Induction of oral immune regulation towards liver-extracted proteins for treatment of chronic HBV and HCV hepatitis: results of a phase I clinical trial.
BACKGROUND
Anti-viral immunity can be modulated via oral feeding of viral proteins. Hepatitis B and C viral (HBV, HCV)-associated hepatocellular injury is mediated by a defective host anti-viral immune response.


OBJECTIVE
To determine the effect of oral administration of a mixture of liver-extracted proteins with HBV/HCV proteins, on viral load, liver injury, and the anti-viral T-cell response of chronic HBV/HCV patients.


METHODS
Fourteen patients with chronic HBV and 15 patients with chronic HCV were treated orally with hepatocyte-extracted proteins and HBV or HCV viral proteins for 24 weeks, and followed for an additional 26 weeks. Patients were monitored for HBV-DNA or HCV-RNA levels, liver enzymes and liver histology. Viral-directed T-cell immunity was assessed by IFNgamma and IL10 ELISPOT, viral-specific T-cell proliferation, cytotoxicity, and cytokines assays, and followed for peripheral natural killer T-cell (NKT) number.


RESULTS
In both chronic HBV and HCV patients, oral administration of a mixture of selected liver-extracted proteins and viral proteins induced a favorable increase in viral-specific T-cell proliferation, and IFNgamma-secreting clones, along with a significant decrease in the anti-viral IL10-secreting T-cell clones. However, the effects of modulation of the anti-viral immunity differed between the HBV and HCV patients. In both groups, no major adverse events were noted. In chronic HBV patients, a significant decrease in viral load was observed in 5/14 (35.7%) of patients. HB surface antigen/HB nucleocapsid antigen scores on liver biopsy improved in 46.1% and 50%, respectively, and the histological necroinflammatory score improved in 4/13 (30.7%). Forty percent of the patients with elevated liver enzymes showed a favorable biochemical response. In contrast, an improvement in the histological necroinflammatory score was observed in only 2/12 (17%) of the chronic HCV patients. No significant decrease in HCV RNA was noted in any of these patients.


CONCLUSIONS
Immune regulation of the anti-HBV/HCV immune response via oral administration of a mixture of liver-extracted and viral proteins significantly altered the viral-specific immunity. This effect was associated with clinical and virological improvements in chronic HBV patients.
Liver Unit, Department of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Eran
E
Israeli
Rifaat
R
Safadi
Alaa
A
Melhem
Orit
O
Pappo
Oren
O
Shibolet
Athalia
A
Klein
Nilla
N
Hemed
Barbara
B
Thalenfeld
Dean
D
Engelhardt
Elazar
E
Rabbani
Yaron
Y
Ilan
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D002455:Cell Division / Q000276:immunology; D002860:Chromium Radioisotopes; D005260:Female; D006513:Hepatitis B e Antigens / Q000378:metabolism; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000276:immunology*; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000276:immunology; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D016896:Treatment Outcome; D019562:Viral Load; D014764:Viral Proteins / Q000008:administration & dosage* / Q000009:adverse effects
D002860:Chromium Radioisotopes; D006513:Hepatitis B e Antigens; D014764:Viral Proteins; D016753:Interleukin-10; D007371:Interferon-gamma