Dr Margaret Hunt

BACTERIOLOGY

IMMUNOLOGY

MYCOLOGY

PARASITOLOGY

VIROLOGY

INTERFERON
Interferons play an important role in the first line of defense against viral infections. They are part of the non-specific immune system and are induced at an early stage in viral infection before the specific immune system has had time to respond. Interferons are made by cells in response to an appropriate stimulus, and are released into the surrounding medium; they then bind to receptors on target cells and induce transcription of approximately 20-30 genes in the target cells, and this results in an antiviral state in the target cells. TYPES OF INTERFERON: TYPE I interferon: Interferon-alpha (leukocyte interferon) is produced by virus-infected leukocytes, etc Interferon-beta (fibroblast interferon) is produced by virus-infected fibroblasts, or Interferon virus-infected epithelial cells, etc response to an acute virus Interferon-a (a family of about 20 related proteins) and interferon-b are particularly potent infection as antiviral agents. They are not expressed in normal cells, but viral infection of a cell causes interferons to be made and released from the cell (that cell will often eventually die as a result of the infection). The interferon binds to target cells and induces an antiviral state. Both DNA and RNA viruses induce interferon but RNA viruses tend to induce higher levels. Double-stranded RNA produced during viral infection may be an important inducing agent. Other stimuli will also cause these interferons to be made: e.g. exogenous doublestranded RNA, lipopolysaccharide, other components of certain bacteria. TYPE II inteferon Interferon-gamma (immune interferon) is produced by certain activated T-cells and NK cells. Interferon-gamma is made in response to antigen (including viral antigens) or mitogen

stimulation of lymphocytes.

INTERFERON-alpha AND INTERFERON-beta (TYPE I INTERFERONS) These interferons induce about 20-30 proteins, and the function of many of these is not fully understood. However, three of the proteins that appear to play an important role in the induction of the anti-viral state have been intensively studied. Expression of one of these proteins (25 oligo A synthase) results in activation of the second of these proteins (a ribonuclease) which can break down mRNA, and expression of the third protein (a protein kinase) results in inhibition of the initiation step of protein synthesis. These activities target viral protein synthesis, but also result in inhibition of host protein synthesis. Thus it is important that these proteins are only made and activated when needed. Effects of interferon Interferon treatment induces the synthesis of the inactive form of these proteins in the target cell. Double-stranded RNA is needed for activation of these proteins. It directly activates 25 oligo A synthase and protein kinase R, and indirectly activates ribonuclease L (since this needs 2'5'oligo A, the product of 25 oligo A synthase, for activation). Thus, these potentially toxic pathways are only activated in the interferon-treated cell if double-stranded RNA is made, this will usually only happen if virus infection actually occurs. The activation of these proteins may sometimes result in the death of the cell, but at least the progress of the infection is prevented.

OTHER EFFECTS OF INTERFERONS The pathway described above is by no means the only way that interferons protect cells against viruses and other pathogens. All three interferons increase expression of class I MHC molecules and thus promote recognition by cytotoxic T cells. All three interferons can activate NK cells which can then kill virus-infected cells. Interferon-gamma increases expression of class II MHC molecules on antigen-presenting cells and thus promotes presentation of antigens to helper T cells. Interferon-gamma can also activate the ability of macrophages to resist viral infection (intrinsic antiviral activity) and to kill other cells if they are infected (extrinsic antiviral activity). Interferons have many other effects on gene expression, not all of which are understood. THERAPEUTIC USES OF INTERFERONS Interferons-alpha and -beta have been used to treat various viral infections. One currently approved use for various types of interferon-a is in the treatment of certain cases of acute

and chronic hepatitis C and chronic hepatitis B. Interferon-gamma has been used to treat a variety of disease in which macrophage activation might play an important role in recovery, eg. lepromatous leprosy, leishmaniasis, toxoplasmosis. Since interferons have anti-proliferative effects, they have also been used to treat certain tumors such as melanoma and Kaposis sarcoma.

SIDE EFFECTS OF INTERFERONS Common side effects of interferons: fever, malaise, fatigue, muscle pains High levels of interferons can cause kidney, liver, bone marrow and heart toxicity.

VIRAL DEFENSES AGAINST THE NON-SPECIFIC AND SPECIFIC IMMUNE SYSTEMS Not surprisingly, some viruses have developed defenses against the interferon-induced antiviral response and other aspects of the immune defense system. For example, viruses may code for proteins which block interferon binding to cells, inhibit the action of the interferon-induced protein kinase, inhibit NK function, interfere with cell surface expression of MHC, block complement activation, prevent the host cell committing apoptosis, etc.

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Interferon is a complex family of natural proteins induced in response to various stimuli by the host. The gene regulation of interferon synthesis may explain the various effects which are observed during viral, malignant and angiogenic diseases.

Interferon types
There are many types of interferon molecules: Interferon type I (, , , ) is a family of products related to genes situated on chromosome 9. Their biological activity is very diverse: virus inhibition, reduced tumour proliferation, antigen modulation, immuno-modulation. Interferon type II ( ) has other receptors and actions.

Antitumour activity
Interferon has been tested in many different malignant diseases for which some positive effects have been observed :

Melanoma (increase of survival at high dosage), Kidney cancer (10 to 15% response rate), Myeloid chronic leukaemia (response rate in aproximatively 60% of chemoresistant forms),

Kaposi's sarcoma associated with AIDS (with a lymphocyte CD4 level higher than 250/mm3), Hairy cell leukaemia (normalisation of biology).

It is difficult to explain by which mechanism an antitumour effect is observed among certain patients, since there are great heterogeneities between patients themselves, solid tumours generally being less sensitive than liquid tumours. Among the different mechanisms implied in the tumour response, the following are mentioned in literature:

A direct effect on cell proliferation (modulation of STAT signaling), Enzyme induction, particularly for neopterin, Cell differentiation with modifications in reactions to growth factors, Modulation of antigen activities of the tumour surface antigen (particularly for melanoma), Stimulation of Natural Killer Cells, macrophages and dendritic cells, Stimulation of specific cytotoxic T lymphocytes, Stimulation of the production of antitumour immunoglobulins, Activation of other cytokines around the tumour cells (particularly Interleukine 2 or IL-2).

Toxic effects
Acute effects General acute effects are the most commonly observed manifestations: fever, shuddering, headache, muscle pains, nausea, vomiting, diarrhoea. Prolonged hyperthermia, tachycardia, anaemia, moderate neutropenia and/or rashes are also frequently observed. More rarely observed: rhabdomyolysis, sub-acute liver necrosis. Chronic side effects Certain of which are almost constant: anorexia, dysgueusia (perversion of taste), fatigue, depression. Others are rare: weight loss, alopecia, hypothyroidism. And others very exceptional: nephrotic syndrome.

Recombining interferon

For oncology (at least in France) we can use Interferon 2-b with the following indications

Hairy cell leukaemia, Asymptomatic evolutive Kaposi's sarcoma, Chronic Myelogenic leukaemia (in chronic phase), T Cell cutaneous lymphoma, Follicular Non Hodgkin's Lymphoma, Kidney cancer (advanced disease), Malignant melanoma (stage II), Multiple myeloma (after efficient chemotherapy).

The usual dosage varies according the pathology from 1 Million Units to 18 Millions Units, and is generally administered intramuscularly.