Interferon

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References

Abe N, Ebina T, Ishida N. Interferon induction by glycyrrhizin and glycyrrhetinic acid in mice. Microbiol Immunol 1982;26(6):535-539.

Abe Y, Ueda T, Kato T, Kohli Y. [Effectiveness of interferon, glycyrrhizin combination therapy in patients with chronic hepatitis C]. Nippon Rinsho 1994 Jul;52(7):1817-1822. [Article in Japanese]
Abstract: SNMC (stronger Neominophagen C), whose active component is glycyrrhizin (a saponin extracted from licorice) has been utilized to improve the liver function in Japan. To assess the effectiveness of interferon (IFN), SNMC combination therapy in patients, who did not respond to IFN therapy alone, we investigate 28 patients with histology of CAH 2B at 12 weeks after IFN administration. 15 patients received IFN alone continuously (group A), and 13 patients received IFN with SNMC (group B) for 12 weeks thereafter. Normalization of serum ALT level was observed in 33.3% of group A and in 64.3% of group B. Disappearance of serum HVC RNA was 13.3% in group A and 38.5% in group B. But these data were not significant statistically. Histological improvement was not significant, between group A and B by Knodel's HAI score, but reversal of histological grade (Europe classification) was noted more frequently in group B. A case of posttransfusion hepatitis type C, exacerbated by IFN therapy is reported. HLA class I antigen was strongly expressed in the liver tissue after administration of IFN. In this case, potentiation of cellular immunity was thought to be the cause of the exacerbation and IFN, SNMC combination therapy was useful in improving liver function.

Acharya SK, Dasarathy S, Tandon A, Joshi YK, Tandon BN. A preliminary open trial on interferon stimulator (SNMC) derived from Glycyrrhiza glabra in the treatment of subacute hepatic failure. Indian J Med Res 1993 Apr;98:69-74.
Abstract: The efficacy of the interferon stimulator named Stronger Neo Minophagen-C (SNMC) derived form the plant G. glabra was studied at a dose of 40 or 100 ml daily for 30 days followed by thrice weekly intravenously for 8 wk in 18 patients of subacute hepatic failure due to viral hepatitis. The survival rate amongst these patients was 72.2 per cent, as compared to the earlier reported rate of 31.1 per cent in 98 patients who received supportive therapy (P < 0.01). Death in four of the five patients was due to associated infections leading to hepatorenal failure and terminal coma. Further studies are necessary to standardize the dose and duration of therapy with SNMC in subacute hepatic failure.

Eisenburg, J. [Treatment of chronic hepatitis B. Part 2: Effect of glycyrrhizic acid on the course of illness]. Fortschr Med 1992 Jul 30;110(21):395-398. [Article in German]
Abstract: AIMS: Testing of the therapeutic efficacy of Remefa S, a pharmaceutical comprising glycyrrhizinic acid, the major active substance of licorice, on the evolution of the disease in late chronic viral hepatitis B. METHODS: Prospective evaluation of the biochemical, virus-serological and histomorphological data (blind liver aspiration, laparoscopy) during and following 12 months of application (three times a week, short infusions) of Remefa S, and comparison with the course of the disease (12 months) prior to treatment. PATIENTS: Intermediate report on an ongoing multicentre study begun in 1989, with evaluation of 7 subjects receiving the preparation and 3 controls after 12 months of treatment and 10 months of follow-up. RESULTS: During or after treatment, 4 patients experienced a regression of biochemical disease activity. In 2 of the 4 patients, during treatment, an HBe-Ag seroconversion occurred for the first time and has persisted (to date 10 months); in another patient with no detectable HBe-Ag prior to treatment, HBe antibodies were formed under treatment, and have persisted to the present time. In 2 of these responders, histology also revealed an unequivocal reduction in disease activity. In contrast, HBs-Ag seroconversion was observed in none of the patients treated. Since in these three patients the virus genome was already integrated within the chromosome of the host cell (hybridization), this had not been expected from the start. CONCLUSIONS: Intravenous chronic application (12 months) of glycyrrhizinic acid in the form of Remefa S in patients with chronic viral hepatitis B, is capable of exercising a positive effect on the evolution of the disease. On the basis of the results obtained so far (30-40% success rate), a comparison with the results obtained with interferon suggests itself.

