Mechanistic insights into immunomodulation by hepatic stellate cells in mice: a critical role of interferon-gamma signaling.

UNLABELLED: The liver is considered to be an immune-privileged organ that favors the induction of tolerance. The underlying mechanisms are not completely understood. Interestingly, liver transplants are spontaneously accepted in several animal models, but hepatocyte transplants are acutely rejected, suggesting that liver nonparenchymal cells may effectively protect the parenchymal cells from immune attack. We have shown the profound T cell inhibitory activity of hepatic stellate cells (HSCs). Thus, cotransplantation with HSCs effectively protects islet allografts from rejection in mice. In this study, using T cell receptor transgenic and gene knockout approaches, we provided definitive evidence that HSCs protected cotransplanted islet allografts by exerting comprehensive inhibitory effects on T cells, including apoptotic death in graft-infiltrating antigen-specific effector T cells and marked expansion of CD4(+) Forkhead box protein (Foxp)3(+) T regulatory (Treg) cells. All these effects required an intact interferon-gamma (IFN-gamma) signaling in HSCs, demonstrated by using HSCs isolated from IFN-gamma receptor 1 knockout mice. B7-H1 expression on HSCs, a product molecule of IFN-gamma signaling, was responsible for induction of T cells apoptosis, but had no effect on expansion of Treg cells, suggesting that undetermined effector molecules produced by IFN-gamma signaling is involved in this process. CONCLUSION: Upon inflammatory stimulation, specific organ stromal cells (such as HSCs in the liver) demonstrate potent immune regulatory activity. Understanding of the mechanisms involved may lead to development of novel strategies for clinical applications in transplantation and autoimmune diseases.

Cotransplantation with myeloid-derived suppressor cells protects cell transplants: a crucial role of inducible nitric oxide synthase.

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.