Inhibition of gelatinase activity in pancreatic islet graft reduces cellular inflammation and restores islet function
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Islet transplantation provides an approach to compensate for loss of insulin producing cells in patients with type 1 diabetes. However, the intraportal route of transplantation is associated with instant inflammatory reactions against the graft and subsequent islet destruction as well. While matrix metalloproteases (MMP) 2 and 9 are involved both in remodelling of extracellular matrix and leukocyte migration, their influence on the outcome of islet transplantation has not been characterized.Analysis of MMP-2 and MMP-9 in islet cells by zymography, gelatin dequenching assays, and western blot showed that in normal state, islets were expressing less MMP but treatment with inflammatory cytokines increased MMP-2 and MMP-9 secretions from them. However, islet transplantation in mice liver showed less MMP activity in the transplanted islet and more with the recipient liver. We observed comparable MMP-2 mRNA expressions in control and transplanted groups of mice, whereas MMP-9 mRNA and protein expression levels increased after islet transplantation. Immunostaining for CD11b (Mac-1) expressing leukocytes (macrophage, neutrophils) and Ly6G (neutrophils) revealed substantially reduced inflammatory cell migration into islet-transplanted liver in MMP-9-knockout (KO) recipients. Moreover, gelatinase inhibition resulted in a significant increase in the insulin content of transplanted pancreatic islets and reduced macrophage and neutrophil influx as compared to the control group. These results indicate that increase of MMP-9 expression and activity after islet transplantation is directly related to enhanced leukocyte migration and that early islet graft survival can be improved by inhibiting MMP-9 (gelatinase B) activity.Verknüpfung zu Publikationen oder weiteren Datensätzen
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Giessen : VVB Laufersweiler