Newer treatments attempt to target the aspects of the immune response that cause tissue damage, such as cytokine action, while avoiding wholesale immunosuppression, but even these therapeutic agents can affect important components of the response to infectious disease. The most immediate way of inhibiting a particular part of the immune response is via highly specific antibodies, usually directed against specific proteins expressed and/or secreted by immune cells. Approaches of this type that were experimental at the time of previous editions of this book are now part of established medical practice. Anticytokine monoclonal antibodies, such as the drug infliximab (anti-TNF-α) used in the treatment of rheumatoid arthritis, can neutralize local excesses of cytokines or chemokines or target natural cellular regulatory mechanisms to inhibit unwanted immune responses. Proteins besides antibodies are also in use to control immune responses, an example being abatacept, a fusion protein consisting of the Fc region of an immunoglobulin fused to the extracellular domain of CTLA-4. Abatacept reduces co-stimulation of T cells by binding to B7 molecules and blocking their interactions with CD28, and it is currently used to treat patients with rheumatoid arthritis who fail to respond to antiTNF-α therapy.
16-1 Corticosteroids are powerful anti-inflammatory drugs that alter the transcription of many genes.
Corticosteroid drugs are powerful anti-inflammatory and immunosuppressive agents that are used widely to attenuate the harmful effects of autoimmune or allergic immune responses (see Chapters 14 and 15), as well as responses against transplanted organs. Corticosteroids are derivatives of the glucocorticoid family of steroid hormones that play a crucial role in maintaining the body’s homeostasis; one of the most widely used is prednisone, a synthetic version of the hormone cortisol. Corticosteroids cross the cell’s plasma
Treatment of unwanted immune responses.
membrane and bind to intracellular receptors of the nuclear receptor family. Activated glucocorticoid receptors are transported to the nucleus, where they bind directly to DNA and interact with other transcription factors to regulate as many as 20% of the genes expressed in leukocytes. The response to steroid therapy is complex, given the large number of genes regulated in leukocytes and in other tissues. With respect to immunosuppression, corticosteroids exert multiple anti-inflammatory effects, which are briefly summarized in Fig. 16.3.
Corticosteroids target the pro-inflammatory functions of monocytes and macrophages and reduce the number of CD4 T cells. They can induce the expression of certain anti-inflammatory genes, such as AnxaI, which encodes a protein inhibitor of phospholipase A2 and thereby prevents this enzyme from generating pro-inflammatory prostaglandins and leukotrienes (see Sections 3-3 and 14-7). Conversely, corticosteroids can also suppress the expression of pro-inflammatory genes, including those encoding the cytokines IL-1β and TNF-α.