Dexamethasone-Induced Myeloid-Derived Suppressor Cells Prolong Allo Cardiac Graft Survival through iNOS- and Glucocorticoid Receptor-Dependent Mechanism

Abstract

How to induce immune tolerance without long-term need for immunosuppressive drugs has always been a central problem in solid organ transplantation. Modulating immunoregulatory cells represents a potential target to resolve this problem. Myeloid-derived suppressor cells (MDSCs) are novel key immunoregulatory cells in the context of tumor development or transplantation, and can be generated in vitro. However, none of current systems for in vitro differentiation of MDSCs have successfully achieved long-term immune tolerance. Herein, we combined dexamethasone (Dex), which is a classic immune regulatory drug in the clinic, with common MDSCs inducing cytokine granulocyte macrophage colony stimulating factor (GM-CSF) to generate MDSCs in vitro. Addition of Dex into GM-CSF system specifically increased the number of CD11b+ Gr-1int/low MDSCs with an enhanced immunosuppressive function in vitro. Adoptive transfer of these MDSCs significantly prolonged heart allograft survival and also favored the expansion of regulatory T cells in vivo. Mechanistic studies showed that inducible nitric oxide sythase (iNOS) signaling was required for MDSCs in the control of T-cell response and glucocorticoid receptor (GR) signaling played a critical role in the recruitment of transferred MDSCs into allograft through upregulating CXCR2 expression on MDSCs. Blockade of GR signaling with its specific inhibitor or genetic deletion of iNOS reversed the protective effect of Dex-induced MDSCs on allograft rejection. Together, our results indicated that co-application of Dex and GM-CSF may be a new and important strategy for the induction of potent MDSCs to achieve immune tolerance in organ transplantation.

Myeloid-derived suppressor cells expand after transplantation and their augmentation increases graft survival

“…However, MDSCs are known to expand after kidney transplantation in humans 9 . Animal studies have shown that adoptive transfer of MDSCs can prolong survival of islets, skin, as well as cardiac allografts 4,5,36‐38 ; but little more is known about the ability of MDSCs to control graft survival. Our group recently showed that anti‐thymocyte globulin affects MDSC expansion and survival, suggesting that common transplant drugs may alter the immunosuppressive capacities of MDSCs 3 .…”

“…For example, anti‐thymoglobulin is known to reduce populations of MDSCs, but its primary effect was on PMN‐MDSCs, rather than on M‐MDSCs 3 . Cyclosporine is known to decrease MDSC populations, whereas rapamycin and corticosteroids are known to increase MDSC populations 36,37,40 . Accordingly, we used a model of transplant in which animals did not receive immunosuppression; all animals demonstrated expanded MDSCs and these MDSCs were suppressive of T cell responses.…”

Myeloid‐derived suppressor cells: Roles in the tumor microenvironment and tumor radiotherapy

“…In addition, IDO raises the expression of cytotoxic lymphocyte (CTLA4), CD200, and GITR, reprogramming DC into DCs with function of tolerance by combining with aromatic hydrocarbon receptor AhR . On the other side, iNOS in MDSCs can produce NO to inhibit JAK3/STAT5 signaling pathway to reduce the expression of MHC II molecules, finally resulting in the apoptosis of T cells . MDSCs can also inhibit the migration of T cells to peripheral lymph nodes by decreasing the expression of CD62L on the surface of immature T cells to suppress the activation of T cells .…”

The Yin and Yang of Myeloid Derived Suppressor Cells

“…Accumulation of M-MDSCs as well as Tregs is reported to enhance graft survival in Almost Tolerant Kidney Transplant Recipient (ATKTR) individuals ( 147 ). A recent report has shown Dexamethasone induced Myeloid-Derived suppressor cells prolong allocardiac graft survival through iNOS and glucocorticoid receptor-dependent mechanism ( 148 ). MDSCs based cell therapy aids in prolonging graft survival and transplantation tolerance reflects the “ Yang” behavior of MDSCs.…”