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.
Highlights
Mesenchymal stem cells (MSCs) have demonstrated efficacy in treating inflammatory, ischemic, and immunological disorders in experimental animal models [1] and have yielded promising results in human clinical trials [2]
Data from this study provide unambiguous evidence of productive allo-recognition by B cells and anti-donor T and natural killer (NK) cell responses following allogeneic MSC administration into immuno-competent rhesus macaques, which are consistent with previous findings [16]
Expansion of NK subsets in these recipients is consistent with mismatches at the Mamu E allele and expression by donor MSCs of the poliovirus receptor (PVR) and UL16 binding protein 3 (ULBP3) (Fig. 10), which bind to activating receptors on NK cells [38,39]
Summary
Mesenchymal stem cells (MSCs) have demonstrated efficacy in treating inflammatory, ischemic, and immunological disorders in experimental animal models [1] and have yielded promising results in human clinical trials [2]. MSCs suppress T cell proliferation in response to allo-antigens [3,4] and induce the formation of T cells with a regulatory phenotype [5] They inhibit the differentiation of naıve CD4 T cells into pro-inflammatory TH17 cells [6], block dendritic cell maturation and function [7], secrete factors that enhance neutrophil anti-microbial activity and chemotaxis [8] and suppress NK cell activation and cytolysis [9]. The detection of donor-specific antibodies in the serum of transplant recipients provides clear evidence of allo-antigen recognition by B cells These findings are consistent with reports indicating that allogeneic MSCs exhibit shorter retention times in vivo [17,18] and accelerate rejection of solid organs [19]. The immune privileged status of allogeneic MSCs remains ambiguous and questions their utility for treating human disease
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