Clinical organ transplantation has been applied for decades, but the outcomes of cell transplants remain disappointing. This is true in animal models;liver transplants in mice are spontaneously accepted, whereas hepatocyte transplants are acutely rejected, suggesting a crucial immune regulatory role of non-parenchymal cells (NPC). After analyzing various liver NPC, we identified that hepatic stellate cells (HpSC), the specific stromal cells in the liver, have potent immune suppressive activity. Co-transplantation with HpSC effectively protects islet allografts from rejection, achieving long-term survival (>100 days) in 66% of the grafts without requirement of immunosuppression via induction of local T cell hyporesponsiveness. This approach has great potential for clinical application. A hurdle is that the co-transplanted HpSC have to be from recipient himself, since allogeneic HpSC do not well protect islet allografts. Obtaining sufficient HpSC adds risk to patients. A solution merges based on our recent preliminary data, showing that HpSC are potent inducers of myeloid-derived suppressor cells (MDSC) which is mediated by soluble factors, and that MDSC can be generated in vitro. We hypothesize that local delivery of in vitro generated MDSC may be able to replace HpSC in protecting cell transplants from immune attack. This hypothesis will be tested in following Specific Aims: 1) to determine the efficacy of local delivery of MDSC on protection of cell transplants. MDSC will be generated by co-culture of BM cells with HpSC, and tested for their protective efficacy by co-transplanted with islet allografts. The optimal dose of MDSC will be determined, and the fate and migration capacity of co-transplanted MDSC will be examined using CD45.1 congenic approach;2) to determine the optimal culture conditions to generate MDSC in vitro. We will determine the optimal dose of iC3b for generation of MDSC from BM cells, and elucidate the underlying molecular mechanisms-the role of ligation of iC3b and CD11b in MDSC differentiation. We will also determine whether addition of other cytokines, such as IL-6 and/or G-CSF, enhances growth of MDSC. Achievement of these aims will substantially facilitate cell transplantation in clinical application.

Public Health Relevance

Outcome of cell transplants are markedly inferior to organ transplants, probably because cell transplants lack protection of specific stromal cells. We have demonstrated that hepatic stellate cells (HpSC), specific stromal cells in the liver, have potent immunosuppressive activity. Co-transplantation with HpSC can effectively protect cell transplants from rejection without requirement of immunosuppression. This approach has great clinical application potential, but obtaining sufficient HpSC is difficult. Recent data suggest that protection of cell transplants by HpSC is mediated by myeloid-derived suppressor cells (MDSC). This proposal is to explore the possibility to protect cell transplants by local delivery of MDSC that are generated in vitro culture. The completion of this study will enhance the feasibility in clinical application.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Transplantation, Tolerance, and Tumor Immunology (TTT)
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Kehn, Patricia J
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Cleveland Clinic Lerner
Other Basic Sciences
Schools of Medicine
United States
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Qin, Jie; Arakawa, Yusuke; Morita, Miwa et al. (2017) C-C Chemokine Receptor Type 2-Dependent Migration of Myeloid-Derived Suppressor Cells in Protection of Islet Transplants. Transplantation 101:1793-1800
Moris, Demetrios; Lu, Lina; Qian, Shiguang (2017) Mechanisms of liver-induced tolerance. Curr Opin Organ Transplant 22:71-78
Morita, Miwa; Joyce, Daniel; Miller, Charles et al. (2015) Rejection triggers liver transplant tolerance: Involvement of mesenchyme-mediated immune control mechanisms in mice. Hepatology 62:915-31
Bhatt, Sumantha; Qin, Jie; Bennett, Carole et al. (2014) All-trans retinoic acid induces arginase-1 and inducible nitric oxide synthase-producing dendritic cells with T cell inhibitory function. J Immunol 192:5098-108
Arakawa, Yusuke; Qin, Jie; Chou, Hong-Shuie et al. (2014) Cotransplantation with myeloid-derived suppressor cells protects cell transplants: a crucial role of inducible nitric oxide synthase. Transplantation 97:740-7
Charles, Ronald; Chou, Hong-Shiue; Wang, Lianfu et al. (2013) Human hepatic stellate cells inhibit T-cell response through B7-H1 pathway. Transplantation 96:17-24
Hsieh, Ching-Chuan; Chou, Hong-Shiue; Yang, Horng-Ren et al. (2013) The role of complement component 3 (C3) in differentiation of myeloid-derived suppressor cells. Blood 121:1760-8
Chou, Hong-Shiue; Hsieh, Ching-Chuan; Charles, Ronald et al. (2012) Myeloid-derived suppressor cells protect islet transplants by B7-H1 mediated enhancement of T regulatory cells. Transplantation 93:272-82
Charles, Ronald; Lu, Lina; Qian, Shiguang et al. (2011) Stromal cell-based immunotherapy in transplantation. Immunotherapy 3:1471-85
Chou, Hong-Shiue; Hsieh, Ching-Chuan; Yang, Horng-Ren et al. (2011) Hepatic stellate cells regulate immune response by way of induction of myeloid suppressor cells in mice. Hepatology 53:1007-19

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