Abstract
The in vitro culture period prior to cell transplantation (i.e. pancreatic islet transplantation) enables cell modification and is thus advantageous. However, the islet preconditioning method has not been fully explored. Here we present a simple approach for islet preconditioning that uses the antibiotic mitomycin C (MMC), which has antitumor activity, to reduce islet immunogenicity and prevent proinflammatory events in an intraportal islet transplantation model. Freshly isolated mice islets were treated for 30 min with 10 μg/mL MMC or not, cultured for 20 h and transplanted into the livers of syngeneic or allogeneic diabetic mouse recipients. In the allogeneic model, MMC preconditioning significantly prolonged graft survival without requiring immunosuppressants. In vitro, MMC treatment suppressed the expression of proinflammatory cytokines in islet allografts, while immunohistochemical studies revealed the suppression of inflammatory cell infiltration into MMC-treated allografts relative to untreated allografts. Furthermore, MMC preconditioning significantly suppressed the mRNA expression of proinflammatory cytokines into the transplant site and induced the differentiation of regulatory T cells with the ability to suppress CD4+ T cell-mediated immune responses. In conclusion, islet preconditioning with MMC prolonged graft survival in an intraportal islet transplantation model by suppressing proinflammatory events and inducing potentially regulatory lymphocytes.
Highlights
Several centres subject human islets to a culture period before transplantation[13]
Islet allografts are transplanted into the liver via the portal vein
We initially evaluated the graft survival times in the control and mitomycin C (MMC) groups to assess the effects of MMC preconditioning before intraportal islet allotransplantation
Summary
Several centres subject human islets to a culture period before transplantation[13]. Other reports demonstrated that the pre-treatment and subsequent culture of donor islets with mitomycin C (MMC), an antibiotic with antitumor activity, significantly prolonged graft survival in a mouse model of renal subcapsular islet transplantation[16,17]. The above-described preconditioning methods have been applied only in mouse models of renal subcapsular islet transplantation. This transplant site is not suitable for preclinical studies of islet infusion because of differences in the innate and alloimmune systems; rather, the liver is considered more a ppropriate[18]. The aims of this study are to test our hypothesis that the efficacy of MMC preconditioning, which prolongs islet allograft survival in renal subcapsular islet transplantation, can be applied to intraportal islet transplantation as well as to elucidate its mechanism
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