Transplantation of allogeneic islets of Langerhans in the rat liver: Effects of macrophage depletion on graft survival and microenvironment activation

Rita Bottino, Luis A. Fernandez, Camillo Ricordi, Roger Lehmann, Min Fu Tsan, Robert Oliver, Luca A Inverardi

Research output: Contribution to journalArticle

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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-α, interleukin-1β, and NO and interference with the rate of immune response to the islets.

Original languageEnglish
Pages (from-to)316-323
Number of pages8
JournalDiabetes
Volume47
Issue number3
DOIs
StatePublished - Mar 19 1998

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Islets of Langerhans Transplantation
Graft Survival
Clodronic Acid
Macrophages
Liver
Kupffer Cells
Endothelial Cells
Microspheres
Allografts
Transplants
Macrophage Activation
Homologous Transplantation
Interleukin-1
Islets of Langerhans
Free Radicals
Hepatocytes
Tumor Necrosis Factor-alpha
Cytokines
Control Groups

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Transplantation of allogeneic islets of Langerhans in the rat liver : Effects of macrophage depletion on graft survival and microenvironment activation. / Bottino, Rita; Fernandez, Luis A.; Ricordi, Camillo; Lehmann, Roger; Tsan, Min Fu; Oliver, Robert; Inverardi, Luca A.

In: Diabetes, Vol. 47, No. 3, 19.03.1998, p. 316-323.

Research output: Contribution to journalArticle

Bottino, Rita ; Fernandez, Luis A. ; Ricordi, Camillo ; Lehmann, Roger ; Tsan, Min Fu ; Oliver, Robert ; Inverardi, Luca A. / Transplantation of allogeneic islets of Langerhans in the rat liver : Effects of macrophage depletion on graft survival and microenvironment activation. In: Diabetes. 1998 ; Vol. 47, No. 3. pp. 316-323.
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