Type I IFN signaling is species specific, limiting interpretation of cross-species preclinical toxicity models. Type I IFN proteins (-α and -β) act through a common receptor (IFNAR), leading to activation of downstream IRGs. (A) Preclinical toxicity testing of human recombinant type I IFN utilizes cross-species testing. Human recombinant type I IFN does not elicit a downstream IFN response in mouse endothelial cells, as measured by quantitative PCR for type I IRGs in BEND.5 brain endothelial cell line. Despite extensive preclinical testing (355 mice tested with human IFN-α, 347 mice tested with human IFN-β), no reports of small vessel toxicity were observed in publically available preclinical tests for human recombinant type I IFN therapies tested in rodents.^31,32  (B) In contrast, dose-dependent upregulation of IRGs is observed in mouse endothelial cells exposed to same-species recombinant type I IFN in vitro (data represent mean ± standard error of the mean [SEM]; *P < .05, Student t test compared with no IFN; n = 3 experiments, IFN-α shown).