhemorrhage formation, and morbidity following induction of CD8 T cell-initiated blood–brain barrier (BBB) disruption. We present the three-dimensional volume of gadolinium leakage as measured using T1-weighted magnetic resonance imaging (MRI) in a representative animal treated with (A) phosphate-buffered saline (PBS) or (B) NRP-1 inhibitor, 24 hours post-induction of vascular permeability with intravenous injection of VP2121-130 peptide. In (C), we demonstrate reduced three-dimensional volumes of gadolinium leakage in animals receiving NRP-1 inhibitor as compared to sham PBS-treated controls (P < 0.001). T2 MRI was performed on animals receiving (D) sham PBS treatments or (F) NRP-1 inhibitor. Following these scans, the ventricle size was determined (red outline) and subsequently not included in the analysis of microhemorrhage area (green outlines) determined in (E) PBS-treated and (G) NRP-1 inhibitor-treated groups analyzed by T2*-weighted MRI. Using this method of analysis, we observed reduced microhemorrhage in NRP-1 inhibitor-treated animals as compared to PBS-treated controls (P = 0.023). All MRI scans were analyzed blind before breaking the code of each treatment group. (I) Quantification of FITC-albumin leakage into the brain reveals that pretreatment with DC101 antibody to flk-1, but not DC6.12 antibody to flt-1, is effective in reducing CNS vascular permeability (P = 0.003). In (J), administration of NRP-1 inhibitor enhances survival of mice undergoing CD8 T cell-initiated CNS vascular permeability (P = 0.014).