Human immune cells infiltrate the lesioned spinal cord and impair recovery after spinal cord injury in humanized mice

Abstract

Summary PointsImmune compromised mice require ~4 months of engraftment with human umbilical cord blood CD34+ stem cells to develop a full and functional human immune systemThe human neuroinflammatory response elicited after spinal cord injury in humanized mice is limited at 2 months post-engraftment but matures by 4 monthsIntraspinal neuroinflammation consists of a florid human T cell and macrophage response, and human T cells co-localize with human macrophagesA human intraspinal neuroinflammatory response exacerbates lesion pathology and impairs functional recoveryAbstractHumanized mice are a useful tool to help better understand how the human immune system responds to central nervous system (CNS) injury. However, the optimal parameters for using humanized mice in preclinical CNS injury models have not been established. Here, we show that it takes 3-4 months after engraftment of neonatal immune compromised mice with human umbilical cord stem cells to generate a robust human immune system. Indeed, sub-optimal human immune cell responses occurred when humanized mice received spinal contusion injuries at 2 months vs. 4 months post-engraftment. Human T cells directly contact human macrophages within the spinal cord lesion of these mice and the development of a mature human immune system was associated with worse lesion pathology and neurological recovery. Together, data in this report establish an optimal experimental framework for using humanized mice to help translate promising preclinical therapies for CNS injury.