Monocytic suppressive cells mediate cardiovascular transplantation tolerance in mice
Mercedes Rodriguez Garcia, … , Jonathan S. Bromberg, Jordi C. Ochando
Mercedes Rodriguez Garcia, … , Jonathan S. Bromberg, Jordi C. Ochando
Published June 14, 2010
Citation Information: J Clin Invest. 2010;120(7):2486-2496. https://doi.org/10.1172/JCI41628.
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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.

Authors

Mercedes Rodriguez Garcia, Levi Ledgerwood, Yu Yang, Jiangnan Xu, Girdhari Lal, Bryna Burrell, Ge Ma, Daigo Hashimoto, Yansui Li, Peter Boros, Marcos Grisotto, Nico van Rooijen, Rafael Matesanz, Frank Tacke, Florent Ginhoux, Yaozhong Ding, Shu-Hsia Chen, Gwendalyn Randolph, Miriam Merad, Jonathan S. Bromberg, Jordi C. Ochando

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Figure 3

Mechanisms of action of tolerogenic CD11b+CD115+Gr1+ monocytes.

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Mechanisms of action of tolerogenic CD11b+CD115+Gr1+ monocytes. (A) ...
(A) Cardiac allografts were accepted by tolerogen-treated Ccr2–/– mice receiving 1 × 106 bone marrow Gr1+ monocytes from Ifng–/– mice, but rejected by mice receiving 1 × 106 bone marrow Gr1+ monocytes from Ifngr–/–, Stat1–/–, Irf1–/–, or Nos2–/– mice (n = 5 per group). (B) Representative images of immunohistochemical analysis of iNOS+ cells around graft endothelial cells 2 days after transplantation (n = 5 mice per group). Original magnification, ×40. (C) Fluorescent immunohistochemistry of CFSE-labeled adoptively transferred monocytes stained with iNOS in the allograft (n = 2 ± 0.3 cells/vessel; 20 vessels/heart; n = 3 mice). Original magnification, ×40. (D) Real-time RT-PCR of iNOS, arginase, and IL-4R expression in CD11b+Gr1+ monocytes in the allograft 2 days after transplantation. Data are representative of 3 independent experiments; SEM of PCR triplicates are shown. P values were determined by Student’s t test. (E) Freshly isolated CD3+CD4+ T cells from C57BL/6 mice were sorted and labeled with CFSE, and 5 × 104 cells/well were cultured with CD11b+Gr1+ allograft monocytes (2.5 × 104 cells/well) in the presence of BALB/c or CBA APC (2.5 × 104 cells/well) for 72 hours. Proliferation of T cells was measured by CFSE dilution. Percentages of divided and undivided cells are shown. Data are representative of 3 independent experiments. (F) Expression of PD-L1 and MHC-II in CD115+Gr1+ and CD115+Gr1– monocytes in the allografts of tolerant mice. Mice were sacrificed on day 2 after transplantation. Results are mean ± SEM (n = 5 mice). Donor DST cells were labeled with ER-Tracker blue-white dye to exclude donor monocyte contamination.