Innate and adaptive immune barriers to neural stem/progenitor cell transplantation
- Stem cells and their derivatives, engineered in vitro prior to transplantation or patterned endogenously by the environment following transplant, are hailed for their promise in treating numerous diseases, from heart disease to diabetes and arthritis. However, one substantial barrier to the success of such treatments is the effect of the immunological response on survival and function of the cells. To this end, the transplantation of neural progenitor cells (NPCs) into the healthy brain provides one of the most favorable situations for graft survival, since the central nervous system is an immune privileged site and NPC are immune privileged cells. Herein, we address whether major histocompatibility complex (MHC) mismatch results in the rejection of NPC grafts placed in the murine hippocampus and investigate which immune effectors affect graft outcome. These transplantation studies reveal that while some allogeneic cells survive, MHC incompatibility strongly inhibits the differentiation and retention of graft-derived as well as endogenously produced new neurons. We also demonstrate that inhibiting innate immune activation with non-steroidal anti-inflammatory drugs decreases observed microglial activation and restores allogeneic neuron production and retention to levels seen in syngeneic grafts. Additionally, we show that MHC and activating ligand expression profiles on NPC facilitates recognition by Natural Killer (NK) cells. We utilize animals deficient for critical innate and adaptive immune receptors to establish that both NK cells and T cells influence graft survival and differentiation. Finally, we evaluate how MHC expression intrinsically influences NPC arborization in vitro. Intriguingly, MHC deficiency results in longer and more extensively branched processes. Taken together, our data suggest that MHC expression on grafted NPC facilitates NPC interaction with multiple other cell types, and consequently cannot be ignored when considering NPC transplantation clinically. Indeed, clinical application of NPC will undoubtedly place these cells into injured or diseased brains, where immune barriers may be more substantial. However, these data provide a starting point for evaluation of appropriate immune modulation strategies for such transplants.
|Type of resource
|electronic; electronic resource; remote
|1 online resource.
|Phillips, Lori Katherine
|Stanford University, Department of Immunology.
|Statement of responsibility
|Lori Katherine Phillips.
|Submitted to the Department of Immunology.
|Ph.D. Stanford University 2012
- © 2012 by Lori Katherine Phillips
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