Yusuke Arakawa1, Jie Qin, Hong-Shuie Chou, Sumantha Bhatt, Lianfu Wang, Dennis Stuehr, Arnab Ghosh, John J Fung, Lina Lu, Shiguang Qian. 1. 1 Department of General Surgery, Transplantation Center, Digestive Disease Institute, 2 Department of Immunology and 3 Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH. 4 Address correspondence to: Shiguang Qian, M.D., Department of Immunology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave., NE60, Cleveland, OH.
Abstract
BACKGROUND: Islet transplantation is an alternative to pancreas transplantation to cure type 1 diabetes, but both require chronic immunosuppression, which is often accompanied by deleterious side effects. The purpose of this study was to explore prolongation of islet allograft survival by cotransplantation with myeloid-derived suppressor cells (MDSCs) without requirement of immunosuppression and determine the role of inducible nitric oxide synthase (iNOS) produced by MDSCs in immune regulation. METHODS: Bone marrow cells were isolated from wild-type (WT) or iNOS mice and cultured in the presence of granulocyte-macrophage colony-stimulating factor and hepatic stellate cells (HSCs), resulting in the generation of MDSCs. WT or iNOS MDSCs were cotransplanted with islet allografts under the renal capsule of diabetic recipient mice. RESULTS: Addition of HSCs into DC culture promoted generation of MDSCs (instead of DCs). MDSCs had elevated expression of iNOS upon exposure to IFN-γ and inhibited T-cell responses in an MLR culture. Cotransplantation with WT MDSCs markedly prolonged survival of islet allografts, which was associated with reduced infiltration of CD8 T cells resulting from inhibited proliferative response. These effects were significantly attenuated when MDSCs were deficient in iNOS. Furthermore, iNOS MDSCs largely lost their ability to protect islet allografts. CONCLUSIONS: Cotransplantation with HSC-induced MDSCs significantly extends islet allograft survival through iNOS-mediated T-cell inhibition. The results demonstrate the potential use of in vitro generated MDSCs as a novel adjunctive immunotherapy for islet transplantation.
BACKGROUND: Islet transplantation is an alternative to pancreas transplantation to cure type 1 diabetes, but both require chronic immunosuppression, which is often accompanied by deleterious side effects. The purpose of this study was to explore prolongation of islet allograft survival by cotransplantation with myeloid-derived suppressor cells (MDSCs) without requirement of immunosuppression and determine the role of inducible nitric oxide synthase (iNOS) produced by MDSCs in immune regulation. METHODS: Bone marrow cells were isolated from wild-type (WT) or iNOSmice and cultured in the presence of granulocyte-macrophage colony-stimulating factor and hepatic stellate cells (HSCs), resulting in the generation of MDSCs. WT or iNOS MDSCs were cotransplanted with islet allografts under the renal capsule of diabetic recipient mice. RESULTS: Addition of HSCs into DC culture promoted generation of MDSCs (instead of DCs). MDSCs had elevated expression of iNOS upon exposure to IFN-γ and inhibited T-cell responses in an MLR culture. Cotransplantation with WT MDSCs markedly prolonged survival of islet allografts, which was associated with reduced infiltration of CD8 T cells resulting from inhibited proliferative response. These effects were significantly attenuated when MDSCs were deficient in iNOS. Furthermore, iNOS MDSCs largely lost their ability to protect islet allografts. CONCLUSIONS: Cotransplantation with HSC-induced MDSCs significantly extends islet allograft survival through iNOS-mediated T-cell inhibition. The results demonstrate the potential use of in vitro generated MDSCs as a novel adjunctive immunotherapy for islet transplantation.
Authors: Cheng-Hsu Chen; Liang-Mou Kuo; Yigang Chang; Wenhan Wu; Christina Goldbach; Mark A Ross; Donna B Stolz; Liepin Chen; John J Fung; Lin Lu; Shiguang Qian Journal: Hepatology Date: 2006-11 Impact factor: 17.425
Authors: R Y Calne; R A Sells; J R Pena; D R Davis; P R Millard; B M Herbertson; R M Binns; D A Davies Journal: Nature Date: 1969-08-02 Impact factor: 49.962
Authors: Lalit Batra; Pradeep Shrestha; Hong Zhao; Kyle B Woodward; Alper Togay; Min Tan; Orlando Grimany-Nuno; Mohammad Tariq Malik; María M Coronel; Andrés J García; Haval Shirwan; Esma S Yolcu Journal: J Immunol Date: 2020-04-06 Impact factor: 5.422