Fujisawa K. Interferon therapy in hepatitis C virus (HCV) induced chronic hepatitis: clinical significance of pretreatment with glycyrhizine. Trop Gastroenterol 1991 Oct-Dec;12(4):176-179.

Ishizaki T, Sasaki F, Ameshima S, Shiozaki K, Takahashi H, Abe Y, Ito S, Kuriyama M, Nakai T, Kitagawa M. Pneumonitis during interferon and/or herbal drug therapy in patients with chronic active hepatitis. Eur Respir J 1996 Dec;9(12):2691-2696.
Abstract: We report four cases of acute pneumonitis due either to interferon, or a herbal drug, "Sho-saiko-to", or both in combination, in patients with chronic active hepatitis, focusing on its pathogenesis and response to prednisolone therapy. These cases shared common clinical features: fever, dry cough, dyspnoea, hypoxaemia, diffuse infiltrates both on chest radiography and chest computed tomography, restrictive pulmonary functional impairment, and alveolitis on examination of transbronchial lung biopsy, all of which suggest acute interstitial pneumonia. Furthermore, lymphocytosis was observed in association with the dominant CD8+ T-cell subset in bronchoalveolar lavage fluid. A lymphocyte stimulation test using peripheral blood was positive to interferon in one case and to Sho-saiko-to in another. All patients responded to oral prednisolone therapy. Peripheral soluble interleukin-2 receptor levels decreased in parallel with improvement in the clinical course. All patients were free of symptoms with a follow-up of 1-3 yrs. We conclude that interferon- and/or Sho-saiko-to-induced acute pneumonitis may be due to allergic-immunological mechanisms rather than toxicity, and that peripheral levels of soluble interleukin-2 receptor appear to be good markers of disease activity.

Kakumu S, et al. Effects of TJ-9 Sho-saiko-to (kampo medicine) on interferon gamma and antibody production specific for hepatitis B virus antigen in patients with type B chronic hepatitis. Int J Immunopharmacol. 1991; 13(2-3): 141-146.
Abstract: To examine whether Sho-saiko-to (kampo medicine) could modulate the immune response of immunocompetent cells to hepatitis B virus (HBV)-associated antigens, we investigated in vitro interferon gamma (IFN-gamma) and antibody (antibody to HB core and e antigens; anti-HBc and anti-HBe) production by peripheral blood mononuclear cells (PBMC) from eight patients with chronic active hepatitis (CAH) (four with HBeAg and four with anti-HBe) in the presence of recombinant HBcAg and purified HBeAg. IFN-gamma and antibody production were measured using ELISA and RIA, respectively. PBMC from both HBeAg and anti-HBe positive patients generated significantly increased IFN-gamma and antibody (anti-HBc and anti-HBe) production in the culture containing Sho-saiko-to (TJ-9) in a dose-dependent manner in comparison with those of medium alone culture. Similarly, when various concentrations of TJ-9 were added to the HBV antigen-stimulated cultures, TJ-9 was found to enhance both IFN-gamma and antibody production dose-dependently. These results indicate that TJ-9 is able to modulate both cellular and humoral immune responses specific for HBV-associated antigens. These findings also may account for, at least in part, the efficacy of TJ-9 treatment for type B chronic hepatitis.

Kawakita T, Nakai S, Kumazawa Y, Miura O, Yumioka E, Nomoto K. Induction of interferon after administration of a traditional Chinese medicine, xiao-chai-hu-tang (shosaiko-to). Int J Immunopharmacol 1990;12(5):515-521.
Abstract: We examined the ability of a traditional chinese herbal medicine, xiao-chai-hu-tang (Japanese name: shosaiko-to) to induce IFN in mice. A maximum activity (105 units/ml) of interferon (IFN) appeared in the serum of mice 16 h after intraperitoneal (i.p.) treatment with 250 mg/kg of shosaiko-to. Addition of polymyxin B did not abrogate the ability of shosaiko-to to induced serum IFN. The IFN was identified as IFN-alpha/beta by neutralizing test using anti-IFN alpha/beta antibodies. Pretreatment of mice with carrageenan suppressed the IFN induction by shosaiko-to, whereas the IFN induction by shosaiko-to was impaired neither in mice treated with anti-asialo-GM1 antibody nor in T-cell-deficient athymic nude mice. IFN was produced in vitro by spleen cells obtained from shosaiko-to treated mice. Moreover, spleen cells from untreated mice could also produce IFN when they were cultured with shosaiko-to. Additionally, serum IFN was also induced by the adoptive transfer of spleen cells from shosaiko-to treated mice to normal mice. On the other hand, peroral administration of shosaiko-to also induced IFN-alpha/beta in the serum. While IFN activity induced by i.p. administration of shosaiko-to declined after repeated treatments, the activity induced by its peroral administration did not decline during a long term treatment. These results showed that shosaiko-to is an IFN-alpha/beta inducer capable of repeated peroral administration.

