Improving engraftment of hepatocyte transplantation using alpha-1 antitrypsin as an immune modulator

Charlotte Lee; Anil Dhawan; Valeria Iansante; Celine Filippi; Ragai Mitry; Joanne Tang; Simon Walker; Raquel Fernandez DaCosta; Siddharth Sinha; Robin D. Hughes; Maria Koulmanda; Emer Fitzpatrick

doi:10.1007/s00109-019-01747-3

Improving engraftment of hepatocyte transplantation using alpha-1 antitrypsin as an immune modulator

Charlotte Lee, Anil Dhawan^*, Valeria Iansante, Celine Filippi, Ragai Mitry, Joanne Tang, Simon Walker, Raquel Fernandez DaCosta, Siddharth Sinha, Robin D. Hughes, Maria Koulmanda, Emer Fitzpatrick

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

8 Citations (Scopus)

Abstract

Abstract: 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 × 10 ⁷ 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.

Original language	English
Pages (from-to)	563-577
Number of pages	15
Journal	Journal of Molecular Medicine
Volume	97
Issue number	4
Early online date	28 Feb 2019
DOIs	https://doi.org/10.1007/s00109-019-01747-3
Publication status	E-pub ahead of print - 28 Feb 2019

Keywords

Alpha-1 antitrypsin
Hepatocyte transplantation
Instant blood-mediated inflammatory reaction
Liver-based metabolic diseases

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Lee, C., Dhawan, A., Iansante, V., Filippi, C., Mitry, R., Tang, J., Walker, S., Fernandez DaCosta, R., Sinha, S., Hughes, R. D., Koulmanda, M., & Fitzpatrick, E. (2019). Improving engraftment of hepatocyte transplantation using alpha-1 antitrypsin as an immune modulator. Journal of Molecular Medicine, 97(4), 563-577. Advance online publication. https://doi.org/10.1007/s00109-019-01747-3

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title = "Improving engraftment of hepatocyte transplantation using alpha-1 antitrypsin as an immune modulator",

abstract = " Abstract: 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 × 10 7 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. ",

keywords = "Alpha-1 antitrypsin, Hepatocyte transplantation, Instant blood-mediated inflammatory reaction, Liver-based metabolic diseases",

author = "Charlotte Lee and Anil Dhawan and Valeria Iansante and Celine Filippi and Ragai Mitry and Joanne Tang and Simon Walker and {Fernandez DaCosta}, Raquel and Siddharth Sinha and Hughes, {Robin D.} and Maria Koulmanda and Emer Fitzpatrick",

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doi = "10.1007/s00109-019-01747-3",

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T1 - Improving engraftment of hepatocyte transplantation using alpha-1 antitrypsin as an immune modulator

AU - Lee, Charlotte

AU - Dhawan, Anil

AU - Iansante, Valeria

AU - Filippi, Celine

AU - Mitry, Ragai

AU - Tang, Joanne

AU - Walker, Simon

AU - Fernandez DaCosta, Raquel

AU - Sinha, Siddharth

AU - Hughes, Robin D.

AU - Koulmanda, Maria

AU - Fitzpatrick, Emer

PY - 2019/2/28

Y1 - 2019/2/28

N2 - Abstract: 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 × 10 7 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.

AB - Abstract: 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 × 10 7 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.

KW - Alpha-1 antitrypsin

KW - Hepatocyte transplantation

KW - Instant blood-mediated inflammatory reaction

KW - Liver-based metabolic diseases

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DO - 10.1007/s00109-019-01747-3

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SP - 563

EP - 577

JO - Journal of Molecular Medicine

JF - Journal of Molecular Medicine

IS - 4

ER -

Improving engraftment of hepatocyte transplantation using alpha-1 antitrypsin as an immune modulator

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Keywords

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