Myeloid-derived suppressor cells therapy enhance immunoregulatory properties in acute graft versus host disease with combination of regulatory T cells

Abstract

Background Myeloid-derived suppressor cells (MDSCs) play a critical role in modulating the immune response and promoting immune tolerance in models of autoimmunity and transplantation. Regulatory T cells (Tregs) exert therapeutic potential due to their immunomodulatory properties, which have been demonstrated both in vitro and in clinical trials. Cell-based therapy for acute graft-versus-host disease (aGVHD) may enable induction of donor-specific tolerance in the preclinical setting. Methods We investigated whether the immunoregulatory activity of the combination of MDSCs and Tregs on T cell and B cell subset and alloreactive T cell response. We evaluated the therapeutic effects of combined cell therapy for a murine aGVHD model following MHC-mismatched bone marrow transplantation. We compared histologic analysis from the target tissues of each groups were and immune cell population by flow cytometric analysis. Results We report a novel approach to inducing immune tolerance using a combination of donor-derived MDSCs and Tregs. The combined cell-therapy modulated in vitro the proliferation of alloreactive T cells and the Treg/Th17 balance in mice and human system. Systemic infusion of MDSCs and Tregs ameliorated serverity and inflammation of aGVHD mouse model by reducing the populations of proinflammatory Th1/Th17 cells and the expression of proinflammatory cytokines in target tissue. The combined therapy promoted the differentiation of allogeneic T cells toward Foxp3 + Tregs and IL-10-producing regulatory B cells. The combination treatment control also activated human T and B cell subset. Conclusions Therefore, the combination of MDSCs and Tregs has immunomodulatory activity and induces immune tolerance to prevent of aGVHD severity. This could lead to the development of new clinical approaches to the prevent aGVHD.

Immunosuppressive Mechanisms of Regulatory B Cells

“…The induction of tolerance to exogenous antigens by IL-10 + Bregs has been further explored in the field of allograft transplantation. Studies in a model of hematopoietic stem cell transplantation (HSCT) demonstrated that both donor and host IL-10-producing B cells are required to prevent acute and chronic GVHD, in part due to the suppression of T cell cytokine production and induction of Tregs ( 37 , 116 , 262 – 264 ). Similarly, a protective role of IL-10 + Bregs in human GVHD has been suggested after higher frequencies of these cells were found reconstituting recipients of HSCT who developed tolerance, compared to those who developed GVHD ( 53 , 138 , 265 , 266 ).…”

Myeloid-Derived Suppressor Cells Alleviate Renal Fibrosis Progression via Regulation of CCL5-CCR5 Axis

“…Although natural MDSCs increase their number in inflammation, their immunosuppressive activity might be limited in a highly inflammatory environment due to myeloid differentiation, inflammatory mediator production, and cellintrinsic inflammasome upregulation (41). Nevertheless, researchers have found that in vitro-induced MDSCs after culturing BM cells with G-CSF and GM-CSF obtained a phenotype similar to that of natural MDSCs with a protective effect in various primary target organs and inhibited GVHDcorrelated death by 80% (42,43). This indicated the potent treatment efficiency of adoptive transference of MDSC-enriched populations after in vitro expansion.…”

TGF-β1-overexpressing mesenchymal stem cells reciprocally regulate Th17/Treg cells by regulating the expression of IFN-γ

“…Treg can inhibit the activation and proliferation of CD4 + and CD8 + T lymphocytes, which is related to the direct contact between cells and paracrine cytokines IL-10 and TGF-β [ 18 ]. Interleukin-2 (IL-2) and other immunoregulatory molecules have been shown to control the generation of Tregs [ 19 ]. It can also indirectly inhibit the immune response by inhibiting the activity of APC while maintaining the microenvironment of immune tolerance.…”