There are currently no approved antifibrotic therapies for liver cirrhosis. We used vitamin A-coupled liposomes to deliver small interfering RNA (siRNA) against gp46, the rat homolog of human heat shock protein 47, to hepatic stellate cells. Our approach exploits the key roles of these cells in both fibrogenesis as well as uptake and storage of vitamin A. Five treatments with the siRNA-bearing vitamin A-coupled liposomes almost completely resolved liver fibrosis and prolonged survival in rats with otherwise lethal dimethylnitrosamine-induced liver cirrhosis in a dose- and duration-dependent manner. Rescue was not related to off-target effects or associated with recruitment of innate immunity. Receptor-specific siRNA delivery was similarly effective in suppressing collagen secretion and treating fibrosis induced by CCl(4) or bile duct ligation. The efficacy of the approach using both acute and chronic models of liver fibrosis suggests its therapeutic potential for reversing human liver cirrhosis.

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CD4+FoxP3+ regulatory T cells (Tregs) play a central role in the maintenance of immune tolerance after allogeneic hematopoietic stem cell transplantation. We recently reported that daily administration of low-dose IL-2 induces selective expansion of functional Treg and clinical improvement of chronic graft-versus-host disease (GVHD). To define the mechanisms of action of IL-2 therapy we examined the immunologic effects of this treatment on homeostasis of CD4 T cell subsets after transplant. We first demonstrate that chronic GVHD is characterized by constitutive phosphorylation of Stat5 in conventional CD4 T cells (Tcon) associated with elevated levels of IL-7 and IL-15 and relative functional deficiency of IL-2. IL-2 therapy resulted in the selective increase of Stat5 phosphorylation in Treg and decrease of pStat5 in Tcon. Over an eight-week period, IL-2 therapy induced a series of changes in Treg homeostasis, including increased proliferation, increased thymic export and enhanced resistance to apoptosis. Low-dose IL-2 had minimal effects on Tcon. These findings define the mechanisms whereby low-dose IL-2 therapy restores the homeostasis of CD4 T cell subsets and promotes the re-establishment of immune tolerance.

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