The following is the official description of IFNa and how it works. It was written by a researcher for Amarillo Biosciences in the year 2000.

Potential Mechanisms of Action of Low Dose Orally-Administered IFNa

IFNa is the major IFN produced in response to viral respiratory tract infections of calves and man.¹ This is one of the earliest responses of the innate immune system to microbial challenge. Although IFNa is not detected in the NS of normal healthy individuals, it is rapidly induced in the NS by viruses, rickettsia, mycoplasma or chlamydia.^1-3 Following exposure to viruses in vivo, IFNa can be detected in the nasal secretions at low concentrations ( 10-100 IU/ml). These small, physiologic concentrations of endogenously produced IFNa are believed to exert their biological activities by stimulation of an elaborate immunological cascade. Exogenous IFNa administered in similar doses to the oral cavity by a slowly dissolving lozenge likely mimics this physiologic mechanism of action.

IFNa binds to type I-specific interferon receptors located on tissues in the oropharyngeal region. These receptors have been demonstrated in mammals on lymphoid tissues in this area and on mucosal epithelial cells. When radiolabeled IFNa was given orally to mice, there was retention of the labeled IFNa on the posterior tongue, posterior nasal cavity and small intestine.⁴ In 5 human cancer patients, radiolabeled IFNa injected intravenously was transiently, but significantly, detected in the mouth, nose and paranasal sinuses 60-75 minutes after IV administration.⁵ Activity of orally-administered IFN has been shown in many experimental models. Following oral dosing with 10,000 IU of murine type I IFN (a mixture of IFNa and IFNb ) in mice, a marked increase in 2',5'-oligoadenylate synthetase (2-5AS) activity (a marker for IFN activity) was found in lymphoid tissues of the oropharynx (but not spleen) 24 hours after treatment.⁶ In contrast, mice given murine IFNa at 0.1-100 units/day for 7 days have a significant increase in 2-5AS activity in the spleen, but not the cervical lymph nodes.⁷ Clear evidence exists for the central role of IFN receptors in induction of effects following oral dosing. Critically, systemic effects of orally administered IFN, such as protection of mice against lethal viral challenge, were lost in animals where the IFN receptor had been inactivated by homologous recombination.⁸

IFNa given orally and swallowed additionally may reach receptors located in more distal regions of the gastrointestinal tract. Increases in Mx mRNA expression (a marker for type I IFN receptor interaction) have been shown in splenocytes and peripheral blood mononuclear cells after IFN ingestion.⁹ It is also possible that orally-administered IFNa could reach sites within minor salivary glands by traversing the short ducts which communicate with the mucosal surface. Although there is abundant evidence that low dose oral IFNa can stimulate systemic responses, it appears clear that these effects are mediated through ligation of specific, localized receptors and not by drug distributed via the circulation, as IFNa cannot be detected in the serum after oral dosing. Indeed, studies with radiolabeled IFNa given orally have shown that radioactivity subsequently detected in serum represents biologically inactive low molecular weight degradative products.⁶

The lack of detectable IFNa in serum following oral dosing makes standard pharmacokinetic studies impossible and has raised questions as to the ability of this method of administration to have significant biological and therapeutic effects. However, there is now convincing evidence that specific biologic effects can be recognized with oral dosing, often at low doses, even in the absence of measurable serum levels of the cytokine. For example, when mice were infected with a lethal dose of encephalomyocarditis virus and then were given either oral or injected IFN, both groups were protected to a similar extent, although the orally-treated animals did not have detectable serum levels of IFN.⁴ Similarly, MHC class I antigen expression was upregulated on oropharyngeal lymphoid tissues in mice after oral IFN dosing, without effects on peripheral blood mononuclear cells or splenic lymphocytes and without measurable increases in serum IFN concentrations.⁶ As noted above, the binding and activation of IFN receptor-bearing cells present at epithelial borders, recognized as a cardinal component of the innate immune system, obviate the need for obtaining circulating levels of IFNa to induce biological responses.

At present, the specific signal transduction mechanisms and subsequent messengers induced by receptor ligation are unclear. What has been shown in extensive animal and in vitro studies is that low dose oral IFNa can induce a number of significant systemic immunological effects, including upregulation of IFNg , induction of Th1-type cytokines, modulation of activities of mature T and B cells, and increased NK cell activity.^6-8,10 Oral administration of IFNa , with subsequent activation of oropharyngeal lymphoid and epithelial cells, may induce production of potent soluble factors which could mediate immunological reactivity at a distance. Oral IFNa also might activate specific cell populations in the oropharynx which could then be distributed in the circulation and function distally. For example, it has been suggested that IFN potentiates clonal expansion and survival of CD8+ cells. Stimulating effects have been shown on NK cell activity, as well. Thus, it is clear that IFNa , administered orally in low concentrations, does not only act locally, but also has systemic effects.^4,10-13

In summary, low dose oral IFNa administration is felt to exert its biological effects by triggering physiologic mechanisms of the innate immune system via ligation of type I IFN receptors in the oropharyngeal region. This helps to explain the wide range of beneficial therapeutic effects found in clinical studies of numerous indications and the minimal adverse effects of the treatment.