Liposomal encapsulation significantly enchances the immunosuppressive effect of tacrolimus in a discordant islet xenotransplant model.

摘要

BACKGROUND: Encapsulation of tacrolimus (TAC) in a lipid bilayer to form liposome-encapsulated tacrolimus (LTAC) alters the biodistribution profile, half-life, and efficacy in organ allotransplantation models. LTAC has not been applied to either cell transplantation or xenotransplantation. METHODS: To test the efficacy of LTAC in a discordant islet xenograft model, tilapia (fish) islets were transplanted under the left kidney capsules of streptozotocin-diabetic Balb/c mice. Recipient mice (groups I-VI) were treated with: I, untreated; II, empty liposomes; III, TAC (2 mg/kg/day); IV, TAC (5 mg/kg/day); V, LTAC (2 mg/kg/day); or VI, LTAC (5 mg/kg/day); all treatments were for 35 days or until rejection (i.e., two glucose measurements >200 mg/dl). Graft-bearing kidneys were removed for histology after rejection. RESULTS: Mean graft survival time (mGST) for control groups I and II were 6.7+/-1.4 (n=6) and 7.5+/-1.3 days (n=4), respectively. Daily TAC treatment at 2 mg/kg/d (III) did not prolong graft function (mGST=7.7+/-1.6; n=6) although 5 mg/kg/day (IV) produced minimal prolongation to 12.8+/-4.8 days (n=12). Treatment with LTAC at 2 mg/kg/day (V) significantly prolonged mGST to 26.6+/-4.9 (n=5); however, all recipients rejected during treatment (i.e.,<35 days). LTAC at 5 mg/kg/day (VI) further prolonged mGST to 39.9+/-11.8 days (n=12) with only one mouse rejecting before day 35. Histologically, at the time of functional rejection, grafts were generally either totally or partially effaced by mononuclear cells, eosinophils, and fibrosis. In groups VI, islet grafts removed from two mice that died while they were normoglycemic and from a mouse terminated while it was normoglycemic at day 36 were viable, well-granulated, and free from cellular infiltration. The group VI grafts examined at rejection (i.e., 1-2 weeks after discontinuing LTAC) were generally totally obliterated and were in two instances associated with nodular aggregates of atypical lymphocytes resembling posttransplant lymphoproliferative disorder. CONCLUSIONS: LTAC is the most potent immunosuppressive compound we have tested in our discordant fish-to-mouse islet xenograft model; however, toxicity is an issue at high doses.