Upregulation of Heme Oxygenase-1 Endues Immature Dendritic Cells With More Potent and Durable Immunoregulatory Properties and Promotes Engraftment in a Stringent Mouse Cardiac Allotransplant Model

Yue Zhao; Yu Jia; Lu Wang; Song Chen; Xia Huang; Bingyang Xu; Guangyuan Zhao; Ying Xiang; Jun Yang; Gang Chen

doi:10.3389/fimmu.2018.01515

Upregulation of Heme Oxygenase-1 Endues Immature Dendritic Cells With More Potent and Durable Immunoregulatory Properties and Promotes Engraftment in a Stringent Mouse Cardiac Allotransplant Model

Front Immunol. 2018 Jul 2:9:1515. doi: 10.3389/fimmu.2018.01515. eCollection 2018.

Authors

Yue Zhao^{1

2

3}, Yu Jia^{1

4}, Lu Wang^{1

5

6}, Song Chen^{1

5

6}, Xia Huang^{1

5

6}, Bingyang Xu¹, Guangyuan Zhao¹, Ying Xiang^{1

5

6}, Jun Yang^{1

5

6}, Gang Chen^{1

5

6}

Affiliations

¹ Institute of Organ Transplantation, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China.
² Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, Chengdu, China.
³ School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
⁴ Department of Nephrology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China.
⁵ Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China.
⁶ Key Laboratory of Organ Transplantation, Ministry of Public Health, Wuhan, China.

Abstract

Heme oxygenase-1 (HO-1) is critical for the ability of immature dendritic cells (imDCs) to suppress T-cell responses. Induction of high HO-1 expression may markedly improve the tolerogenic capacity of imDCs. Here, we generated bone marrow-derived DCs (BMDCs) from BALB/c mice with low doses of GM-CSF and IL-4. The adherent BMDCs were obtained as imDCs. Upregulation of HO-1 in imDCs (HO-1^hi-imDCs) was achieved by cobalt protoporphyrin treatment. HO-1^hi-imDCs proved to be more maturation-resistant than conventional imDCs, with an enhanced ability to inhibit allogeneic T-cell proliferation stimulated by anti-CD3/CD28 antibodies. When donor-derived DC adoptive transfer was performed in a stringent mouse cardiac allotransplant model, the extent of graft prolongation observed with HO-1^hi imDCs was superior to that obtained with conventional imDCs. T-cell activation and proliferation in cardiac allograft recipients was more strongly suppressed in the HO-1^hi imDC transfusion group than that in the untreated imDC group. Furthermore, donor HO-1^hi imDCs were able to maintain a status of high HO-1 expression and survived longer in the recipient spleens than did untreated imDCs after adoptive transfer. In vitro-generated HO-1^hi imDCs had an enhanced tolerogenic capacity to modulate alloimmune responses both in vitro and in vivo, and thus may offer a novel antigen-specific and cost-effective strategy to induce transplant tolerance.

Keywords: dendritic cells; heart transplantation; heme oxygenase-1; immunoregulation; mouse.