Steven Dow,     Fort Collins, Colorado

Jessica M. Quimby,     Fort Collins, Colorado

Role of Immune-Stimulatory and Immunosuppressive Therapy

Some infections in dogs and cats cannot be treated effectively with antimicrobial drugs alone. Often these are chronic infections, typically in sites that may not be fully accessible so that effective antimicrobial drug concentrations can be reached. These difficult-to-treat infections include chronic viral infections in cats (e.g., feline herpesvirus 1, feline calicivirus, feline coronavirus, feline immunodeficiency virus infections) as well as chronic infections in dogs caused by certain intracellular pathogens (e.g., Toxoplasma gondii, Mycobacterium spp, Ehrlichia canis, Coccidioides immitis, canine papilloma virus). For these infections, active immunotherapy can be an effective alternative or adjunct to conventional antimicrobial therapy.

At the other extreme, there are some infections in which the immune response to infection elicits such a marked inflammatory response that inflammation actually causes more injury to the host than the pathogen itself. Examples of these infections include acute rickettsial infections (e.g., E. canis and Rickettsia rickettsii infection), hemoplasma infections (e.g., Mycoplasma haemofelis, Candidatus Mycoplasma haemominutum), and some bacterial pneumonias and meningitides. For these infections, brief immunosuppression with glucocorticoids can reduce host inflammatory responses and thereby ameliorate the damage caused by unchecked inflammation, while at the same time not interfering with the overall effectiveness of treatment with conventional antimicrobial drugs (see Chapter 278).

Principles of Immune-Stimulatory Therapy

The primary goal of active immunotherapy for treatment of most infections is to induce repeated production of large amounts of both type I interferons, or IFNs (IFN-α, IFN-β) and type II IFNs (IFN-γ). Depending on the site and distribution of infection, the immune-stimulatory drug is administered either locally (e.g., intranasally) or systemically. Strong IFN responses, particularly those that include type I IFNs, can suppress replication and increase intracellular killing of most pathogens, including viral, bacterial, and fungal pathogens. In addition, repeated activation of innate immune responses can lead to the generation of pathogen-specific T-cell responses.

Effective Immune Therapeutics and Balanced Interferon Production

Both type I and type II IFNs are important for controlling persistent infections by viruses, fungi, and bacteria. Therefore the most effective immunotherapeutics are those that produce balanced induction of both type I and type II IFN responses. For example, Zylexis, a veterinary immune stimulant produced from inactivated parapoxviral particles, has been shown potently to induce IFN production (Fachinger et al, 2000). Type I IFN and type II IFNs exert critical and nonredundant activities against intracellular pathogens. However, although most currently licensed veterinary immune therapeutics can elicit some IFN-γ production, few are strong inducers of IFN-α production, with the possible exception of Zylexis. Thus there is still a need for veterinary immune therapeutics capable of potently activating both IFN-α and IFN-γ production in vivo.

Cytokine Induction Profiles of Currently Available Immune Therapeutics

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).

In contrast, immune stimulants based on purified or enriched bacterial or fungal extracts tend to induce high levels of tumor necrosis factor-α (TNF-α) production, but lower amounts of IFN-γ and little or no IFN-α production. For example, killed Propionibacterium acnes (ImmunoRegulin) has been reported to induce TNF-α production by bovine leukocytes. Likewise, Staphylococcus phage lysate (SPL) has been reported to activate innate immunity. Cell wall extracts of Aloe vera (Acemannan Immunostimulant), which are rich in polysaccharides, are reported to induce TNF-α production by macrophages in vitro (Zhang and Tizard, 1996).