PREVENTION OF PANCREATIC-ISLET XENOGRAFT REJECTION BY DIETARY VITAMIN-E

In pancreatic islet transplantation, the adhesion of activated leukocy tes to endothelial cells and the loss of microvascular integrity repre sent the critical microcirculatory events, which promote loss of graft function clue to rejection, With the view that oxygen radicals may co ntribute to graft rejection, we studied the effect of the antioxidant vitamin E on microvascular rejection of islet grafts. Islets were tran splanted syngeneically and xenogeneically (rat) into dorsal skin-fold chambers of hamsters, which received a non-vitamin-E-supplemented labo ratory chow, Treated animals with xenografts were fed with a diet supp lemented with vitamin E in a low (150 mg/kg) and high (8000 mg/kg) con centration. Intravital fluorescence microscopy demonstrated complete v ascularization of syngeneic grafts at day 10 after transplantation, in tact islet microcirculation at day 20 with a functional capillary dens ity of 653 +/- 6 cm(-1), and only few leukocytes adherent to the endot helial lining of the islets' microvasculature (88 +/- 23 mm(-2)). Xeno geneic islets showed initial signs of rejection at day 6, including ad hesion of leukocytes to the microvascular endothelium (610 +/- 110 mm( -2)) and loss of endothelial integrity. After 20 days, functional capi llary density was significantly lower (173 +/- 68 cm(-1)) when compare d with syngeneic grafts, indicating failure of graft acceptance, Suppl ementation of the diet with low and high concentrations of vitamin E r esulted in a significant (P < 0.05) reduction of xenograft leukocyte-e ndothelium interaction (146 +/- 29 mm(-2) and 109 +/- 42 mm(-2)) at da y 6 after transplantation and adequate development of functional capil lary density at day 20 (478 +/- 36 cm(-1) and 533 +/- 86 cm(-1); P < 0 .05), indicating prevention of microvascular rejection. We conclude th at dietary supplementation of the lipophilic antioxidant vitamin E att enuates leukocyte-endothelial cell interactions, preserves microvascul ar integrity, and thus inhibits microvascular rejection in a dose-depe ndent fashion. Our study underscores the pivotal mediator role of reac tive oxygen species ill islet xenograft rejection and furthermore, sug gests that dietary vitamin E may act as an adjunct anti-rejection trea tment in clinical islet transplantation.