Oromucosal Interferon Therapy: Pharmacokinetics and Pharmacodynamics

Abstract

Oromucosal administration of [125I]-labeled recombinant human interferon-alpha1-8 (IFN-alpha1-8), which is biologically active in the mouse, resulted in readily detectable levels of radioactivity in the serum of animals within 5 min. Biologically active IFN could not be detected in the serum at any time after oromucosal administration, however, and SDS-PAGE analysis showed that the material present in the serum was of low molecular weight and most probably reflected absorption of degradation products following digestion of IFN in the stomach and small intestine. Furthermore, oromucosal administration of murine IFN-alpha/beta (MuIFN-alpha/beta) had no significant effect on the expression of IFN-responsive genes in either peripheral blood mononuclear cells or splenic lymphocytes even though in the same animals IFN treatment activated gene transcription locally in the lymphoid tissue of the oropharyngeal cavity and caused a marked systemic antiviral activity. Oromucosal administration of MuIFN-alpha/beta had no significant effect on either the number of circulating peripheral blood leukocytes or the number of granulocyte-macrophage colonies recovered from the bone marrow of IFN-treated animals. These results suggest that the mechanism of action of oromucosal IFN therapy is distinct from that of parenterally administered IFN and may involve, in the abundant lymphoid or epithelial tissue of the oropharyngeal cavity, either production of a soluble factor or activation of a specific cell population that enters the circulation to mediate the elimination of virus-infected or neoplastic cells.

Effect of Oromucosal Administration of IFN-αon Allergic Sensitization and the Hypersensitive Inflammatory Response in Animals Sensitized to Ragweed Pollen

“…route in the absence of the leukopenia or mylosuppression produced by parenteral administration of the same dose of IFN-a. (20) In contrast, the allergen-specific IgG response was increased following i.p. administration of the highest doses of IFN-a tested (10 4 IU), suggesting that modulation of Ig production and Ig isotype selection by type I IFN (4) may account at least in part for the reported exacerbation of symptoms in patients with underlying asthma treated with high-dose parenteral IFN therapy.…”

“…(20) The inhibition of allergen-specific IgE levels and eosinophil recruitment observed following oromucosal administration of IFN-a may result, therefore, from local action on the mucosa. The process of sensitization usually results from contact of allergens with mucosal surfaces, and recent evidence suggests that IgE is produced mucosally and is exported to the lumen under the control of IL-4.…”

Oral administration of interferon-β suppresses experimental autoimmune uveoretinitis

“…Interestingly, the mechanism of action of orally administered IFNs is believed to be distinct from that of IFNs given either intravenously or intraperitoneally. This is based on animal studies showing that the oral administration of IFN-β in mice does not result in detectable levels of IFN-β in the serum, in contrast to intravenous or intraperitoneal injection [14]. Both oral and intraperitoneal administration of IFN can decrease peripheral white blood cell counts, although circulating antibody to IFN can block this effect only with intraperitoneal administration but not with oral administration [16].…”

Virulence of aMycobacterium tuberculosisclinical isolate in mice is determined by failure to induce Th1 type immunity and is associated with induction of IFN-α/β

“…Stocks of IFN-␥ and IFN-␣͞␤ were stored at Ϫ80°C. Cytokines were kept at 4°C and administered intranasally for 5 consecutive days per week for four weeks for a total of 20 days (final dose of 10 4 units͞mouse͞day) (18). Ten l applied directly to the nostrils were readily aspirated by the mouse.…”