In Vivo Immunogenic Response to Allogeneic Mesenchymal Stem Cells and the Role of Preactivated Mesenchymal Stem Cells Cotransplanted with Allogeneic Islets

Abstract

Mesenchymal stem cells (MSCs) are multipotent cells capable of differentiating into cells from the mesenchymal lineage. The hypoimmunogenic characteristic of MSCs has encouraged studies using allogeneic MSCs for the treatment of autoimmune diseases and inflammatory conditions. Promising preclinical results and the safety of allogeneic MSC transplantation have created the possibility of “off-the-shelf” clinical application of allogeneic cells. This study has aimed to evaluate the survival of untreated and IFN-γ- and TNF-α-treated (preactivated) allogeneic MSCs transplanted under the kidney capsule of immunocompetent mice together with the role of preactivated MSCs after cotransplantation with allogeneic islets. The preactivation of MSCs upregulated the gene expression of anti-inflammatory molecules and also enhanced their immunomodulatory capacity in vitro. In vivo, allogeneic MSCs provoked an immunogenic response, with the infiltration of inflammatory cells at the transplant site and full graft rejection in both the untreated and preactivated groups. Allogeneic islets cotransplanted with preactivated MSCs prolonged graft survival for about 6 days, compared with islet alone. The present results corroborate the hypothesis that allogeneic MSCs are not immune-privileged and that after playing their therapeutic role they are rejected. Strategies that reduce allogeneic MSC immunogenicity can potentially prolong their in vivo persistence and improve the therapeutic effects.

Allogeneic Umbilical Cord-Derived Mesenchymal Stem Cells as a Potential Source for Cartilage and Bone Regeneration: An In Vitro Study

“…Immune reactions and short engraftment time have also been described by Tano et al [ 64 ] in a model of allogeneic MSC transplantation on the epicardial surface of rat hearts. A similar paradigm has been confirmed recently by Oliveira et al [ 65 ] in a preclinical model of MSC transplantation in the murine kidney. They observed lymphocytic infiltration and allogeneic MSC rejection no later than 28 days after transplantation.…”

Differential effects of heat-inactivated, secretome-deficient MSC and metabolically active MSC in sepsis and allogenic heart transplantation

“…The different immunogenicity of donor‐derived MSCs/HI‐MSCs in the transplant model and syngeneic MSCs/HI‐MSCs in the CLP model should also be considered when interpreting the in vivo effects in both models. It has been demonstrated that allogeneic MSCs are immunogenic and can sensitize the recipient, a factor that is not present in the case of syngeneic MSCs. However, the overall immunogenic potential of allogeneic MSCs seems to be less compared with other allogeneic cell types, and MSCs' immunogenicity seems not be determining for the differential effects of MSCs and HI‐MSCs in this study.…”

Hypoxia‐induced increase in Sug1 leads to poor post‐transplantation survival of allogeneic mesenchymal stem cells

“…However, recent data from preclinical studies and clinical trials strongly suggest that even though allogeneic MSCs display immunoprivilege under in vitro conditions, late after transplantation in the host microenvironment, MSCs become immunogenic and provoke an immune response resulting in rejection. 12,24,56 We found that hypoxic or ischemic environment in the host tissue leads to the upregulation of CIITA and cell surface immune antigen MHC-II in rat and human MSCs. In the current study, we also found that preventing hypoxia-induced MHC-II upregulation in MSCs by knocking down Sug1 preserved the immunoprivilege of MSCs in vivo in the ischemic heart, mitigated host immune response, and improved survival of transplanted cells in a rat model of myocardial infarction.…”