TRANSPLANTATION OF ALLOGENEIC ISLETS OF LANGERHANS IN THE RAT-LIVER -EFFECTS OF MACROPHAGE DEPLETION OF GRAFT-SURVIVAL AND MICROENVIRONMENT ACTIVATION

Early impairment of islet function and graft loss Limit the success of allogeneic islet transplantation, Nonspecific inflammatory events occ urring at the transplant site immediately after grafting, involving th e production of cytokines and free radicals and sinusoidal endothelial cell (SEC) activation, may contribute to islet cell damage, To evalua te whether Kupffer cell inactivation would result in prolonged allogra ft survival in a model system of intrahepatic islet transplantation in rats, rye systemically administered either gadolinium chloride (GdCl3 ) or dichloromethylene diphosphonate (Cl2MDP) to assess the effects of macrophage inactivation on rejection and on the release of proinflamm atory molecules, as well as to assess the functional profile of SEC, T he results obtained were compared with those observed in untreated, sh am-injected animals and in rats receiving intraportal infusions of mic robeads, Transient macrophage inhibition, particularly in hepatic Kupf fer cells, is associated with significant prolongation of graft surviv al 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) a nd 15.6 days in the Cl2MDP group (P < 0.0006), respectively, Although systemic release of inflammatory mediators was observed only when isle t transplantations were performed and it could be inhibited by macroph age-targeting treatments, perturbation of the functional profile of en dothelial cells was also observed when microembolization was induced b y the use of microbeads and could not be prevented by macrophage inhib ition, These experiments provide evidence to support the concept that macrophages play a key role in early inflammatory events known to adve rsely affect islet engraftment and suggest that manipulation of nonspe cific immune activation by inhibition of macrophage function may facil itate hepatic engraftment of islet allografts, The mechanisms mediatin g this effect are likely to include prevention of release of tumor nec rosis factor-alpha, interleukin-1 beta, anal NO and interference with the rate of immune response to the islets.