Basic Study
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Oct 21, 2016; 22(39): 8760-8769
Published online Oct 21, 2016. doi: 10.3748/wjg.v22.i39.8760
Oral administration of a non-absorbable plant cell-expressed recombinant anti-TNF fusion protein induces immunomodulatory effects and alleviates nonalcoholic steatohepatitis
Yaron Ilan, Ami Ben Ya'acov, Yehudit Shabbat, Svetlana Gingis-Velitski, Einat Almon, Yoseph Shaaltiel
Yaron Ilan, Ami Ben Ya'acov, Yehudit Shabbat, Gastroenterology and Liver Units, Department of Medicine, Hadassah Hebrew University Medical Center, Jerusalem IL91120, Israel
Svetlana Gingis-Velitski, Einat Almon, Yoseph Shaaltiel, Protalix Biotherapeutics, Carmiel 20100, Israel
Author contributions: All authors contributed to the conception, experiments, writing and final approval of the manuscript.
Supported by Protalix Biotherapeutics and The Roman-Epstein Liver Research Foundation (in part).
Conflict-of-interest statement: Ilan Y is a consultant for Protalix, Gingis-Velitski S, Almon E, Shaaltiel Y are employees of Protalix. The study was supported in part by Protalix, Israel.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Yaron Ilan, MD, Gastroenterology and Liver Units, Department of Medicine, Hadassah Hebrew University Medical Center, Ein-Karem, POB 1200, Jerusalem IL91120, Israel. ilan@hadassah.org.il
Telephone: +972-2-6778231
Received: May 25, 2016
Peer-review started: May 27, 2016
First decision: July 13, 2016
Revised: July 21, 2016
Accepted: August 5, 2016
Article in press: August 5, 2016
Published online: October 21, 2016
Processing time: 147 Days and 19.2 Hours
Abstract
AIM

To evaluate the immunomodulatory effect of oral administration of PRX-106 in the high-fat diet model.

METHODS

For 22 wk, C57BL/6 HFD-fed mice received daily oral treatments with BY-2 cells expressing recombinant anti-tumor necrosis factor alpha fusion protein (PRX-106). Mice were followed for serum liver enzyme and triglyceride levels, liver histology and intrahepatic and systemic FACS.

RESULTS

The orally administered non-absorbable PRX-106 was biologically active. Altered distribution of CD4+CD25+FoxP3+ between the liver and spleen and an increase in the intrasplenic-to-intrahepatic CD4+CD25+FoxP3+ ratio and a decrease in the intrasplenic-to-intrahepatic CD8+CD25+FoxP3+ ratio were observed. An increase in intrahepatic NKT cells and a decrease in the intrasplenic-to-intrahepatic NKT ratio were noted. Assessment of the CD4-to-CD8 ratios showed sequestration of CD8+ lymphocytes in the liver. These effects were associated with a decrease in serum triglyceride levels, decrease in the aspartate aminotransferase levels, serum glucose levels, and HOMA-IR score. A decrease in hepatic triglycerides content was observed in the high dose-treated mice.

CONCLUSION

Orally administered PRX-106 shows biological activity and exerts an immunomodulatory effect, alleviating liver damage. The data suggest that PRX-106 may provide an oral immunotherapy for nonalcoholic steatohepatitis.

Keywords: Nonalcoholic steatohepatitis; Nonalcoholic fatty liver disease; Tumor necrosis alpha; Enbrel; Diabetes

Core tip: The BY-2 plant cell-expressed recombinant anti-tumor necrosis factor alpha (TNF) fusion protein (PRX-106) that consists of the soluble form of the human TNF receptor fused to the Fc component of a human IgG1 domain was orally administered in high-fat diet model. Altered distribution of CD4+CD25+FoxP3+ and a decrease in the intrasplenic-to-intrahepatic CD8+CD25+FoxP3+ ratio were observed. These effects were associated with a decrease in serum triglyceride levels, decrease in the aspartate aminotransferase levels, serum glucose levels, and HOMA-IR score. A decrease in hepatic triglycerides content was observed in the high dose-treated mice. The data suggest that PRX-106 may provide an oral immunotherapy for nonalcoholic steatohepatitis.