Immunological tolerance in a mouse model of immune-mediated liver injury induced by 16,16 dimethyl PGE2 and PGE2-containing nanoscale hydrogels.

Abstract

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 concanavalin A(Con A)-induced immune-mediated liver injury. The immunological tolerogenic effect of 16,16 dimethyl PGE2 (dmPGE2) pretreatment in C57B/6 male mice with Con A-induced liver injury was observed, and it was revealed that its response was partially associated with the expression of interleukin (IL)-10, an anti-inflammatory cytokine, in Kupffer cells. 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). 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. Nanogel-based prostaglandin administration might be developed as a therapeutic agent to induce immunological tolerance, which is necessary in allogenic organ and cell transplantation.