Treating patients suffering from rheumatoid arthritis or multiple sclerosis by using anti-CD4 antibodies has been tried, but with disappointing results. In controlled studies, the antibodies showed only small therapeutic effects but caused depletion of T lymphocytes from peripheral blood for more than 6 years after treatment. The likely explanation for the failure seems to be that these antibodies failed to delete already primed CD4 T cells secreting pro-inflammatory cytokines, and may thus have missed their target. This cautionary tale shows that it is possible to deplete large numbers of lymphocytes and yet completely fail to kill the cells that matter.
16-8 Biologics that block TNF-α, IL-1, or IL-6 can alleviate autoimmune diseases.
Anti-inflammatory therapy either can attempt to eliminate an autoimmune response altogether, as with immunosuppressive drugs or depleting antibodies, or it can try to reduce the tissue injury caused by the immune response. This second category of treatment is called immunomodulatory therapy, and is illustrated by the use of conventional anti-inflammatory agents such as aspirin, nonsteroidal anti-inflammatory drugs, or low-dose corticosteroids. A newer avenue of immunomodulatory therapy using biologics is illustrated by several FDA-approved antibodies that block the activity of powerful pro-inflammatory cytokines such as TNF-α, IL-1, and IL-6.
Anti-TNF therapy was the first specific biological therapeutic to enter the clinic. Anti-TNF-α antibodies induced striking remissions in rheumatoid arthritis (Fig. 16.9) and reduced inflammation in Crohn’s disease, an inflammatory bowel disease (see Section 15-23). Two types of established biologics are used to antagonize TNF-α in clinical practice. The first type comprises the antiTNF-α antibodies, such as infliximab and adalimumab, which bind to TNF-α and block its activity. The second type is a recombinant human TNF receptor (TNFR) subunit p75–Fc fusion protein called etanercept, which also binds TNF-α, neutralizing its activity. These are extremely potent anti-inflammatory agents, and the number of diseases in which they have been shown to be effective is growing as further clinical trials are performed. In addition to rheumatoid arthritis, the rheumatic diseases ankylosing spondylitis, psoriatic arthropathy, and juvenile idiopathic arthritis (other than the systemic-onset subset) respond well to blockade of TNF-α, and this treatment is now routine in many cases.
An illustration of the importance of TNF-α in defending against infection is the observation that TNF-α blockade carries a small but increased risk of patients developing serious infections, including tuberculosis (see Section 3-20). AntiTNF-α therapy has not been successful in all diseases. TNF-α blockade as a treatment for experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, led to amelioration of the disease, but in human patients with multiple sclerosis treated with anti-TNF-α, relapses became more frequent, possibly because of an increase in T-cell activation.
Antibodies and recombinant proteins against the pro-inflammatory cytokine IL-1 and its receptor have not proved as effective as TNF-α blockade for treating rheumatoid arthritis in humans, despite being equally powerful in animal models of arthritis. An antibody against the cytokine IL-1 has been licensed for clinical use against the hereditary autoinflammatory disease Muckle– Wells syndrome (see Section 13-9), and blockade of the IL-1β receptor by the recombinant protein anakinra (Kineret) has also proven useful in adults with moderate to severe rheumatoid arthritis.