Corticosteroids

Corticosteroids are among the most commonly used immunosuppressive and antiinflammatory agents. Their effects, however, differ among species. Mammals may be classified as corticosteroid sensitive or resistant depending on the ease by which they can be depleted of lymphocytes. Laboratory rodents and humans are much more sensitive to the immunosuppressive effects of corticosteroids than are the major domestic mammals, and care should be taken not to extrapolate laboratory animal results directly to other species.

The effects of corticosteroids on cell function have a common pathway (Figure 39-1). Corticosteroids are absorbed directly into cells, where they bind to receptors in the cytosol. The corticosteroid-receptor complexes are then transported to the nucleus, where they stimulate the synthesis of IκBα, the inhibitor of NF-κB. In a resting cell, NF-κB is inactive since its nuclear binding site is masked by IκBα. When a lymphocyte is stimulated, the two molecules dissociate, the IκBα is degraded by proteasomes, and the released NF-κB moves to the nucleus and activates genes involved in inflammation and immunity. Corticosteroids, however, stimulate the production of excess IκBα. This excess continues to block NF-κB-mediated processes, including cytokine synthesis and T cell responses. As a result, corticosteroids suppress both immunological and inflammatory processes.

Corticosteroids influence immunity in four areas (Box 39-1): they affect leukocyte production and circulation; they influence the effector mechanisms of lymphocytes; they modulate the activities of inflammatory mediators; and they modify protein, carbohydrate, and fat metabolism.

The effects of corticosteroids on leukocytes vary among species. In horses and cattle, the number of circulating eosinophils, basophils, and lymphocytes declines within a few hours of corticosteroid administration as a result of sequestration in the bone marrow. The numbers of neutrophils, on the other hand, increase as a result of decreased adherence to vascular endothelium and reduced emigration into inflamed tissues. Neutrophil, monocyte, and eosinophil chemotaxis are suppressed by corticosteroids, but neutrophil random migration is enhanced. Corticosteroids suppress the cytotoxic and phagocytic abilities of neutrophils in some species, but in others, such as the horse and goat, they have no effect on phagocytosis. Macrophage production of prostaglandins and cytokines such as interleukin-1 (IL-1), as well as antigen processing, is reduced in some species.

Corticosteroids cause apoptosis of thymocytes and thus induce thymic atrophy. They also suppress the ability of T cells to produce cytokines. The most important exception to this is IL-2, which is not regulated by NF-κB (Chapter 8). Lymphocyte proliferation in response to foreign cells is suppressed, suggesting that there is interference with the recognition of MHC class II molecules. Corticosteroids also block production of lymphotoxin. NK and some antibody-dependent cellular cytotoxicity (ADCC) reactions may be refractory to corticosteroid treatment, although in cattle corticosteroids may increase serum interferon (IFN) levels. The effects of corticosteroids on antibody responses are variable and depend on timing and dose. In general, B cells tend to be corticosteroid resistant, and enormous doses are usually required to suppress antibody synthesis. It is interesting to note, however, that in horses, moderate doses of dexamethasone suppress IgG1 and IgG4 responses while having no apparent effect on IgG3 responses. Corticosteroids also upregulate the expression of CD121b. This is a decoy receptor that can bind active IL-1 but will not transduce a signal, effectively blocking IL-1 activity.

Synthetic corticosteroids suppress acute inflammation. They inhibit increases in vascular permeability and vasodilation. As a result they prevent edema formation and fibrin deposition. At the same time, they block the emigration of leukocytes from capillaries. They inhibit the release of lysosomal enzymes and impair antigen processing by macrophages. Corticosteroids can also inhibit phospholipases and so prevent the production of leukotrienes and prostaglandins. In the later stages of inflammation, they inhibit capillary and fibroblast proliferation (perhaps by blocking IL-1 production) and enhance collagen breakdown. As a result, corticosteroids delay wound and fracture healing.

When systemic corticosteroid therapy is initiated, prednisolone or methylprednisolone are usually the agents selected for small animal treatment, and betamethasone and dexamethasone are commonly employed in large animal practice. Cats may require significantly higher doses than dogs to achieve a significant clinical response. Once a response has been induced, the dose of corticosteroids should be gradually reduced by lengthening the dose interval and then decreasing the amount given. This treatment is not without risks since it has the potential to suppress the pituitary-adrenal axis and induce Cushing’s syndrome. By suppressing inflammation and phagocytosis, corticosteroids may render animals highly susceptible to infection.

Cytotoxic Drugs

Cytotoxic drugs inhibit cell division by blocking nucleic acid synthesis and activity. The major cytotoxic drugs currently in use are alkylating agents, folic acid antagonists, and DNA synthesis inhibitors.

Alkylating Agents

Alkylating agents cross-link DNA helices, preventing their separation, and thus block cell division. The most important of these is cyclophosphamide (Figure 39-2). Cyclophosphamide is toxic for resting and dividing cells, especially for dividing immunocompetent cells. It impairs both B and T cell responses, especially the primary immune response. It blocks mitogen and antigen-induced cell division and the production of IFN-γ. It prevents B cells from renewing their antigen receptors. Early in therapy, cyclophosphamide tends to destroy more B cells than T cells. In long-term therapy it affects both cell populations. It also suppresses macrophage function. Cyclophosphamide may be administered parenterally or orally and is inactive until biotransformed in the liver. It has a half-life of about 6 hours and is largely excreted through the kidney. It is of interest to note that corticosteroids enhance the metabolism of cyclophosphamide and so reduce its potency. The main toxic effect of cyclophosphamide is bone marrow suppression, leading to leukopenia with a predisposition to infection. Other adverse effects may include thrombocytopenia, anemia, and bladder damage. Cyclophosphamide may be of benefit in the treatment of lymphoid neoplasia and in the treatment of immune-mediated skin diseases, although its potential toxicity suggests that other, less-toxic alternatives be considered first.