SELECTIVE TARGETING OF KUPFFER CELLS WITH LIPOSOMAL BUTYRATE AUGMENTSPORTAL VENOUS TRANSFUSION-INDUCED IMMUNOSUPPRESSION

Background. Enhanced Kupffer cell production of the immunosuppressive arachidonic acid metabolite prostaglandin E-2 (PGE(2)) has been shown to be a mechanism of the immunosuppressive effect of portal venous tra nsfusions (PVT). Butyrate, a four-carbon short-chain fatty acid, has r eceived increased attention because of its ability to enhance gene tra nscription. This study tested the hypothesis that the intrahepatic del ivery of butyrate enhances Kupffer cell PGE(2) production and thus aug ments the immunosuppressive effect of PVT. Methods. Butyrate was incor porated into liposomes and administered intravenously to Lewis rats. C ontrol rats were administered liposomes without butyrate. Twenty-four hours after liposome injection, rats were administered a PVT of 1 ml o f Wistar-Furth blood. Kupffer cells mere isolated, and PGE(2) and tumo r necrosis factor-alpha levels were measured in the culture medium aft er 24 hr. Additionally Kupffer cells from butyrate-treated and control animals were added to one-way mixed lymphocyte reaction cultures. Res ults. Intrahepatic delivery of butyrate via liposomes increased Kupffe r cell PGE(2) (3800+/-1220 vs. 1010+/-119 pg/ml, P<0.05) and decreased tumor necrosis factor-alpha (1670+/-81 vs. 3360+/-415 pg/ml, P<0.01) production as compared with controls. Butyrate also augmented the Kupf fer cell-mediated immunosuppression as demonstrated by significant dep ression of the mixed lymphocyte reaction (690+/-119 vs. 3850+/-148 cpm , P<0.01). Conclusion. The results support the hypothesis that intrahe patic delivery of butyrate enhances Kupffer cell PGE(2) production, an d specific targeting of Kupffer cells with liposomes containing immuno modulating agents such as butyrate may be a useful means of augmenting immunosuppression protocols in organ transplantation.