Matsushima T. [Drug-induced pneumonitis and related diseases]. Nippon Naika Gakkai Zasshi 1997 Mar 10;86(3):457-62. [Article in Japanese] (Review)

Matsuura K, Kawakita T, Nakai S, Saito Y, Suzuki A, Nomoto K. Role of B-lymphocytes in the immunopharmacological effects of a traditional Chinese medicine, xiao-chai-hu-tang (shosaiko-to). Int J Immunopharmacol 1993 Feb;15(2):237-243.
Abstract: We previously reported that a traditional Chinese medicine, Xiao-chai-hu-tang (Japanese name: Shosaiko-to), induced interferon (IFN) activity in the serum of mice after intraperitoneal (i.p.) administration. In the present study in which murine spleen cells were cultured in vitro with Shosaiko-to, B-cells isolated by anti-immunoglobulin-coated plates were confirmed to generate IFN in response to Shosaiko-to stimulation. IFN activity was induced in the serum after i.p. administration of Glycyrrhizae radix, Scutellariae radix, Bupleuri radix and Pinelliae tuber which are included in Shosaiko-to as its constituent. Such an IFN-inducing activity was confirmed to exist in methanol-insoluble fractions of these extracts derived from Shosaiko-to and these constituents but not in methanol-soluble fractions. These four extracts as well as Shosaiko-to, induced interleukin 6 (IL-6) in the serum after the administration. In in vitro stimulation of spleen cells, Shosaiko-to and extracts of Glycyrrhizae radix, Bupleuri radix and Pinelliae tuber showed mitogenic activity, but an extract of Scutellariae radix with in vivo IFN-inducing activity did not. B-cells appear to participate in the immunopharmacological effects of Shosaiko-to through mitogenic activity, IFN induction and the effect of IL-6.

Murakami K, Okajima K, Sakata K, Takatsuki K. [A possible mechanism of interstitial pneumonia during interferon therapy with sho-saiko-to]. Nihon Kyobu Shikkan Gakkai Zasshi 1995 Apr;33(4):389-394. [Article in Japanese]
Abstract: Interstitial pneumonia has been reported to be a side effect of treatment with interferon, and Sho-saiko-to (Xiao-Chai-Hu-Tang) may enhance this side effect. It is well known that activated neutrophils are important mediators of pulmonary fibrosis, so we studied the effects of interferon and Sho-saiko-to on neutrophil activation. Homogenized lung myeloperoxidase (MPO) activity was assayed after intraperitoneal injection of interferon with or without pretreatment with Sho-saiko-to. Although Sho-saiko-to alone did not change the lung MPO content, MPO in the lung was significantly increased by interferon administration. The increase was enhanced further by pretreatment with Sho-saiko-to. When the accumulated neutrophils are activated by some cytokines, such as TNF alpha or IL-1 beta from monocytes/macrophages, they may damage lung tissue. We therefore studied the effects of Sho-saiko-to and interferon on TNF alpha production in freshly isolated human monocytes. Sho-saiko-to increased the production of TNF alpha, but interferon did not. In addition, Sho-saiko-to significantly increased the production of TNF alpha by monocytes stimulated by lipopolysaccharide. Taken together, these data indicate that interferon causes neutrophils to accumulate in the lung. Sho-saiko-to alone may not injure lung tissue, but it increases the effect of interferon. When stimulated by some antigen, Sho-saiko-to may overstimulate the neutrophils. Granulocytes elastase and oxygen radicals released from activated neutrophils may damage lung tissue. The fibroblasts that repair the damaged tissue may increase the risk of pulmonary fibrosis.

