Modifying the immune response (Proceedings)

Why??? One of two goals: Enhancing the immune response (e.g. infection, cancer); or 2) suppressing the immune response (e.g. autoimmune disease). Results are often broad in scope, when usually we want a focused effect; for example, enhancing certain components of the immune response, like CMI in FIP, or suppressing only certain components of the immune response, like B lymphocytes that recognize an allergen, and produce IgE. Thus, manipulation requires caution as it may lead to untoward effects.

Immunosuppression includes use of anti-inflammatory and immunosuppressive drugs. These fall into several categories: steroidal, nonsteroidal, T cell inhibitors, and cytotoxic drugs. Corticosteroids are derivatives of glucocorticoids and act through receptor binding. These receptors are present in the cell membrane as well as intracellular locales; the result of binding is altered gene transcription within the cell. These drugs also have direct cellular effects, such as altering cell membrane properties – this affects intracellular calcium levels. Corticosteroids impact a wide population of cells - as much as 20% of WBC genes may be affected (induced or suppressed). Products vary in potency and duration; some specific effects include reduced expression of inflammatory cytokines, decreased phagocytosis, decreased antigen presentation, complement inhibition, reduced extravasation of WBC, and decreased T helper cell numbers and cytokine production. Cats generally require higher dosages and are more resistant to effects – lower receptor density. Cats appear to be less susceptible to side effects from corticosteroids, but when they do occur, they may be severe, such as cutaneous atrophy, increased skin fragility, congestive heart failure, and increased susceptibility to diabetes mellitus.

Nonsteroidal anti-inflammatories (NSAID) are most commonly used for pain management. Most prevent prostaglandin (PG) synthesis from arachidonic acid through inhibition of cyclooxygenase (COX). COX-1 is expressed in many tissues, while COX-2 induced by cytokines in inflamed tissue. Most NSAID's target COX-2 specifically. Some of these drugs are toxic to cats. NSAID's, by inhibiting prostaglandin synthesis, inhibit the response to PG's: arteriolar dilation, increased vascular permeability, enhance stimulation of nociceptors (pain) and sensitivity to touch. Use only at recommended dosages in both dogs and cats.

Dual Inhibitors inhibit not only COX-2 but Lipooxygenase (LOX) as well. LOX converts arachadonic acid to leukotrienes which are also potent inflammatory mediators; these drugs may provide superior effectiveness and reduced adverse events. Tepoxalin has been approved for veterinary use (dogs). COX-2 selectivity doesn't insure gastric protection – it may exacerbate existing mucosal damage. Don't use with other NSAID's or at higher doses than approved dosages. In addition, COX-2 has a role in maintenance of renal function. To date, no studies have shown any impairment of renal function by COX-2 selective NSAID's.

Tetracyclines have multiple anti-inflammatory effects – they inhibit inflammatory bacterial products and inhibit release of neutrophil chemoattractants even if bacterial numbers are unaffected.

Tetracyclines also inhibit chemotaxis – it chelates intracellular calcium which inhibits microtubule assembly. They also inhibit matrix metalloproteases which are zinc dependent enzymes involved in inflammation.

T cell inhibitors were originally developed to inhibit graft rejection. Cyclosporine and tacrolimus are two of the best-known drugs, developed from Tolypocladium fungus and Streptomyces bacteria respectively. They inhibit IL-2 gene expression which alters T cell activation and proliferation. In addition, they interfere with expression of IL-2 receptors. These drugs are lipophilic – they penetrate lipid membrane and act on intracellular second messengers in T cells → block activation of genes involved in activation such as IL-2. Tacrolimus most commonly used to treat KCS while CsA Used to treat immune-mediated diseases and allergies in dogs and cats. Side effects include vomiting, anorexia, and diarrhea; callusing of footpads; red and swollen ear flaps; gingival proliferation, and may impact vaccine efficacy.

Cytotoxic drugs were developed to treat cancer; now also used to treat some autoimmune diseases. Azathioprine and cyclophosphamide are two well-characterized drugs – they interfere with DNA synthesis, especially in rapidly dividing cells, e.g. cancer cells, lymphocytes. They are nucleotide analogs and lead to chain termination of DNA elongation. These medications also affect skin, intestinal lining, and BM; myelosuppression, anorexia, vomiting and diarrhea may occur. Others include cytosine arabinoside, chlorambucil, procarbazine which are DNA alkylating agents.

