16,16 dimethyl PGE2 and PGE2-containing nano-sized hydrogel administration induces tolerance in a mouse model of immune-mediated liver injury.

Tatsuya Okamoto^1,2,3, Takashi Saito³, Yasuhiko Tabata³, Shinji Uemoto^1,2

¹Department of Surgery (Hepato-pancreatico-biliary and Transplantation), Graduate School of Medicine, Kyoto University; ²Division of Pediatric Surgery, Kyoto University Hospital; ³Field of Tissue Engineering, Institute of Frontier Medical Science, Kyoto University; Kyoto, Japan

Background and Aims: Although immunosuppressive agents play a pivotal role in the success of organ transplantation, chronic toxicity has been a major issue for long-term treatment. The development of therapies that induce donor-specific immunological tolerance remains an important clinical challenge. In the present study, we investigated the underlying mechanisms and applications of prostaglandin (PG) E2 for the induction of immunological tolerance in mice with immune-mediated liver injury.

Methods: Liver injury was induced by concanavalin A (Con A) administration in C57B/6 male mice. The immunological tolerogenic effect of 16,16 dimethyl PGE2 (dmPGE2) in liver injury was assessed, and inflammatory cytokine expression levels were measured. To apply native eicosanoids of PGE2 for tolerance induction in vivo, PGE2 was incorporated into L-lactic acid oligomer-grafted pullulan of an amphiphilic polymer to form a nano-sized hydrogel (PGE2-nanogel). We estimated its pharmacokinetics and effects on liver injury.

Results: dmPGE2 pretreatment ameliorated Con A-induced liver injury in mice. The response was partially associated with the expression of interleukin (IL)-10, an anti-inflammatory cytokine, in Kupffer cells. Pharmacokinetics studies revealed that nanogel incorporation enabled PGE2 to have a prolonged life-time in circulating blood, and a tolerogenic effect was also observed in Con A-induced liver injury, the same as with dmPGE2 pretreatment.

Conclusions: dmPGE2 and PGE2-nanogel both prevented immune-mediated Con A-induced liver injury in mice. Nanogel-based prostaglandin administration might be developed as a therapeutic agent to induce immunological tolerance, which is necessary in allogenic organ and cell transplantation.