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The immunoregulation effect of alpha 1-antitrypsin prolong ?-cell survival after transplantation.

ABSTRACT: Islet transplantation has considerable potential as a cure for diabetes. However, the difficulties that arise from inflammation and the immunological rejection of transplants must be addressed for islet transplantation to be successful. Alpha 1-antitrypsin (AAT) inhibits the damage on ? cells caused by inflammatory reactions and promotes ?-cell survival and proliferation. This protein also induces specific immune tolerance to transplanted ? cells. However, whether the expression of AAT in ? cells themselves could eliminate or decrease immunological rejection of transplants is not clear. Therefore, we established a ? cell line (NIT-hAAT) that stably expresses human AAT. Interestingly, in a cytotoxic T lymphocyte (CTL)-killing assay, we found that hAAT reduced apoptosis and inflammatory cytokine production in NIT-1 cells and regulated the Th1/Th2 cytokine balance in vitro. In vivo transplantation of NIT-hAAT cells into mice with diabetes showed hAAT inhibited immunological rejection for a short period of time and increased the survival of transplanted ? cells. This study demonstrated that hAAT generated remarkable immunoprotective and immunoregulation effects in a model of ? cell islet transplantation for diabetes model.

SUBMITTER: Wang Y

PROVIDER: S-EPMC3983209 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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The immunoregulation effect of alpha 1-antitrypsin prolong β-cell survival after transplantation.

Wang Yun Y Yan Hong-Jie HJ Zhou Shu-Yan SY Wang Yun-Shuang YS Qi Hui H Deng Chun-Yan CY Li Fu-Rong FR

PloS one 20140410 4

Islet transplantation has considerable potential as a cure for diabetes. However, the difficulties that arise from inflammation and the immunological rejection of transplants must be addressed for islet transplantation to be successful. Alpha 1-antitrypsin (AAT) inhibits the damage on β cells caused by inflammatory reactions and promotes β-cell survival and proliferation. This protein also induces specific immune tolerance to transplanted β cells. However, whether the expression of AAT in β cell ...[more]

PMID: 24722487

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Project description:For patients with non-cirrhotic liver-based metabolic disorders, hepatocyte transplantation can be an effective treatment. However, long-term function of transplanted hepatocytes following infusion has not been achieved due to insufficient numbers of hepatocytes reaching the liver cell plates caused by activation of the instant blood-mediated inflammatory reaction (IBMIR). Our aim was to determine if the natural immune modulator, alpha-1 antitrypsin (AAT), could improve engraftment of transplanted hepatocytes and investigate its mechanism of action. A tubing loop model was used to analyse activation of the IBMIR when human hepatocytes were in contact with ABO-matched blood and 4 mg/ml AAT. Platelet and white cell counts, complement and cytokine expression were analysed. To determine if AAT could improve short-term engraftment, female rats underwent tail vein injection of AAT (120 mg/kg) or water (control) prior to the intrasplenic transplantation of 2 × 107 male hepatocytes. At 48 h and 1 week, livers were collected for analysis. In our loop model, human hepatocytes elicited a significant drop in platelet count with thrombus formation compared to controls. Loops containing AAT and hepatocytes showed no platelet consumption and no thrombus formation. Further, AAT treatment resulted in reduced IL-1β, IL-6 and IFN-γ and increased IL-1RA compared to untreated loops. In vivo, AAT significantly improved engraftment of rat hepatocytes compared to untreated at 48 h. AAT infusion may inhibit the IBMIR, thus improving short-term engraftment of donor hepatocytes and potentially improve the outcomes for patients with liver-based metabolic disease. KEY MESSAGES: • Alpha-1 antitrypsin (AAT) acts as an immune modulator to improve the efficacy of hepatocyte transplantation. • Treatment with AAT decreased thrombus formation and pro-inflammatory cytokine expression in a tubing loop model. • AAT significantly improved engraftment of donor hepatocytes within the first 48 h post transplantation.

Dataset Information

The immunoregulation effect of alpha 1-antitrypsin prolong ?-cell survival after transplantation.

Publications

The immunoregulation effect of alpha 1-antitrypsin prolong β-cell survival after transplantation.

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