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

Abstract

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.

Mesenchymal Stem Cell Therapy Promotes Corneal Allograft Survival in Rats by Local and Systemic Immunomodulation

“…As we (10,11) and others (19) have reviewed recently, a number of studies have investigated in vivo immune responses elicited by allo-MSCs. While it is generally 3 Figure 8: Evaluation of delayed-type hypersensitivity (DTH) responses following corneal transplantation.…”

“…They can be isolated from bone marrow (BM) and various other readily accessible adult tissues and have the capacity to extensively proliferate in vitro and be expanded to clinically useful numbers (9). It has been demonstrated both in vitro and, to a lesser degree, in vivo, that MSCs possess potent immunosuppressive properties, predominantly mediated through paracrine effects on processes such as inflammation, tissue repair and angiogenesis (10)(11)(12)(13)(14)(15)(16). For example, MSCs have been shown to inhibit allogeneic T cell proliferation induced either in a mixed lymphocyte culture or by nonspecific mitogens, independent of their MHC haplotype (17).…”

Mesenchymal Stromal Cells in Transplantation Rejection and Tolerance

“…Although, allogeneic MSCs were thought to be immune privileged, evidence now suggests that allogeneic MSCs are recognized by the innate and adaptive immune system (Griffin et al 2013). A clear understanding of how recognition of allogeneic MSCs impacts their capacity for modulating immune responses in vivo is hampered by the lack of appropriate experimental data measuring antidonor T-cell and antibody responses to allogeneic MSC.…”

Adipose Derived Stem Cells Conditioned Media in Combination with Bioceramic-Collagen Scaffolds Improved Calvarial Bone Healing in Hypothyroid Rats

“…Although, clinical application of MSCs have shown beneficial effects in the treatment of various diseases, implanted MSCs do not survive for long after transplantation (44). Also, evidence has shown that allogeneic MSCs can elicit immune response against the transplanted cells and immunological issues present an obstacle for tissue engineering (45). However, MSCs secrete trophic factors that can modulate a large number of cellular responses such as cell survival, proliferation, migration and gene expression (28).…”