The non-parenchymal cells (NPC) that reside within an organ play an important role in regulating local immune responses, thereby protecting parenchymal from immune injury. We have found that hepatic stellate cell (HSC), the principle retinoid (vitamin A) storing cells in the body and known to participate in repair and fibrosis during liver injury, also play a crucial role in regulating liver immunity. To investigate the molecular and cellular mechanisms involved, we have created a HSC/islet co-transplantation model in chemically-induced diabetic mice, in which graft survival can be simply monitored by serum glucose levels. The lymphocytes and graft infiltrating cells can be recovered for further analysis. Taking advantage of the availabilities of many transgenic and knockout mouse lines, this model provides a unique tool for us to understand immune responses regulated by HSC. We have observed that co-transplanted HSC exert profound immunomodulatory activities by direct induction of activated CD8+ T cell apoptosis, generation or accumulation of Gr-1+CD11b+CD11clow myeloid- derived suppressor cells (MDSC) and marked expansion of FoxP3+ T regulatory (Treg) cells, that lead to long term islet allograft survival. Our data also showed that MDSC differentiation in vitro is mediated by the soluble factors, including complement component 3 (C3) and factor H (FH) produced by HSC, and retinoic acid (RA) released from HSC play a role in regulating FH binding. We hypothesize that binding of FH on HSC inactivates C3 to generate fragment iC3b, a ligand of complement receptor (CR)3 (CD11b/CD18). Ligation of iC3b with CR3 on myeloid derived infiltrating progenitors leads to development of MDSC, which consequently expand Treg and eliminate activated effect T cells. We have three Specific Aims:
Aim 1. To define the function, origin and trafficking patterns of the MDSC generated following cotransplantation of HSC and allogeneic islets. We will: 1) determine the phenotypic and functional characteristics of CD11b+CD11clow MDSC recovered from the grafts;2) define their origin (recipient or donor) and track their migration pattern;3) determine whether migration of MDSC to graft draining LN is necessary for MDSC to expand Treg cells.
Aim 2. To test the role of C3 produced by HSC in the development of MDSC. We will determine the impact of C3 /iC3b on MDSC development in HSC/islet cotransplant model using C3-/-, CD11b-/- and FH-/- mice.
Aim 3. To test the effect of RA on regulating FH in HSC. We will determine the role of FH produced by HSC in the activation of C3 during generation of the regulatory MDSC and the impact of RA on FH production/binding by HSC. Delineation of these mechanistic events during inflammatory activation of HSC and the subsequent generation of MDSC will provide insights into a novel strategy for improving outcomes of transplanted cells including allogeneic islets.

Public Health Relevance

The role of tissue stromal cells as a scaffold for parenchymal cells is well known, however growing evidence supports their role as immunoregulators to modulate local immune responses. Recently, we have found that co-transplantation of liver derived stromal cells, in particular the hepatic stellate cell (HSC), can effective protect islet allografts from rejection without immunosuppressive therapy. HSC are the main retinoid storing cells in the body and are known to be actively involved in liver repair and regeneration by synthesizing extracellular matrix protein and secretion of cytokines and growth factors. However, the mechanisms involved in immunoregulation of HSC are under investigation. We have demonstrated that the co-transplanted HSC are powerful inducers of apoptosis of activated T cell that would otherwise destroy the islet allografts, and promote accumulation / generation of myeloid-derived suppressor cells (MDSC) which consequently suppress immune responses at multiple levels. We have also identified the role of complement component C3, factor H (FH) and retinoic acid (RA) produced by HSC contributing to generation of MDSC. Thus, we hypothesize that within the local inflammatory mileu during rejection or infection, activated HSC release C3, FH and RA leading to generation of MDSC, which subsequently eliminate effector CD8+ T cells and expand Treg cells that further modulate immune responses, maintaining long term allograft suvival. In the current proposal, we will use our islet /HSC co-transplant model to study generation and function of MDSC. Understanding of the underlying mechanisms will develop novel strategies for substantial improvement of cell transplant outcomes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IMM-J (02))
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Appel, Michael C
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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; Shen, Gong-Qing; Li, Yan et al. (2015) Hepatic stellate cell-conditioned myeloid cells provide a novel therapy for prevention of factor VIII antibody formation in mice. Exp Hematol 43:277-85
Li, Yan; Tu, Zhidan; Qian, Shiguang et al. (2014) Myeloid-derived suppressor cells as a potential therapy for experimental autoimmune myasthenia gravis. J Immunol 193:2127-34
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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
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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
Tu, Zhidan; Li, Yan; Smith, Dawn et al. (2012) Myeloid suppressor cells induced by retinal pigment epithelial cells inhibit autoreactive T-cell responses that lead to experimental autoimmune uveitis. Invest Ophthalmol Vis Sci 53:959-66

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