Preemptive Donor Apoptotic Cell Infusions Induce IFN-γ–Producing Myeloid-Derived Suppressor Cells for Cardiac Allograft Protection

Abstract

We have previously shown that preemptive infusion of apoptotic donor splenocytes treated with the chemical cross-linker ethylcarbodiimide (ECDI-SPs) induces long-term allograft survival in full MHC-mismatched models of allogeneic islet and cardiac transplantation. The role of myeloid derived suppressor cells (MDSCs) in the graft protection provided by ECDI-SPs is unclear. In this study, we demonstrate that infusions of ECDI-SPs increase two populations of CD11b+ cells in the spleen that phenotypically resemble monocytic-like (CD11b+Ly6CHI) and granulocytic-like (CD11b+Gr1HI) MDSCs. Both populations suppress T cell proliferation in vitro, and traffic to the cardiac allografts in vivo to mediate their protection via inhibition of local CD8 T cell accumulation and potentially also via induction and homing of regulatory T cells. Importantly, repeated treatments with ECDI-SPs induce the CD11b+Gr1HI cells to produce a high level of IFN-γ and to exhibit an enhanced responsiveness to IFN-γ by expressing higher levels of downstream effector molecules ido and nos2. Consequently, neutralization of IFN-γ completely abolishes the suppressive capacity of this population. We conclude that donor ECDI-SPs induce the expansion of two populations of MDSCs important for allograft protection mediated in part by intrinsic IFN-γ dependent mechanisms. This form of preemptive donor apoptotic cell infusions has significant potential for the therapeutic manipulation of MDSCs for transplant tolerance induction.

Immune Tolerance for Autoimmune Disease and Cell Transplantation

“…These cells are typically CD11b + Gr1 + in mouse models of transplantation and are considerably less well defined in human recipients of transplantation; they were only recently identified in renal transplant patients as CD11b + CD33 + HLA-DR − cells with variable levels of expression of CD14 and CD16, underscoring their phenotypic heterogeneity (118–121). They mediate suppression by several mechanisms, including inhibition of cytotoxic T cell responses by generation of reactive oxygen species and IL-10, depletion of L-arginine via arginase 1 and inducible nitric oxide synthase, depletion of tryptophan via indoleamine 2,3-dioxygenase (IDO), and promotion of T reg s via IFN-γ-dependent pathways.…”

“…Moreover, MDSCs were present in the cardiac allograft and suppressed the infiltration of CD8 + T cells and other effectors. MDSCs present in the graft also produced IL-10 and recruited T reg s in a CCL4-dependent manner, and depletion of MDSCs restored CD8 + T cell infiltration and graft rejection (121). …”

The Crosstalk between Myeloid Derived Suppressor Cells and Immune Cells: To Establish Immune Tolerance in Transplantation

“…This result suggested that mobilization of bone marrow CD11b+CD115+Gr-1+ MDSCs under sterile inflammatory conditions could induce indefinite cardiac allograft survival. In another study, Luo's group demonstrated the expansion of two subpopulations of MDSCs induced by donor splenocytes treated with the chemical cross-linker ethylcarbodiimide (ECDI-SPs) was important for cardiac allograft protection [48]. Lastly, mammalian target of rapamycin (mTOR) inhibitors are the main immunosuppressive drugs for organ transplant recipients.…”

Tempering Allorecognition to Induce Transplant Tolerance With Chemically Modified Apoptotic Donor Cells

“…Moreover, MDSCs were found to be present in the cardiac allograft and suppressed the infiltration of CD8 + T cells and other effectors. MDSCs present in the graft were also found to produce IL-10 and to recruit T REGS in a CCL4-dependent manner, and depletion of MDSCs restored CD8 + T cell infiltration and graft rejection (87). Thus, a critical role for MDSCs in allo-ECDI-SP therapy may be the recruitment of T REGS into the graft, which subsequently suppress graft infiltration by CD8 + T cells.…”