The therapeutic effects of corticosteroid drugs are due to their presence at much higher concentrations than the natural concentration of glucocorticoid hormones, causing exaggerated responses with both toxic and beneficial effects. Adverse effects include fluid retention, weight gain, diabetes, bone mineral loss, and thinning of the skin, requiring a careful balance to be maintained between beneficial and harmful effects. These drugs can also decrease in effectiveness over time. Despite these drawbacks, inhaled corticosteroids have proven highly beneficial in the treatment of chronic asthma (see Section 14-13). In the treatment of autoimmunity or allograft rejection, in which high doses of oral corticosteroids are needed to be effective, they are most often administered in combination with other immunosuppressant drugs to keep the corticosteroid dose and side-effects to a minimum. These other drugs include cytotoxic agents that act as immunosuppressants by killing rapidly dividing lymphocytes, and drugs that more specifically target lymphocyte signaling pathways.
16-2 Cytotoxic drugs cause immunosuppression by killing dividing cells and have serious side-effects.
The three cytotoxic drugs most commonly used as immunosuppressants are azathioprine, cyclophosphamide, and mycophenolate. These drugs interfere with DNA synthesis, and their major pharmacological action is on tissues in which cells are continually dividing. Developed originally to treat cancer, these drugs were found to be immunosuppressive after observations that they were cytotoxic to dividing lymphocytes. Azathioprine also interferes with CD28 co-stimulation in T cells, thus promoting T-cell apoptosis (see Section 7-24). The use of these compounds is, however, limited by their toxic effects on all tissues in which cells are dividing, such as the skin, gut lining, and bone marrow. Effects include decreased immune function, as well as anemia, leukopenia, thrombocytopenia, damage to intestinal epithelium, hair loss, and fetal death or injury. As a result of their toxicity, these drugs are used at high doses only when the aim is to eliminate all dividing lymphocytes, as in the treatment of lymphoma and leukemia; in these cases, treated patients require subsequent bone marrow transplantation to restore their hematopoietic function. When used to treat unwanted immune responses such as autoimmune conditions, they are used at lower doses and in combination with other drugs such as corticosteroids.
Azathioprine is converted in vivo to the purine analog 6-thioguanine (6-TG), which is metabolized to 6-thioinosinic acid. This competes with inosine monophosphate, blocking the de novo synthesis of adenosine monophosphate and guanosine monophosphate, thus inhibiting DNA synthesis. 6-TG is also incorporated into the DNA in place of guanine, and accumulation of
Fig. 16.3 Anti-inflammatory effects of corticosteroid therapy. Corticosteroids regulate the expression of many genes, with a net anti-inflammatory effect. First, they reduce the production of inflammatory mediators, including cytokines, prostaglandins, and nitric oxide (NO). Second, they inhibit inflammatory cell migration to sites of inflammation by inhibiting the expression of adhesion molecules. Third, corticosteroids promote the death by apoptosis of leukocytes. The layers of complexity are illustrated by the actions of annexin-1 (originally identified as a factor induced by corticosteroids and named lipocortin), which has been shown to participate in all of the effects of corticosteroids listed on the right. NOS, NO synthase.