Oral administration of a non-absorbable plant cell-expressed recombinant anti-TNF fusion protein induces immunomodulatory effects and alleviates nonalcoholic steatohepatitis

doi:10.3748/wjg.v22.i39.8760

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World Journal of Gastroenterology

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1007-9327

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

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Basic Study

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

Yoseph Shaaltiel, Einat Almon, Svetlana Gingis-Velitski, Yehudit Shabbat, Ami Ben Ya'acov, Yaron Ilan

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.

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.