title: Transplantation of allogeneic islets of Langerhans in the rat liver: effects of macrophage depletion on graft survival and microenvironment activation.
abstract: Early impairment of islet function and graft loss limit the success of allogeneic islet transplantation. Nonspecific inflammatory events occurring at the transplant site immediately after grafting, involving the production of cytokines and free radicals and sinusoidal endothelial cell (SEC) activation, may contribute to islet cell damage. To evaluate whether Kupffer cell inactivation would result in prolonged allograft survival in a model system of intrahepatic islet transplantation in rats, we systemically administered either gadolinium chloride (GdCl3) or dichloromethylene diphosphonate (Cl2MDP) to assess the effects of macrophage inactivation on rejection and on the release of proinflammatory molecules, as well as to assess the functional profile of SEC. The results obtained were compared with those observed in untreated, sham-injected animals and in rats receiving intraportal infusions of microbeads. Transient macrophage inhibition, particularly in hepatic Kupffer cells, is associated with significant prolongation of graft survival after intraportal islet allotransplantation (ITx) in rats: 7.2 days in the control group versus 11.9 days in the GdCl3 group (P < 0.01) and 15.6 days in the Cl2MDP group (P < 0.0006), respectively. Although systemic release of inflammatory mediators was observed only when islet transplantations were performed and it could be inhibited by macrophage-targeting treatments, perturbation of the functional profile of endothelial cells was also observed when microembolization was induced by the use of microbeads and could not be prevented by macrophage inhibition. These experiments provide evidence to support the concept that macrophages play a key role in early inflammatory events known to adversely affect islet engraftment and suggest that manipulation of nonspecific immune activation by inhibition of macrophage function may facilitate hepatic engraftment of islet allografts. The mechanisms mediating this effect are likely to include prevention of release of tumor necrosis factor-alpha, interleukin-1beta, and NO and interference with the rate of immune response to the islets.
authors.affiliation: Diabetes Research Institute, Cell Transplant Center, University of Miami School of Medicine, Florida 33136, USA.
authors.forename: R
authors.initials: R
authors.lastname: Bottino
authors.forename: L A
authors.initials: LA
authors.lastname: Fernandez
authors.forename: C
authors.initials: C
authors.lastname: Ricordi
authors.forename: R
authors.initials: R
authors.lastname: Lehmann
authors.forename: M F
authors.initials: MF
authors.lastname: Tsan
authors.forename: R
authors.initials: R
authors.lastname: Oliver
authors.forename: L
authors.initials: L
authors.lastname: Inverardi
mesh_terms: D000818:Animals; D004002:Clodronic Acid / Q000494:pharmacology; D015331:Cohort Studies; D003921:Diabetes Mellitus, Experimental / Q000601:surgery*; D005682:Gadolinium / Q000494:pharmacology; D006085:Graft Survival / Q000276:immunology / Q000502:physiology*; D006820:Hyaluronic Acid / Q000008:administration & dosage / Q000493:pharmacokinetics; D007165:Immunosuppression Therapy / Q000379:methods*; D007375:Interleukin-1 / Q000097:blood / Q000378:metabolism; D016381:Islets of Langerhans Transplantation / Q000379:methods*; D008264:Macrophages / Q000187:drug effects / Q000502:physiology*; D008863:Microspheres; D009566:Nitrates / Q000097:blood / Q000378:metabolism; D009573:Nitrites / Q000097:blood / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D016042:Transplantation, Heterotopic; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000378:metabolism
chemical_list: D007375:Interleukin-1; D009566:Nitrates; D009573:Nitrites; D014409:Tumor Necrosis Factor-alpha; D004002:Clodronic Acid; D006820:Hyaluronic Acid; D005682:Gadolinium