Nakagawa A, Yamaguchi T, Takao T, Amano H. [Five cases of drug-induced pneumonitis due to Sho-saiko-to or interferon-alpha or both]. Nihon Kyobu Shikkan Gakkai Zasshi 1995 Dec;33(12):1361-1366. [Article in Japanese]
Abstract: We encountered five cases of drug-induced pneumonitis due to Sho-saiko-to or interferon-alpha or both. In all 5 cases the underlying disease was chronic hepatitis or liver cirrhosis caused by hepatitis C virus. Interferon-alpha alone was administered in one case, Sho-saiko-to alone was administered in two cases, and both were administered in two cases. Bronchoalveolar lavage was done in 4 cases. In three cases, lymphocytosis and abnormally low CD4/8 ratios were found on examination of bronchoalveolar lavage fluid. In the only case in which interferon-alpha alone was given the percentage of neutrophils in bronchoalveolar lavage fluid was abnormally high, and the adult respiratory distress syndrome developed. Lymphocyte stimulation tests were done in four cases, and in all four cases the only positive results were against Sho-saiko-to or against interferon-alpha. The frequency of drug-induced pneumonitis among patients with chronic hepatitis or liver cirrhosis was 0.7% in those given only Sho-saiko-to, 0.5% in those given only interferon-alpha, and 4.0% in those given both interferon-alpha and Sho-saiko-to. Therefore, pneumonitis due to Sho-saiko-to and to interferon-alpha is more likely to occur if these two drugs are given simultaneously.

Shinada M, Azuma M, Kawai H, Sazaki K, Yoshida I, Yoshida T, Suzutani T, Sakuma T. Enhancement of interferon-gamma production in glycyrrhizin-treated human peripheral lymphocytes in response to concanavalin A and to surface antigen of hepatitis B virus. Proc Soc Exp Biol Med 1986 Feb;181(2):205-210.
Abstract: The effects of glycyrrhizin, a component of licorice (Glycyrrhiza glabra) roots, on the production of interferon-gamma in human peripheral lymphocyte-macrophage cultures by concanavalin A (Con A) was examined. Interferon-gamma production in normal lymphocyte-macrophage cultures treated with 10 to 100 micrograms/ml of glycyrrhizin at 37 degrees C for 12 hr or longer, and then treated with 10 micrograms/ml of Con A, was enhanced four to eight times compared to control cell cultures. Lymphocyte-macrophage cultures treated with 10 to 100 micrograms/ml of glycyrrhizin alone did not produce interferon. No significant difference in the adsorption of [3H]Con A to glycyrrhizin-treated and control lymphocyte-macrophage cultures was found, but RNA and protein synthesis of the treated lymphocytes was increased compared to control cells; DNA synthesis, however, was reduced. Collaboration between enriched T-lymphocytes and macrophages, both treated with glycyrrhizin, was needed for the enhancement of interferon-gamma production. A smaller increase in interferon production was also observed in the glycyrrhizin-treated peripheral lymphocyte-macrophage cultures derived from an asymptomatic carrier of hepatitis B virus, in response to Con A and surface antigen of hepatitis B virus.

Sugiyama, H, Nagai, M, Kotajima, F, Yoshizawa, A, Kamimura, M, Horiuchi T, Kudo K, Kabe J, Hayashi, S, Umeda, N. A case of interstitial pneumonia with chronic hepatitis C following interferon-alfa and sho-saiko-to therapy. Arerugi 1995 Jul;44(7):711-714. [Article in Japanese]

Yamashiki M, et al. Efficacy of a herbal medicine "sho-saiko-to" on the improvement of impaired cytokine production of peripheral blood mononuclear cells in patients with chronic viral hepatitis. J Clin Lab Immunol. 1992; 37(3): 111-121.
Abstract: Peripheral blood samples were collected from normal subjects and chronic viral hepatitis patients, and the in vitro capability of the peripheral blood mononuclear cells to produce various cytokine (interleukin-1 beta, interleukin-6, interferon-gamma, and granulocyte-macrophage colony-stimulating factor) were analyzed by adding pokeweed mitogen. We then investigated the effects of a herbal medicine "Sho-saiko-to" on the levels of cytokine production. The production levels of the 4 cytokines were significantly lower in the peripheral blood mononuclear cells of the patients (Patient Group) than in those of normal subjects (Control Group). The addition of Sho-saiko-to to the Patient Group resulted in improved productions of those cytokines, as well as an remarkable improvement of interleukin-1 beta production. The results demonstrated that Sho-saiko-to acts to improve such immunological abnormalities as decreased cytokine productions. Administration of Sho-saiko-to to chronic viral hepatitis patients is also expected to have immunological benefits.