Improving engraftment of hepatocyte transplantation using alpha-1 antitrypsin as an immune modulator
| Autor: | Ragai R. Mitry, Joanne Tang, Siddharth Sinha, Celine Filippi, Charlotte A. Lee, Emer Fitzpatrick, Anil Dhawan, Raquel Fernandez Dacosta, Simon Walker, Valeria Iansante, Maria Koulmanda, Robin D. Hughes |
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| Rok vydání: | 2018 |
| Předmět: |
Male
congenital hereditary and neonatal diseases and abnormalities Cell Survival Alpha (ethology) Pharmacology Rats Sprague-Dawley 03 medical and health sciences 0302 clinical medicine In vivo Drug Discovery medicine Animals Humans Immunologic Factors Platelet Thrombus Genetics (clinical) Cells Cultured Hepatocyte transplantation Inflammation business.industry Liver cell Liver Diseases medicine.disease Molecular medicine Alpha-1 antitrypsin 3. Good health Transplantation Instant blood-mediated inflammatory reaction Mechanism of action alpha 1-Antitrypsin Hepatocytes Molecular Medicine Female Original Article medicine.symptom business Liver-based metabolic diseases 030215 immunology |
| Zdroj: | Journal of Molecular Medicine (Berlin, Germany) |
| ISSN: | 1432-1440 |
| Popis: | 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. Electronic supplementary material The online version of this article (10.1007/s00109-019-01747-3) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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