Minimal dose of aerosolized interferon-alpha in human subjects: biological consequences and side-effects

Abstract

Interferon-α (IFN-α) is a leucocyte-derived cytokine with pleiotropic effects on the cells of the immune system, including the ability to promote viral and microbial killing. This study was designed to evaluate the biologically active dosage of aerosolized lymphoblastoid IFN-α, in normal subjects and patients with chronic bronchitis, using serum 2'-5' oligoadenylate synthetase (OAS) as a marker of IFN-α actitivity.Three groups of subjects were included: two healthy groups and one of patients with chronic bronchitis. Group A (controls, n=5) was studied in order to determine the minimal IFN-α dose able to induce biological effects without side-effects. IFN-α was given in a dose escalation trial including 0, 0.3×10 6 , 1.0×10 6 and 3.0×10 6 IU·day -1 (5 day administration). Only the administration of 3.0×10 6 IU·day -1 of IFN-α induced a significant biological activity, increasing serum levels of OAS. Group B (controls, n=5) and C (chronic bronchitis, n=5) were given 3.0×10 6 IU·day -1 (10 day administration) in order to study serum, bronchoalveolar lavage fluid (BALF) and BALF cell modifications, after treatment. OAS serum levels and nitroblue tetrazolium (NBT) reduction tests, the latter used as a measure of phagocyte cell activity, increased both in normal subjects and in patients with chronic bronchitis. No significant change of serum IFN-α levels was found.It is concluded that aerosolized IFN-α administration to the lung is well-tolerated at biologically active doses. The activity can be monitored by quantifying OAS serum levels through a simple blood test.

Effects of Aerosolized Interferon- α in Patients with Pulmonary Tuberculosis

“…As previously shown, this cytokine can be safely delivered to the epithelial surface of the lower respiratory tract without systemic side effects (10). To establish possible mechanisms involved in infection control by IFN-␣, we evaluated several biologic, clinical, and biochemical variables.…”

“…Previous work found that aerosolized IFN-␣ administration to the lung was well tolerated at biologically active doses. 2 Ј -5 Ј Olygoadenilate synthetase (OAS) levels, used as a marker of IFN-␣ activity, increased after local treatment in serum and bronchoalveolar lavage fluid (BALF), suggesting that the inhaled cytokine was active at lung level (9,10).…”

Expression of Many Immunologically Important Genes in Mycobacterium tuberculosis-Infected Macrophages Is Independent of Both TLR2 and TLR4 but Dependent on IFN-αβ Receptor and STAT1

“…Thus, type I IFN may be critical for the innate immune response to Mtb infection. In clinical studies a beneficial effect of treatment of tuberculosis patients with inhaled IFN-␣ has been observed (64,65), and people with STAT1 mutations are susceptible to mycobacterial infections, demonstrating a protective role of IFNs (66). In contrast, treatment of human monocytes with IFN-␣␤ resulted in increased growth of M. bovis Calmette-Guérin bacillus, and intranasal instillation of IFN-␣␤ in Mtb-infected mice increased mycobacterial growth and impaired mouse survival (59,67).…”

Optimal PEGylation can Improve the Exposure of Interferon in the Lungs Following Pulmonary Administration

“…The potent antifibrotic effects of IFNγ have also attracted attention as a therapy for idiopathic pulmonary fibrosis . Of relevance to the inhaled delivery of IFNs, both IFNα and IFNγ have been shown to be physically stable upon aerosolization and exhibit good tolerability when delivered directly to the lungs …”

“…11,12 Of relevance to the inhaled delivery of IFNs, both IFN" and IFN( have been shown to be physically stable upon aerosolization and exhibit good tolerability when delivered directly to the lungs. 13,14 The IFNs are separated into several classes that differ in their biological activity. Type I IFNs (which include subtypes " and $) exist as single polypeptides that primarily exert antiviral activity, but can also inhibit cellular proliferation.…”