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.

Keywords: Allogeneic; Immune recognition; Mesenchymal stem cells; Neural stem cells; Transplantation; Xenogeneic.

Figure 1

Immune recognition of allogeneic and xenogeneic cell grafts following cell grafting in rodent brain. As a result of the transplantation procedure, blood‐brain barrier (BBB) integrity is immediately compromised (1). In response to the ensuing tissue insult and to hypoxia and anoikis‐induced apoptosis or necrosis of the cell graft core (2), neutrophils, complement elements and natural antibodies are rapidly recruited to the graft site between 6 and 24 hours post grafting (3). Local BBB permeability may further be enhanced for several days (exact timing unknown) as a result of the increasingly pro‐inflammatory environment (4). From on day 3 post grafting blood‐borne macrophages and brain‐resident microglia accumulate, respectively, in and around the graft site (5). Between day 3 to day 14 post grafting (or until removal of all antigens), cellular debris is processed by brain‐resident antigen‐presenting cells that migrate toward the lymph nodes and/or drain to the cervical lymph nodes (6) where they are processed by host dendritic cells. From on several days post grafting, in the lymph node, naive allograft/xenograft‐specific T and B cells are activated and proliferate (7). From on 1–2 weeks post grafting, graft‐specific effector T cells (8) and alloreactive/xenoreactive antibodies (9) may accumulate at the graft site.