Interferon
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Interferons (IFNs) are natural proteins produced by the cells of the immune systems of most animals in response to challenges by foreign agents such as viruses, bacteria, parasites and tumour cells. Interferons belong to the large class of glycoproteins known as cytokines.
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Types
In humans, there are 3 major classes of interferon:
- The type I interferons consists of 14 different alpha isoforms (subtypes with slightly different specificities), and single beta, omega, epsilon and kappa isoforms. Homologous molecules are found in many species, including rats and mice (and most mammals) and have been identified in birds, reptiles and fish species. In addition to these IFNs, limitin in mice, interferon tau in ruminants and interferon delta in pigs have been identified. All type I interferons bind to a specific cell surface receptor complex known as IFNAR consisting of IFNAR1 and IFNAR2. These receptors are involved in IFN signaling and the JAK-STAT signaling pathway is one of the well-characterised IFN signaling pathways.
- The type II interferons consists of interferon gamma.
- The recently discovered 3rd class consists of interferon lambda with 3 different isoforms.
Production
Interferon alpha and beta are produced by many cell types, including T-cells and B-cells, and are an important component of the anti-viral response. They stimulate both macrophages and NK cells. Interferons alpha and beta are also active against tumors.
Interferon gamma is involved in the regulation of the immune and inflammatory responses; in humans, there is only one type of interferon-gamma. Interferon-gamma has had some anti-viral and anti-tumor effects, but these are generally weak; however, interferon-gamma potentiates the effects of interferon-alpha and interferon-beta. Unfortunately, interferon-gamma needs to be released at the site of a tumor in very small doses; at this time, interferon-gamma is not very useful for treating cancer.
Interferon gamma is also released by Th1 cells, and recruits leukocytes to a site of infection, resulting in increased inflammation. It also stimulates macrophages to kill bacteria that have been engulfed. The interferon-gamma released by Th1 cells is also important in regulating the Th2 response.
Interferon omega is released by leukocytes at the site of viral infection or tumors.
Pharmacologic uses
Interferon was scarce and expensive until 1980 when the Interferon gene was inserted into bacteria using recombinant DNA technology, allowing mass cultivation and purification from bacterial cultures.
Several different types of interferon are now approved for use in humans, and interferon therapy is used (in combination with chemotheraphy and radiation) as a treatment for many types of systemic cancer. Unfortunately, interferon delivered intravenously is not very effective, and often causes undesirable side effects at high doses.
Interferon alpha was approved by the United States Food and Drug Administration (FDA) on February 25 1991 as a treatment for hepatitis C. Several different forms of interferon alpha, including interferon alpha-2a, interferon alpha-2b, and interferon alfacon-1 are approved for the treatment of viral hepatitis. Interferon alfa 2b is also used for chronic myelogenous leukemia.
About half of hepatitis C patients treated with interferon respond, with better blood tests and better liver biopsies. Half the patients who respond relapse once the interferon is stopped, for a total cure rate of about 25%. There is some evidence that giving interferon immediately following infection can prevent hepatitis C; unfortunately, people infected by hepatitis C often do not display symptoms until months or years later.
More recently, the FDA approved pegylated interferon-alpha, in which polyethylene glycol is added to make the interferon last longer in the body. (Pegylated interferon-alpha-2b was approved in January 2001; pegylated interferon-alpha-2a was appoved in October 2002.) The pegylated form is injected once weekly, rather than three times per week for conventional interferon-alpha. Used in combination with the antiviral drug ribavirin, pegylated interferon produces sustained cure rates of 75% or better in people with genotype 2 or 3 hepatitis C (which is easier to treat) and about 50% in people with genotype 1 (which is most common in the U.S. and Western Europe).
Interferon beta is used in the treatment and control of the neurological disorder multiple sclerosis. Interferon beta also plays a major role in septic shock.