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


CONCLUSIONS
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.
Yaron Ilan, Ami Ben Ya'acov, Yehudit Shabbat, Gastroenterology and Liver Units, Department of Medicine, Hadassah Hebrew University Medical Center, Jerusalem IL91120, Israel.
Yaron
Y
Ilan
Yaron Ilan, Ami Ben Ya'acov, Yehudit Shabbat, Gastroenterology and Liver Units, Department of Medicine, Hadassah Hebrew University Medical Center, Jerusalem IL91120, Israel.
Ami
A
Ben Ya'acov
Yaron Ilan, Ami Ben Ya'acov, Yehudit Shabbat, Gastroenterology and Liver Units, Department of Medicine, Hadassah Hebrew University Medical Center, Jerusalem IL91120, Israel.
Yehudit
Y
Shabbat
Yaron Ilan, Ami Ben Ya'acov, Yehudit Shabbat, Gastroenterology and Liver Units, Department of Medicine, Hadassah Hebrew University Medical Center, Jerusalem IL91120, Israel.
Svetlana
S
Gingis-Velitski
Yaron Ilan, Ami Ben Ya'acov, Yehudit Shabbat, Gastroenterology and Liver Units, Department of Medicine, Hadassah Hebrew University Medical Center, Jerusalem IL91120, Israel.
Einat
E
Almon
Yaron Ilan, Ami Ben Ya'acov, Yehudit Shabbat, Gastroenterology and Liver Units, Department of Medicine, Hadassah Hebrew University Medical Center, Jerusalem IL91120, Israel.
Yoseph
Y
Shaaltiel
D000284:Administration, Oral; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007167:Immunotherapy; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D059828:Plant Cells / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D013154:Spleen / Q000166:cytology; D014280:Triglycerides / Q000097:blood / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D011993:Recombinant Fusion Proteins; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha
Diabetes; Enbrel; Nonalcoholic fatty liver disease; Nonalcoholic steatohepatitis; Tumor necrosis alpha