Neonatal immune-tolerance in mice does not prevent xenograft rejection: a comprehensive analysis using in vivo luciferase tracking

While in vitro iPSC models are proving extremely informative, an in vivo "humanized" chimeric animal model of disease via transplantation of diseased human iPSC-derived cells may prove ideal for therapeutic screening and mechanistic discovery. One of the major challenges for the field is appropriate immune suppression in these xenograft models as it is often ineffective or cost-prohibitive for long term studies, and has also been shown to ameliorate neurological diseases (Rosenstock et al. Neurochem Int. 2011), complicating experimental results. With the promise of transplantation for neurodegenerative diseases, there also is the need for non-invasive in vivo tracking. In the current collaborative study we used a range of techniques and cells to establish tolerance of the neonatal and adult rodent brain to neural xenografts. We show that in contrast to rats, mouse neonates are sensitive to human neural xenografts (from iPSCs, ESCs or fetal tissues). In three mouse strains, prior sensitization had no effect on the severe rejection of the cells. Luciferase imaging was shown to be a powerful predictor of graft survival in the striatum. Together these studies show that neonatal mice reject human cells, and that immune tolerance techniques are not sufficient to prevent rejection in adult mice.