Although organ transplantation has been successful for decades, outcomes for cell transplants remain disappointing. This is true in animal models; liver allografts in mice are spontaneously accepted, but hepatocyte transplants are acutely rejected (sygeneic grafts survive well), suggesting a crucial role of nonparenchymal cells (NPCs) in protecting parenchymal cells from immune attacks.
We have attempted to determine the responsible NPC component(s) in mouse livers and have found that hepatic stellate cells (HpSC), known to participate in repairing and fibrosis during liver injury, also have potent immune inhibitory activity. HpSC express low-key immune molecules in the quiescent stage, whereas upon activation by exposure to IFN-g or activated T cells, HpSC become positive for B7-H1 and inhibitory cytokines IL-10 and TGF-b. Activated (not quiescent) HpSC potently inhibit T-cell responses in vitro. This is associated with enhanced T-cell apoptosis and is partially mediated by B7-H1 ligation. HpSC are also capable of stimulating naïve T cells to expand Foxp3+ T regulatory (Treg) cells. Interestingly, islet allografts are effectively protected when co-transplanted with activated HpSC. These co-transplanted HpSC form a capsule surrounding islet grafts, providing a local immune protection.
We are focusing on determining the underlying mechanisms and exploring the approaches toward clinical application. The potent immune regulatory activity of these tissue cells may be a crucial step in development of peripheral tolerance.
In other words ...
- Mechanistic insights into liver transplant tolerance
- The role of myeloid suppressor cells in induction of transplant tolerance (supported by Schering-Plough Research Institute)