Another cytokine antagonist in clinical use is the humanized antibody tocilizumab; by virtue of being directed against the IL-6 receptor, it blocks the effects of the pro-inflammatory cytokine IL-6. This seems to be as effective as anti-TNF-α in patients with rheumatoid arthritis and also shows promise in treating systemic-onset juvenile idiopathic arthritis, an autoinflammatory condition.
Interferon (IFN)-β (Avonex) is used to treat diseases of viral origin based on its ability to enhance immunity, but is also effective in treating multiple sclerosis, attenuating its course and severity and reducing the occurrence of relapses. Until recently, it was unclear how IFN-β could reduce rather than enhance immunity. In Section 3-9, we described the inflammasome, in which innate sensors of the NLR family activate caspase 1 to cleave the IL-1 pro-protein into the active form of the cytokine (see Fig. 3.19). We now know that IFN-β acts at two levels to reduce IL-1 production. It inhibits the activity of the NALP3 (NLRP3) and NLRP1 inflammasomes and also reduces expression of the IL-1 pro-protein, reducing the substrate available to caspase 1. Thus, IFN-β limits the production of a powerful pro-inflammatory cytokine, which may explain its observed effects on the symptoms of multiple sclerosis.
16-9 Biologic agents can block cell migration to sites of inflammation and reduce immune responses.
Effector lymphocytes expressing the integrin α4:β1 (VLA-4) bind to VCAM-1 on endothelium in the central nervous system, while those expressing integrin α4:β7 (lamina propria-associated molecule 1) bind to MAdCAM-1 on the endothelium in the gut. The humanized monoclonal antibody natalizumab is specific for the α4 integrin subunit and binds both VLA-4 and α4:β7, preventing their interaction with their ligands (Fig. 16.10). This antibody has shown therapeutic benefit in placebo-controlled trials in patients with Crohn’s disease or with multiple sclerosis. The early signs that this treatment could be successful illustrate the fact that disease depends on the continuing emigration of lymphocytes, monocytes, and macrophages from the circulation into the tissues of the brain in multiple sclerosis, and into the gut wall in Crohn’s disease. However, blockade of α4:β1 integrin is not specific and, like anti-TNF therapy, could lead to reduced defense against infection. Rarely patients treated with natalizumab have developed progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus. This led to the temporary withdrawal of natalizumab from the market in 2005, but in June 2006 it was again allowed to be prescribed for multiple sclerosis and for Crohn’s disease.
A similar problem with multifocal leukoencephalopathy led to the withdrawal from the market in the United States and Europe in 2009 of another anti-integrin antibody, efalizumab; this drug targets the αL subunit CD11a and had shown promise in treating psoriasis, an inflammatory skin disease driven primarily by T cells that produce pro-inflammatory cytokines.
16-10 Blockade of co-stimulatory pathways that activate lymphocytes can be used to treat autoimmune disease.