orabase and Respiratory-Tract-Infections

Interferons (IFNs) play a role in innate immunity during many viral, bacterial, and protozoal infections. With the increasing threat of bioterrorist attacks with Bacillus anthracis, its high lethality, and the limited effectiveness of antibiotics, alternative treatments are being studied. Antibodies to protective antigen (PA) are promising, as is IFN. During many bacterial infections, production of and protection by IFNs has been reported, including B. anthracis in vitro. In vivo, we find that (1) the type I IFN inducer, Poly-ICLC, strongly and rapidly protects mice; (2) the protection is IFN-mediated since recombinant murine IFN-beta can protect, and protection by Poly-ICLC is abrogated in IFN type I receptor knockout mice. The greatest protection by Poly-ICLC was conferred by intranasal treatment. A delay in death was observed with the intramuscular route alone, but was not significant. Together, the results suggest the IFN defense could protect mice, up to 60%, against lethal inhalational anthrax, and thus have important medical implications for therapy of human anthrax.

Topics: Administration, Intranasal; Animals; Anthrax; Bacillus anthracis; Carboxymethylcellulose Sodium; Interferon Inducers; Interferon Type I; Interferon-gamma; Interferons; Mice; Mice, Knockout; Poly I-C; Polylysine; Recombinant Proteins; Respiratory Tract Infections

Acute respiratory virus infections such as SARS and pandemic influenza are highly contagious diseases that cause global crisis, and inflict severe human mortality and morbidity. Vaccines against these viruses are either unavailable or do not provide adequate protection. In the absence of effective vaccines, nucleic acid-based immunomodulators have the potential to offer effective, broad-spectrum protection against these deadly pathogens. Poly ICLC and CpG oligonucleotides are promising gene-based drugs which have been shown in animal studies to protect against acute respiratory virus infections. Poly ICLC is a synthetic double-stranded RNA (dsRNA), and an effective interferon-inducer and natural killer cell activator. When encapsulated in liposomes, poly ICLC offers complete protection (100% survival rate in pretreated group versus 0% survival in control group) against a lethal respiratory challenge of influenza A virus in mice. This antiviral effect has been shown to persist for up to 3 weeks post-drug treatment. Poly ICLC pretreatment also protects mice against a respiratory challenge of western equine encephalitis (WEE) virus, at a level comparable to inactivated WEE vaccine. CpG oligos in liposomes also provided high level of protection against the lethal influenza challenge. Together, these studies suggest nucleic acid-based immunomodulators are promising antiviral agents which can offer effective and non-specific protection against acute respiratory virus infections.

Topics: Animals; Carboxymethylcellulose Sodium; CpG Islands; Encephalitis Virus, Western Equine; Encephalomyelitis, Equine; Humans; Influenza A virus; Influenza, Human; Liposomes; Mice; Oligodeoxyribonucleotides; Poly I-C; Polylysine; Respiratory Tract Infections; Virus Diseases

Recurrent respiratory papillomatosis is a disease caused by a virus in the Papovaviridae family. It tends to recur in the laryngotracheal tree, and treatment is surgical removal with a CO2 laser and suspension microlaryngoscopy. Some patients may require these procedures every few weeks, and a systemic agent to control disease would be ideal for them. Care must be taken in the selection of an agent, as these lesions, similar to other papova virus-induced lesions, are most susceptible to malignant degeneration in the presence of a carcinogen. Eight patients were given 10 courses of polyriboinosinic-polyribocytidylic acid [poly(I,C)-LC] in an attempt to control their disease. The three who were tested were able to produce good titers of interferon. The rate of disease progression was probably slowed in four patients, as reflected by a decrease in the requirement for surgery; however, the medication appeared to be relatively toxic in effective doses. Four of 10 courses were held for hepatotoxicity, and mild hepatotoxicity occurred in four more. One course was held for thrombocytopenia associated with bleeding at the tracheostomy site. We conclude that in its presently available form, poly(I,C)-LC is too toxic to be administered long term for control of this disease.

Topics: Adult; Carboxymethylcellulose Sodium; Child; Child, Preschool; Drug Evaluation; Female; Humans; Interferon Inducers; Kidney; Liver; Lung Diseases; Male; Methylcellulose; Middle Aged; Papillomaviridae; Poly I-C; Polylysine; Polyomaviridae; Recurrence; Respiratory Tract Infections