Concise Review: Innate and Adaptive Immune Recognition of Allogeneic and Xenogeneic Cell Transplants in the Central Nervous System

Abstract

Over the last 30 years, numerous allogeneic and xenogeneic cell grafts have been transplanted into the central nervous system (CNS) of mice and men in an attempt to cure neurological diseases. In the early studies, human or porcine embryonic neural cells were grafted in the striatum of animals or patients in an attempt to replace lost neurons. Although the immune‐privileged status of the brain as a recipient organ was widely accepted, it rapidly became evident that CNS‐grafted allogeneic and xenogeneic cells could be recognized and rejected by the immune system, resulting in poor neural graft survival and limited functional recovery. Since then, the CNS transplantation field has witnessed a sharp rise in the number of studies in which allogeneic and xenogeneic neural or mesenchymal stem cells (NSCs or MSCs, respectively) are transplanted, predominantly aiming at providing trophic stimulation and promoting endogenous repair of the brain. Interestingly, in many recent NSC and MSC‐based publications functional improvement was used as the principal measure to evaluate the success of cell transplantation, while the fate of transplanted cells remained largely unreported. In this review, we first attempt to understand why primary neural cell isolates were largely substituted for NSCs and MSCs in cell grafting studies. Next, we review the current knowledge on the immune mechanisms involved in the recognition and rejection of allogeneic and xenogeneic cellular grafts in the CNS. Finally, we propose strategies to reduce graft immunogenicity and to improve graft survival in order to design improved cell‐based CNS therapies. Stem Cells Translational Medicine 2017;6:1434–1441

Establishment of stable iPS-derived human neural stem cell lines suitable for cell therapies

“…Having obtained current good manufacturing practices (cGMP) certification for hNSCs from miscarriages, we have successfully used them in a phase I trial, with intraspinal transplantation in 18 ALS patients 15 . We are now focusing on resolving the concerns deriving from the use of allogeneic hNSCs and related immune suppression 19 . Since the establishment of autologous hNSCs is both impractical and, de facto, impossible, we have derived these cells from autologous human induced pluripotent stem cells (hiPSCs).…”

The leading edge: Emerging neuroprotective and neuroregenerative cell-based therapies for spinal cord injury

“…may significantly affect downstream graft survival in humans. 215,216 Enhancing endogenous cell proliferation is one strategy to avoid immunorejection; however, endogenous cell pools may still be limited and optimal methods to drive their differentiation and migration have not yet been established. 217 Recently, genetic techniques which modify major histocompatibility complexes and CD47 have been shown to generate immune-evasive iPSC lines.…”

Stem cell therapy for neurological disorders

“…aborted for medical or non-medical reasons) and prepared for allogeneic transplantation purposes. Given the practical and ethical limitations of this scenario, in addition to the risks that transplanted cells might be rejected by the recipient's immune system [5] or that they may be tumorigenic (owing to their heightened proliferative capacity), there has been an appreciable increase in the need for an alternative source. With recent advances in our understanding of stem cell biology, it is possible to differentiate pluripotent stem cells (both ESCs and iPSCs) into neural progenitor or NSC-like cells for therapeutic purposes.…”