Anti‐donor immune responses elicited by allogeneic mesenchymal stem cells: what have we learned so far?

Mesenchymal stem (stromal) cells (MSCs) have potent anti‐inflammatory/immunosuppressive properties which underlie much of their therapeutic potential. This fact has led to the widely accepted belief that MSCs from genetically unrelated individuals (allogeneic (allo)‐MSCs) can be used therapeutically with equal efficacy to autologous MSCs and without triggering the donor‐specific immune responses that are typically associated with allo‐transplants. In this article, we critically review available experimental data to determine whether good in vivo evidence exists in support of the ‘immune privileged’ status of allo‐MSCs. We also examine published studies regarding the immunogenicity of allo‐MSCs following activation (‘licensing’) by inflammatory stimuli or following differentiation. Among the identified studies which have addressed in vivo immunogenicity of allo‐MSCs, there was substantial variability as regards experimental species, disease model, route of MSC administration, cell dose and stringency of the immunological assays employed. Nonetheless, the majority of these studies has documented specific cellular (T‐cell) and humoral (B‐cell/antibody) immune responses against donor antigens following administration of non‐manipulated, interferon‐γ‐activated and differentiated allo‐MSCs. The consequences of such anti‐donor immune responses were also variable and ranged from reduced in vivo survival of allo‐MSCs with accelerated rejection of subsequent allogeneic transplants to apparent promotion of donor‐specific tolerance. On the basis of these findings and on existing knowledge of allo‐antigen recognition from the field of transplant immunology, we propose that the concept of the immune privileged nature of allo‐MSCs should be reconsidered and that the range and clinical implications of anti‐donor immune responses elicited by allo‐MSCs be more precisely studied in human and animal recipients.