Allo-Reactivity of Mesenchymal Stem Cells in Rhesus Macaques Is Dose and Haplotype Dependent and Limits Durable Cell Engraftment In Vivo

Abstract

The emerging paradigm that MSCs are immune privileged has fostered the use of “off-the-shelf” allogeneic MSC-based therapies in human clinical trials. However, this approach ignores studies in experimental animals wherein transplantation of MSCs across MHC boundaries elicits measurable allo-immune responses. To determine if MSCs are hypo-immunogeneic, we characterized the immune response in rhesus macaques following intracranial administration of allogeneic vs. autologous MSCs. This analysis revealed unambiguous evidence of productive allo-recognition based on expansion of NK, B and T cell subsets in peripheral blood and detection of allo-specific antibodies in animals administered allogeneic but not autologous MSCs. Moreover, the degree of MHC class I and II mismatch between the MSC donor and recipient significantly influenced the magnitude and nature of the allo-immune response. Consistent with these findings, real-time PCR analysis of brain tissue from female recipients administered varying doses of male, allogeneic MSCs revealed a significant inverse correlation between MSC engraftment levels and cell dose. Changes in post-transplant neutrophil and lymphocyte counts also correlated with dose and were predictive of overall MSC engraftment levels. However, secondary antigen challenge failed to elicit a measurable immune response in allogeneic recipients. Finally, extensive behavior testing of animals revealed no main effect of cell dose on motor skills, social development, or temperament. Collectively, these data indicate that allogeneic MSCs are weakly immunogenic when transplanted across MHC boundaries in rhesus macaques and this negatively impacts durable engraftment levels. Therefore the use of unrelated donor MSCs should be carefully evaluated in human patients.

Early gestation chorionic villi-derived stromal cells for fetal tissue engineering

“…Cells obtained via methods such as chorionic villus sampling (CVS) allow for the potential development of cell therapies that are autologous (derived from the patient's cells) to the fetus [16][17][18] . Autologous therapies are potentially preferable to allogeneic (not patient specific) therapies, as using the patient's own cells in a therapy should not elicit an immune response [19] . However, where autologous therapies are not required, allogeneic early gestation chorionic villus tissue can be an outstanding cell source for cell therapy as well.…”

Interactions Between Multipotential Stromal Cells (MSCs) and Immune Cells During Bone Healing

“…In these conditions, an increase of the local expression of NK cells, T and B lymphocytes as well as macrophages was detected (181,201,202). In addition, a high expression level of allo-specific antibodies was demonstrated in the recipient hosts (202). It has been proposed that Th1 response evident by increase of IFN-was responsible for the suppression of the bone growth (181).…”

“…Additionally, the chondrogenic potential of synovial MSCs transplanted into allogeneic rat with anterior meniscus defect was impaired relative to autogenic implants (201). In these conditions, an increase of the local expression of NK cells, T and B lymphocytes as well as macrophages was detected (181,201,202). In addition, a high expression level of allo-specific antibodies was demonstrated in the recipient hosts (202).…”

The roles of immune cells in bone healing; what we know, do not know and future perspectives

“…Several studies, in which MSCs were used for bone and cartilage repair, have indicated that the failure of therapeutic effect of allogeneic MSCs was associated with signs of activated immune responses [115,[133][134][135]. However, in other studies where the allogeneic MSCs were loaded into scaffolds, an inflammatory response was similar to that induced by autologous MSCs with better outcomes [136][137][138][139][140][141].…”