TH1/TH2 Serum Cytokine Profiles and soluble TNF-Receptor Response in Patients with Chronic Hepatitis C during Recombinant Human Interleukin-12 (rHuIL-12) Treatment

Abstract

Interleukin-12 (IL-12) has many antiviral properties both in vitro and in vivo, such as enhancing cytotoxic lymphocyte reaction, promoting Th1-helper cell response and inducing interferon-γ - (IFN-γ) production. The present study investigated possible antiviral effects of recombinant human IL-12 in vivo in 11 chronic hepatitis patients treated with rHuIL-12 subcutaneously in 3 different dosages (0.03, 0.1, 0.5 µg/kg) once weekly for a period of 10 weeks. ELISA was employed to determine before onset of therapy the serum concentrations of IL-12, IL-12p40, IFN-γ, IL-4, IL-10, tumor mecrosis factor-α (TNF-α), TNFR p55 and p75, as well as on days 3, 5, 8, 10, 12, 15, 17, 22 after onset of therapy and subsequently weekly until the end of the treatment period and at the end of the 12 months' postobservatory period.

The HCV-RNS serum concentration was determimned by means of an RT-PCR method. Two to three days after the subcutaneous rHuIL-12 injections there was a transient significant rise of n the serum concentrations of IL-12, IL-12p40, IFN-γ and TNFR p55, followed by a decrease to the original level. The increases of the IL-12 and IFN-γ serum concentrations were dose-dependent. In patients where there was a decline of the HCV-RNS concentration in the serum we confirmed a trend to higher IL-12 serum concentrations. The serum levels of IL-2, TNF-α and IL-10 fluctuated only during the treatment period. The present study showed that a once-a-week injection of rHuIL-12 results in a merely transient rise of the IL-12, IL-12-p40- and IFN-γ serum concentrations. This may offer an explamation for the unsatisfactory clinical efficiency of the substance.

Zusammenfassung

Interleukin-12 (IL-12) hat in vitro und in vivo zahlreiche antivirale Eigenschaften wie die Steigerung der zytotoxischen Lymphozytenreaktion, die Förderung einer Th1-Helferzellantwort und die Induktion der Interferon-γ-(IFN-γ-)Produktion. In der vorliegenden Studie wurden mögliche antivirale Effekte von rekombinantem humanen IL-12 in vivo an 11 Patienten mit chronischer Hepatitis untersucht die mit rHuIL-12 s. c. in drei verschiedenen Dosierungen (0,03, 0,1, 0,5 µg/kg) einmal wöchentlich über 10 Wochen behandelt wurden. Die Serumkonzentrationen von IL-12, IL-12p40, IFN-γ, IL-2, IL-4, IL-10, Tumor-Nekrose-Factor-α (TNF-α), TNFR p55 und p75 wurden mittels ELISA vor Therapiebeginn sowie an den Tagen 3, 5, 8, 10, 12, 15, 17, 22, danach bis zum Behandlungsende wöchentlich und am Ende der 12-monatigen Nachbeobachtungszeit bestimmt. Die HCV-RNS-Serumkonzentration wurde mittels einer quantitativen RT-PCR-Methode ermittelt. Zwei bis drei Tage nach den subkutanen rHuIL-12-Injektionen konnte ein transienter signifikanter Anstieg der Serumkonzentrationen von IL-12, IL-12p40, IFN-γ und TNFR p55 gefolgt von einem Abfall auf das Ausgangsniveau beobachtet werden. Die Anstiege der IL-12- und IFN-γ Serumkonzentrationen waren dosisabhängig. Bei Patienten mit einem Abfall der HCV-RNS-Konzentration im Serum konnte ein Trend zu höheren IL-12-Serumkonzentrationen nachgewiesen werden. Die Serumspiegel von IL-2, TNF-α und IL-10 fluktuierten lediglich während der Behandlung. Die vorliegende Untersuchung zeigte, dass die einmal wöchentliche Injektion von rHuIL-12 nur zu einem transienten Anstieg der IL-12-, IL-12-p40- und IFN-γ-Serumkonzentrationen führt. Hierdurch ist möglicherweise die unzureichende klinische Effektivität der Substanz zu erklären.

Key words

Th1/Th2 Cytokines - rHuIL-12 Therapy - Chronic Hepatitis C

Schlüsselwörter

TH1/TH2-Zytokine - Therapie mit rHuIL-12 - Chronische Hepatitis C

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