title: Effects of cotransplanted fetal liver on fetal pancreas isografts.
abstract: Ricordi et al. described a hepatotrophic effect mediated by pancreatic islets on cotransplanted hepatocytes. We found a reciprocal salutary effect of fetal liver (FL) on fetal pancreas (FP) in the intramural small bowel (ISB) site. To further investigate this intriguing finding, composite FP/FL isografts were transplanted to the conventional renal subcapsular (RSC) site and the accessible but historically inhospitable intramuscular site in streptozotocin-diabetic Lewis rats. A comparison of recipients of FP/FL and FP alone found the proportion rendered normoglycemic was site dependent. All recipients of either composite FP/FL grafts or FP alone transplanted in the ISB site became normoglycemic. The proportion of normoglycemic recipients was lower in the RSC site (71% FP and 40% FP/FL) and the i.m. site (14% FP and 67% FP/FL). Importantly, regardless of site, normoglycemia was established with an accelerated time course in recipients of FP/FL versus FP alone (24 +/- 8 vs. 67 +/- 43 days; P = 0.001). Normal (or more rapid) glucose clearance after challenge was achieved in all normoglycemic recipients except those transplanted in the RSC site. On histological examination of excised FP/FL grafts, hepatocytes were present in association with islets. Cyclosporine-induced islet toxicity could not be overcome in 6 recipients of FP alone, but 6 of 8 recipients of FP/FL became normoglycemic (P less than 0.01). To assess the effect of FP on hepatocytes, allografts (Wistar donors) of FP or FP/FL were cotransplanted in the ISB of enzyme-deficient jaundiced Gunn rats. Immunosuppression consisted of rapamycin (0.8 mg/kg/day) infused intravenously for 4 weeks. In the FP/FL group (n = 4), the mean serum bilirubin level decreased from 8.6 to 4.9 mg/dl at 6 weeks after transplantation. This was a significant difference as compared with the increased mean serum bilirubin from 6.9 to 7.8 mg/dl (P less than 0.05; paired Student's t test) in recipients of FL alone (n = 4). In conclusion, we found a mutual paracrine effect on islets and hepatocytes transplanted as a composite FP/FL graft. FL hastened the establishment of normoglycemia following transplantation of FP in diabetic rats, and FP enhanced FL transplant function in Gunn rats.
authors.affiliation: Department of Surgery, University of Pennsylvania, Philadelphia.
authors.forename: X G
authors.initials: XG
authors.lastname: Wang
authors.forename: L
authors.initials: L
authors.lastname: Tafra
authors.forename: R
authors.initials: R
authors.lastname: Berezniak
authors.forename: R V
authors.initials: RV
authors.lastname: Lloyd
authors.forename: L
authors.initials: L
authors.lastname: Muraika
authors.forename: D C
authors.initials: DC
authors.lastname: Dafoe
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000601:surgery; D016332:Fetal Tissue Transplantation / Q000502:physiology*; D007421:Intestine, Small; D008099:Liver / Q000196:embryology; D016031:Liver Transplantation / Q000502:physiology*; D008297:Male; D010179:Pancreas / Q000196:embryology; D016035:Pancreas Transplantation / Q000502:physiology*; D051381:Rats; D011917:Rats, Inbred Lew; D014185:Transplantation, Isogeneic