Chapter 262 Effective immunotherapeutics should induce sustained immune activation and IFN production, which may require the administration of relatively long-acting immune stimulants (e.g., live bacille Calmette-Guérin) or repeated administration of shorter-acting immune activators (e.g., Toll-like receptor 3 [TLR-3] or TLR-9 agonists; see Table 262-1). For example, effective intracellular killing of persistent intracellular pathogens often requires prolonged exposure to activating concentrations of IFNs because effective pathogen elimination typically takes time to develop. This principle is one of the primary drawbacks to the use of recombinant cytokines, such as human recombinant IFN-α (Roferon-A, others), for treatment of persistent viral infections in cats. Frequent and repeated dosing also means that there is a higher likelihood of development of neutralizing antibodies against human recombinant cytokines such as IFN-α (Zeidner et al, 1990). The use of recombinant feline IFN omega (currently available only in Europe) avoids the issue of neutralizing antibodies, but long-term, frequent treatment still is required, and optimal daily dosing regimens have not been established for most pathogens. Currently little published information is available allowing direct comparison of the ability of commercially available immune stimulants to induce production of cytokines (and especially IFN-γ). However, several general trends can be discerned from experimental studies of different classes of immune therapeutics. Immune therapeutics based on nucleic acids (or inactivated viral particles) appear to be the most effective inducers of both type I and type II IFN responses. For example, Zylexis was shown to induce IFN-γ production by porcine peripheral blood mononuclear cells, most likely by activation of the TLR-3 pathway (Fachinger et al, 2000). Likewise, an immune stimulant comprised of cationic liposomes and noncoding plasmid DNA (a TLR-9 agonist) has been shown by us and others to induce high levels of IFN-α and IFN-γ production in mice, cats, and dogs (Kamstock et al, 2006; Veir et al, 2006).
Immunotherapy for Infectious Diseases
Principles of Immune-Stimulatory Therapy
Effective Immune Therapeutics and Balanced Interferon Production
Importance of Sustained Interferon Production
Cytokine Induction Profiles of Currently Available Immune Therapeutics
Immunotherapy for Infectious Diseases
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