title: The portal immunosuppressive storm: relevance to islet transplantation?
abstract: Outcomes in clinical islet transplantation improved substantially with the introduction of combined sirolimus and tacrolimus immunosuppression. However, multiple islet preparations are often required to achieve insulin independence, suggesting that islet engraftment may not be optimal when these agents are absorbed via the portal vein. The current study was designed to assess the differential concentrations of immunosuppressive drugs within the portal and systemic circulations of a large animal model, to assess the local concentrations of drugs to which islets are exposed early after implantation. Chronic catheters were placed in the portal vein and carotid artery of 6 mongrel dogs, and immunosuppressants were administered orally. Blood samples were drawn simultaneously from portal and systemic catheters, and drug concentrations were analyzed. Peak immunosuppressant levels as well as area under the curve were dramatically elevated in portal blood relative to systemic levels for all drugs tested. This "portal storm" of immunosuppression may be relevant to intrahepatic islet transplantation.
authors.affiliation: Department of Surgery, University of Alberta, Edmonton, Alberta, Canada. Shapiro@islet.ca
authors.forename: A M James
authors.initials: AM
authors.lastname: Shapiro
authors.forename: Heather L
authors.initials: HL
authors.lastname: Gallant
authors.forename: Er Geng
authors.initials: EG
authors.lastname: Hao
authors.forename: Jonathan R T
authors.initials: JR
authors.lastname: Lakey
authors.forename: Tara
authors.initials: T
authors.lastname: McCready
authors.forename: Ray V
authors.initials: RV
authors.lastname: Rajotte
authors.forename: Randall W
authors.initials: RW
authors.lastname: Yatscoff
authors.forename: Norman M
authors.initials: NM
authors.lastname: Kneteman
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D002339:Carotid Arteries / Q000502:physiology; D016572:Cyclosporine / Q000008:administration & dosage / Q000097:blood / Q000276:immunology; D004285:Dogs; D007165:Immunosuppression Therapy / Q000379:methods*; D016381:Islets of Langerhans Transplantation / Q000276:immunology* / Q000379:methods; D008102:Liver Circulation / Q000187:drug effects / Q000276:immunology; D011168:Portal System / Q000187:drug effects / Q000276:immunology*; D011169:Portal Vein / Q000502:physiology; D020123:Sirolimus / Q000008:administration & dosage / Q000097:blood / Q000276:immunology; D013607:Tablets; D016559:Tacrolimus / Q000008:administration & dosage / Q000097:blood / Q000276:immunology; D013997:Time Factors
chemical_list: D013607:Tablets; D016572:Cyclosporine; D020123:Sirolimus; D016559:Tacrolimus