| Summary: | 博士 === 東海大學 === 生命科學系 === 98 === Hepatic tolerance was first recognized in 1965 when Garnier et al. found that liver grafts transplanted between outbred pigs survived without the requirement of immunosuppressive agents. Similar findings have since been evidenced in rats, mice and other species. However, the mechanism of hepatic tolerance is still unknown. In renal transplanted patients, we also observed that the recipients with liver dysfunction could maintain good graft function when reduced immunosuppressants were used. Thus, the liver may somewhat modulate the immune response. The hepatic stellate cells (HSCs), located in the perisinusoidal space of Disse, undergo activation and proliferation upon liver injury. As a result, quiescent HSCs change to myofibroblast-like HSCs, increase the production of extracellular matrix (ECM), decrease the degradation of ECM and induce liver cirrhosis. Recent findings indicated that HSCs may have immunoregulatory functions. Using in vivo co-transplant of HSCs in graft-versus-host disease (GVHD) study, we found that HSCs increased allogeneic bone marrow engraftment and prolonged mouse survival from15.3 ± 5.2 to 57.5 ± 30.6 days (P = 0.001). Pathological examinations of the recipient mice which received co-transplantation of bone marrow cells and HSCs showed significant reduction of acute GVHD triad: hepatitis, enteritis and dermatitis. Thus, co-transplantation of HSCs with bone marrow may support hematopoiesis and engraft, reduce acute GVHD and prolong the survival of transplanted mice. To explore the mechanism of immunoregulatory effects of HSCs, we used allogeneic mixed lymphocyte reaction (MLR) to disclose that HSCs could increase CD4+CD25+FoxP3+ regulatory T cells (Treg), induce T cell apoptosis and inhibit effector T cell proliferation. In the transwell experiments, we found that soluble factors released from HSCs play an important role in inhibiting T cell proliferation in allogeneic MLR. To understand how soluble factors execute their functions, we attempt to identify the responsible soluble factors and their immunoregulatory mechanisms. Our study may discover the immunological function of HSCs and extend the understanding of liver tolerance. It may provide a biological manipulation of alloreactivity in transplantation medicine.
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