tretinoin and Cholangitis--Sclerosing

To perform an exploratory pilot study of all-trans retinoic acid (ATRA) combined with ursodeoxycholic acid (UDCA) in patients with primary sclerosing cholangitis (PSC).. PSC is a progressive disorder for which there is no accepted therapy. Studies in human hepatocyte cultures and in animal models of cholestasis indicate that ATRA might have beneficial effects in cholestatic disorders.. ATRA (45 mg/m/d, divided and given twice daily) was combined with moderate-dose UDCA in patients with PSC who had incomplete response to UDCA monotherapy. The combination was administered for 12 weeks, followed by a 12-week washout in which patients returned to UDCA monotherapy. We measured alkaline phosphatase (ALP), alanine aminotransferase (ALT), bilirubin, cholesterol, bile acids, and the bile acid intermediate 7α-hydroxy-4-cholesten-3-one (C4) at baseline, week 12, and after washout.. Fifteen patients completed 12 weeks of therapy. The addition of ATRA to UDCA reduced the median serum ALP levels (277±211 to 243±225 U/L, P=0.09) although this, the primary endpoint, did not reach significance. In contrast, median serum ALT (76±55 to 46±32 U/L, P=0.001) and C4 (9.8±19 to 7.9±11 ng/mL, P=0.03) levels significantly decreased. After washout, ALP and C4 levels nonsignificantly increased, whereas ALT levels significantly increased (46±32 to 74±74, P=0.0006), returning to baseline.. In this human pilot study, the combination of ATRA and UDCA did not achieve the primary endpoint (ALP); however, it significantly reduced ALT and the bile acid intermediate C4. ATRA appears to inhibit bile acid synthesis and reduce markers of inflammation, making it a potential candidate for further study in PSC (NCT 01456468).

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alanine Transaminase; Alkaline Phosphatase; Bile Acids and Salts; Cholagogues and Choleretics; Cholangitis, Sclerosing; Cholestenones; Drug Therapy, Combination; Female; Humans; Liver; Liver Function Tests; Male; Middle Aged; Pilot Projects; Treatment Outcome; Tretinoin; Ursodeoxycholic Acid; Young Adult

Lymphocytes primed by intestinal dendritic cells (DC) express the gut-homing receptors CCR9 and alpha4beta7, which recognize CCL25 and mucosal addressin cell-adhesion molecule-1 in the intestine promoting the development of regional immunity. In mice, imprinting of CCR9 and alpha4beta7 is dependent on retinoic acid during T-cell activation. Tissue specificity is lost in primary sclerosing cholangitis (PSC), an extraintestinal manifestation of inflammatory bowel disease, when ectopic expression of mucosal addressin cell-adhesion molecule-1 and CCL25 in the liver promotes recruitment of CCR9+alpha4beta7+ T cells to the liver. We investigated the processes that control enterohepatic T-cell migration and whether the ability to imprint CCR9 and alpha4beta7 is restricted to intestinal DCs or can under some circumstances be acquired by hepatic DCs in diseases such as PSC.. Human and murine DCs from gut, liver, or portal lymph nodes and hepatic stellate cells were used to activate CD8 T cells. Imprinting of CCR9 and alpha4beta7 and functional migration responses were determined. Crossover activation protocols assessed plasticity of gut homing.. Activation by gut DCs imprinted high levels of functional CCR9 and alpha4beta7 on naïve CD8 T cells, whereas hepatic DCs and stellate cells proved inferior. Imprinting was RA dependent and demonstrated plasticity.. Imprinting and plasticity of gut-homing human CD8 T cells requires primary activation or reactivation by gut DCs and is retinoic acid dependent. The inability of liver DCs to imprint gut tropism implies that alpha4beta7+CCR9+ T cell that infiltrate the liver in PSC are primed in the gut.

Topics: Animals; CD8-Positive T-Lymphocytes; Cell Movement; Cells, Cultured; Cholangitis, Sclerosing; Dendritic Cells; Gastrointestinal Tract; Hepatic Stellate Cells; Humans; Integrins; Liver; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Receptors, CCR; Receptors, Lymphocyte Homing; Time Factors; Tretinoin; Up-Regulation

Topics: Adult; Antineoplastic Agents; Bile Ducts, Extrahepatic; Bile Ducts, Intrahepatic; Cholangiopancreatography, Endoscopic Retrograde; Cholangitis, Sclerosing; Humans; Leukemia, Promyelocytic, Acute; Male; Respiratory Distress Syndrome; Tonsillitis; Tretinoin