Monocytic suppressive cells mediate cardiovascular transplantation tolerance in mice

Abstract

One of the main unresolved questions in solid organ transplantation is how to establish indefinite graft survival that is free from long-term treatment with immunosuppressive drugs and chronic rejection (i.e., the establishment of tolerance). The failure to achieve this goal may be related to the difficulty in identifying the phenotype and function of the cell subsets that participate in the induction of tolerance. To address this issue, we investigated the suppressive roles of recipient myeloid cells that may be manipulated to induce tolerance to transplanted hearts in mice. Using depleting mAbs, clodronate-loaded liposomes, and transgenic mice specific for depletion of CD11c + , CD11b + , or CD115 + cells, we identified a tolerogenic role for CD11b + CD115 + Gr1 + monocytes during the induction of tolerance by costimulatory blockade with CD40L-specific mAb. Early after transplantation, Gr1 + monocytes migrated from the bone marrow into the transplanted organ, where they prevented the initiation of adaptive immune responses that lead to allograft rejection and participated in the development of Tregs. Our results suggest that mobilization of bone marrow CD11b + CD115 + Gr1 + monocytes under sterile inflammatory conditions mediates the induction of indefinite allograft survival. We propose that manipulating the common bone marrow monocyte progenitor could be a useful clinical therapeutic approach for inducing transplantation tolerance.

Crucial Role of Granulocytic Myeloid-Derived Suppressor Cells in the Regulation of Central Nervous System Autoimmune Disease

“…Extensive studies established a prominent role for MDSCs in the regulation of immune responses in mice during cancer (11,15,16), infections (15,17), and transplantation (18)(19)(20); in humans, MDSC accumulation at tumor sites downregulates antitumor immunity, promoting tumor surveillance and growth (21,22). A variety of mechanisms has been attributed to the MDSC-mediated suppression of immune responses, ranging from cell-to-cell contact to soluble mediators (23,24).…”

Mesenchymal Stem/Stromal Cells Protect against Autoimmunity via CCL2-Dependent Recruitment of Myeloid-Derived Suppressor Cells

“…However, as we demonstrated in this study, MDSCs, which serve a deleterious role in cancer and chronic infection, can have favorable effects on autoimmunity and transplantation. In support for the potential benefits of MDSCs in immune-related diseases, several studies demonstrated that MDSCs suppress immune responses in models for multiple sclerosis (15)(16)(17) and autoimmune arthritis (21), and induce immune tolerance of kidney or cardiovascular allografts (54,55).…”

Conversion of Th17 into IL-17Aneg Regulatory T Cells: A Novel Mechanism in Prolonged Allograft Survival Promoted by Mesenchymal Stem Cell–Supported Minimized Immunosuppressive Therapy

“…7). The indicated mechanism of tolerance induction may be present in other therapeutic approaches where monocytic MDSC-mediated T reg induction plays an essential role, for example, donor-specific transfusion (40) inducing analogous prolongation of allograft acceptance (26).…”