Background: In Australia this year, approximately 60 babies will be affected by perinatal stroke, leading to significant neurological and cognitive deficits. Neural stem cells (NSCs) have anti-inflammatory and neuroregenerative properties, making them a promising therapeutic for perinatal stroke. Further, NSCs are able to engraft into the damaged brain, potentially replacing lost cells. NSCs possess class I and II MHC antigens, making them susceptible to rejection in the host brain. Therefore, it may be necessary to give NSCs in conjunction with immunosuppression, just as you would with an organ transplant. Immunosuppression could promote NSC survival, ensuring a maximal and prolonged response, however, the safety of immunosuppression in the neonate has not yet been examined.
Aims/hypothesis: To determine whether an immunosuppressive drug (tacrolimus) is safe and can promote the engraftment and integration of NSCs into the damaged rat brain following HI injury. It is hypothesised that tacrolimus will increase the survival of NSCs, promoting a further reduction in brain injury and behavioural deficits compared to NSC treatment alone.
Methods: PND8 Sprague-Dawley rat pups will receive daily intraperitoneal injections of tacrolimus (0.05 or 1 mg/kg/day). Pups will be culled at either PND11, 12 or 17 and flow cytometry of blood, spleen and brain will determine the number of T cells, B cells, monocytes and microglia. A group of pups and will undergo behavioural testing at PND40. Based on the results obtained, we will determine how long the drug takes to suppress the immune system. Based on timing, we will transplant neural stem cell with and without tacrolimus following HI surgery (left carotid artery ligation, followed by 8% oxygen for 90 minutes).
Conclusions: Based on results from this study, we hope to determine whether immunosuppression is safe in the neonate and necessary to improve NSC engraftment for perinatal stroke.