Whole organ transplantation gets great success, while the outcomes of cell transplants remain poor, suggesting a critical role of non-parenchymal cells in immune regulation. Through dissecting the tolerant liver transplants in mice, we found the immense immune regulatory activity of hepatic stellate cells (HSC), which can protect islet allografts via induction of myeloid suppressor cells (MDSC). This approach holds great clinical application potential, but availability of HSC is a hurdle. We demonstrated that addition of HSC into DC culture generated large amounts of MDSC (mediated by soluble factors, including iC3b). The generated MDSC inhibited T cell response in vitro and can also protect cell transplants in vivo by either local or systemic delivery. To study the involved mechanisms, B6 MDSC (2 ´ 10⁶) were i.v. injected into B6 STZ-induced diabetic recipients immediately before BALB/c islets were transplanted. ∼60% islet grafts gained long-term survival without immunosuppression (compared to <17 day survival in islet alone grafts), associated with reduced number of CD8 infiltrating cells, but enhanced Treg cells. The injected MDSC (generated from CD45.1 congenic mice) were traced, which quickly accumulated in islet grafts on POD1 and 2 (9.2 and 16% respectively) and reduced to 4.1 and 4% on POD 4 and 7, respectively. Very few CD45.1⁺ cells were seen in spleen, suggesting preferentially homing to the grafts. These seeded MDSC recruited more MDSC of recipient origin. The HSC-induced MDSC expressed high CCR2 (compared to DC), which was further enhanced by exposure to INF-g. CCR2 null MDSC showed comparable T cell suppressive activity in vitro, but, lost ability to protect islet allografts, which was characterized by impaired T cell inhibition, Treg induction and recipient-origin MDSC recruitment. Administered CCR2^-/- MDSC failed to migrate to islet grafts. Indeed, local delivered CCR2^-/- MDSC protected the islet grafts. In conclusion, systemic administration of in vitro generated MDSC exerts immune regulatory activity by migrating to the inflammatory sites, a CCR2 dependent process, represents a novel therapeutic approach for transplantation and autoimmune diseases.

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