Neural Progenitor Cells (NPC) are multipotent progenitors found within the brain that differentiate into neurons, oligodendrocytes, and astrocytes. Transplantation of NPC has been proposed as therapy to enhance central nervous system regeneration for a variety of neurodegenerative diseases. However, MHC mismatch in NPC transplantation is a complex and controversial problem. Although immune responses in the brain are tightly regulated under normal conditions, transplantation by stereotactic delivery of the cells induces inflammation accompanied by leukocyte infiltration. Our previous work indicates that natural killer (NK) cells can target NPC in vitro in a manner that is MHC- and NKG2D-dependent. NKG2D is an activating receptor expressed on NK cells and a subset of T cells. Given this data, we transplanted GFP+ BALB/c (H-2^d) NPC into the dentate gyrus of C57BL/6 (H-2^b) WT and NKG2D-/- (H-2^b) mice and assessed survival and the ability of NPC grafts to differentiate into neurons. At two weeks, allografts in NKG2D-/- hosts showed greater GFP+ cell retention (p=0.05) as well as more neurogenesis, with 2.3 times more transitional neurons and 2 times more mature neurons (p=0.05, 28.38%±3.72, n=11 vs 12.31%±2.63, n=7 and p=0.06, 10.87%±1.31 vs 5.48%±0.6 for transitional and mature neurons in NKG2D-/- and WT hosts, respectively). Given the importance of T cells in allograft rejection in the periphery, we asked whether the absence of adaptive immunity would also benefit the differentiation of allogeneic NPC grafts in the brain, using RAG2-/- mice. Allografts in RAG2-/- hosts showed significantly more neurogenesis, with 4 times more mature neurons (p=0.035, 24.96%±4.98, n=8 vs 5.48%±0.64, n=7 in RAG2-/- and WT hosts, respectively). In order to elucidate how these responses might be coordinated, lymphocyte trafficking to the brain was evaluated at 8h, 24h, 3d, 5d, 7d and 14d post transplant by immunohistochemistry. Results indicate that NK cells can enter the brain through the needle trajectory within 24 hours after transplantation, with maximal NK cell accumulation at the graft site at 7d. A significant number of NK cells remain at the graft at 14d. These results indicate that both innate and adaptive immune responses attenuate survival and neurogenesis of NPC allografts and suggest that targeting NKG2D, or its ligands, can improve the outcome of NPC transplantation.

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