Immunostimulation and -modulation are also done in veterinary medicine. One of the most notable methods is through vaccination. For some vaccines, enhancement of the response is needed, for which vaccine adjuvants are added. These are used most commonly in noninfectious vaccines. Generally these fall into one of two categories: concentrating depot – insures antigen is present at sufficient levels and duration to stimulate a protective response and immune enhancers which quantitatively and qualitatively direct the immune response.

Cytokines are secreted low MW molecules that influence regulatory pathways of the immune response and mediate cell-to-cell communication. The act through binding of receptors on target cells with high affinity. They may bind cell that secreted it (autocrine), cell in close proximity (paracrine), or distant cell (endocrine). They may influence innate and adaptive immunity. Cytokine receptors may be expressed constitutively or they may be induced by other triggers, such as antigen recognition. The binding leads to alteration of gene expression of the cell. The pattern of cytokines produced "directs" the immune response. Combinations may provide synergistic effects. Cytokines have also been used with therapeutic as well as prophylactic vaccines e.g. cancer vaccines. Interferon is an important antiviral cytokine. The different forms (α, β, γ, ω) vary in effects – they may induce cell-mediated immunity (γ), induce antiviral state in cells (α, β), enhance antigen presentation, and many other immuno-enhancing effects.

Interleukins and growth factors have also been used therapeutically. IL-2has a broad array of effects on the immune response: it induces proliferation of lymphocytes, supports their growth, and enhances NK cell function among other effects. Colony Stimulating Factors (CSF) are growth factors for various myeloid cell lines that have been used therapeutically with varying success.

Other immunostimulants include Staphylococcus Aureus Phage Lysate, a bacteriophage that increases macrophage ability to inactivate Staph. organisms. Staph protein A is a cell wall surface polypeptide that activates T and B cells and stimulates IFN production. CpG oligodeoxynucleotides are bacterial DNA sequences that are recognized as foreign; they induce innate immune response (CK's, NK cells) as well as lymphocyte proliferation.

Some newer products include Lymphocyte T-Cell Immunomodulator (LTCI) produced by thymic stromal epithelial cell line and functions in T lymphocyte production and activation; it has shown promise for retrovirus-infected cats. Polyprenyl – phosphoryated linear isoprenols – holds promise for the dry form of FIP. It up-regulates Th1 cytokines through an unknown mechanism.

References

Spickler, A. R., and J. A. Roth. 2003. Adjuvants in Veterinary Vaccines: Modes of Action and Adverse Effects. J Vet Intern Med, 17:273-281.

Rhen, T., and J. A. Cidlowski. 2005.Antiinflammatory Action of Glucocorticoids: New Mechanisms for Old Drugs. New Engl J Med, 353:1711-1723.

Robson, D. 2003. Review of the properties and mechanisms of action of cyclosporine with an emphasis on dermatological therapy in dogs, cats and people. Vet Rec, 152:768-782.

Webster, G., and J. Q. Del Rosso. 2007. Anti-inflammatory Activity of Tetracyclines. Dermatol Clin, 25: 133-135.

Cummins, J. M., G. S. Krakowka, and C. G. Thompson. 2005. Systemic effects of interferons after oral administration in animals and humans. AJVR 66(1):164-176.

Fernández-Varó, E. and L. Villamayor. 2007. Granulocyte and granulocyte macrophage colony-stimulating factors as therapy in human and veterinary medicine. Vet J, 174:33-41.

Gingerich, D. A. 2008. Lymphocyte T-cell Modulator: Review of the Immunopharmacology of a New Veterinary Biologic. Intern J Appl Res Vet Med, 6(2):61-68.

Clark, T. P. 2006. The Clinical Pharmacology of Cyclooxygenase-2-Selective and Dual Inhibitors. VCNA, 36:1061-1085.

Thacker, E. L. 2010. Immunomodulators, Immunostimulants and Immunotherapies in Small Animal Veterinary Medicine. VCNA, 40(3):473-484.