Skip Navigation LinksHome > April 15, 2014 - Volume 97 - Issue 7 > Cotransplantation With Myeloid-Derived Suppressor Cells Prot...
doi: 10.1097/01.TP.0000442504.23885.f7
Basic and Experimental Research

Cotransplantation With Myeloid-Derived Suppressor Cells Protects Cell Transplants: A Crucial Role of Inducible Nitric Oxide Synthase

Arakawa, Yusuke1; Qin, Jie2; Chou, Hong-Shuie2; Bhatt, Sumantha2; Wang, Lianfu1; Stuehr, Dennis3; Ghosh, Arnab3; Fung, John J.1; Lu, Lina1,2; Qian, Shiguang1,2,4

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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.

© 2014 by Lippincott Williams & Wilkins





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