The experimental and clinical applications of cytokines, as biologic response modifiers and therapeutic agents, have been greatly expanded in recent years. Some cytokines, such as tumor necrosis factor and interferon alfa, have direct antitumor activity. Other cytokines affect tumor immune responses by lymphokine-activated killer cells, tumor-infiltrating lymphocytes, and activated natural killer cells. Cytokines have been used to activate immune cells ex vivo prior to adoptive transfer or have been given concurrently with activated effector cells. Phase I and phase II trials of cellular adoptive therapy, with IL-2 activated killer cells, for the treatment of renal cell carcinoma and melanoma have demonstrated feasibility and regression of metastasis in some patients. Modest results, significant morbidity, and high cost have hampered widespread adoption of these techniques.
Interferon alfa is used in hairy cell leukemia, chronic myelogenous leukemia, Kaposi’s sarcoma, and chronic active hepatitis B and C. Interferon beta is used for multiple sclerosis and interferon gamma for the treatment of chronic granulomatous disease. Constitutional symptoms are common with cytokine therapy, and in some instances toxicity is considerable.
Tumor Necrosis Factor (TNF) Antagonists
Several approaches have been developed to mitigate the biologic effects of TNF, a cytokine produced by macrophages and other antigen-presenting cells. TNF activates gene expression of proinflammatory mediators, up-regulates adhesion molecule expression, stimulates neutrophil function, possesses antitumor and antiviral activity, and is an endogenous pyrogen. In addition to its proinflammatory properties, TNF has been associated with induction of matrix metalloproteanases, alterations in vascular permeability and angiogenesis, leading to bone resorption, cartilage degradation, and rheumatic joint disease. Two molecules have been designed to inhibit binding of TNF to its cellular receptor and thereby reduce its cellular and biologic effects. Etanercept is a dimeric construct - containing the soluble TNF receptor - joined to the Fc domain of a human IgG molecule. Infliximab is a chimeric antibody molecule containing a human Fc domain and a murine variable region. Both are disease-modifying antirheumatic drugs (DMARDs) that have been shown to slow joint destruction and markedly decrease symptoms of rheumatoid arthritis. Etanercept has shown efficacy in ankylosing spondylitis. It must be administered by subcutaneous injection twice weekly; infliximab is given intravenously every 2 months.
Soluble IL-1 Receptor Antagonist
Anakinra, a recombinant, nonglycosylated soluble IL-1 receptor antagonist, competitively inhibits the binding of IL-1 to its cellular receptor. IL-1 is a major immunomodulatory cytokine, proinflammatory agent, and endogenous pyrogen. Through receptor blockade, anakinra has proved to be anti-inflammatory and efficacious in the treatment of rheumatoid arthritis.
Omalizumab is a recombinant, humanized, murine monoclonal antibody with affinity for human IgE. By binding to the Fc-binding domain of circulating serum IgE, omalizumab prevents IgE binding to Fc-receptors on human mast cells. With ongoing subcutaneously injected treatment, tissue mast cells are effectively “disarmed” and less capable of activation through allergen-IgE interactions. Both early and late phase allergic reactions can be suppressed, and omalizumab has shown to be effective for control of symptoms, improvement in pulmonary function, and improvement in quality of life for patients with allergic asthma and allergic rhinitis. Improvement is not sustained after cessation of therapy, and chronic treatment is necessary for long-term disease control.
Intravenous Gamma Globulin
Immune globulin IV (IGIV) has numerous immunomodulatory and anti-inflammatory activities and is the standard of care for immunologically mediated disorders such as Kawasaki’s syndrome and for antibody replacement in humoral immunodeficiency. When used in humoral immunodeficiency, serum IgG levels can become normal but the IGIV contains virtually no IgM and only traces of IgA.
Each lot of IGIV produced from donated serum contains millions of antibody specificities, reflecting the humoral immune repertoire from thousands of normal blood donors. Most current products undergo numerous purification and viral inactivation steps, including solvent-detergent treatment or pasteurization. The antibody reactivities can be directed against a wide range of foreign and self antigens. In addition to the above disorders, IGIV is effective in Guillain-Barre syndrome, immune-mediated neuropathies, idiopathic thrombocytopenic purpura, pediatric HIV infection, and after bone marrow transplantation. Many other potential indications have been supported only by anecdotal reports or uncontrolled trials.
Allison AC: Immunosuppressive drugs: the first 50 years and a glance forward. Immunopharmacology 2000;47:63.
Allison AC et al: Mycophenolate mofetil and its mechanisms of action. Immunopharmacology 2000;47:85.
First MR: Immunosuppressive agents and their actions. Transplant Proc 2002;34:1369.
Matsuda S et al: Mechanisms of action of cyclosporine. Immunopharmacology 2000;47:119.
Revision date: July 6, 2011
Last revised: by David A. Scott, M.D.