http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1438657/pdf/jrsocmed00264-0079.pdf
D A J Tyrrell FRCPath FRS
Division of Communicable Diseases
MRC Clinical Research Centre, Harrow, Middlesex HAI 3UJ
Journal of the Royal Society of Medicine Volume 74 February 1981 145
Interferon - Introduction
Interferon was discovered as a result of study of the phenomenon of virus interference. This
refers to occasions when cells inoculated with one virus, either alive or inactivated, are then
inoculated with a second which is found not to grow because the first virus has induced a state
of 'interference'.
Interferon was discovered by Isaacs & Lindenmann (1957) after years of investigation of the biology of interference. They used chick membranes suspended in a simple medium and infected with influenza viruses, and found that those cells in which interferon was induced with inactivated virus released into the medium a substance which rendered other cells resistant to infection with a live virus.
This mediator of interference they showed to be a protein and not a virus particle and they named it interferon, though subsequent work has shown that there are families of interferons, differing between species and also within an animal according to the cell that makes it: IFNc from virus-challenged blood leukocytes, IFN/3 from fibroblasts, and IFN, immune interferon from transformed lymphocytes.
At present there are numerous research groups around the world investigating the biology and
chemistry of interferon, developing large-scale production methods and studying its use in
clinical medicine (Gresser 1979). However, it may be useful at this stage to give a thumbnail
sketch of what has happened between 1957 and the present.
The original discovery was reported in 1957 and, not long after, it was suggested that
interferon might be used as an antiviral drug; however, it was soon found that chicken
interferon had no effect on human cells and that interferon for clinical use would have to
come from human or monkey cells.
A Scientific Committee on Interferon was set up, with participants from the Medical Research Council and three pharmaceutical research laboratories. At first, although Isaacs was a skilled experimenter as well as an imaginative investigator, this enterprise was not highly regarded: some doubted whether interferon really existed and others that it would ever be produced in useful amounts, particularly when the first batches of monkey interferon were found to protect the human skin but not the respiratory tract.
The Committee continued to operate, however, and meetings often comprised seminars or
discussion groups exchanging and arguing about the latest research on the nature of
interferon and its action, or its production and purification. This was wise because further
advances depended on the application of biological data.
It was then discovered that double-stranded RNA and similar molecules, such as poly I: C,
stimulated interferon production. This led to the idea of giving interferon inducers instead of
preformed interferon, and consequently inhibited work on interferon production for a while.
Only gradually, as no way round the toxicity of poly I: C was found, did enthusiasm wane.
We must all be grateful that in Helsinki, and through the 1970s, Cantell steadily improved the
production of leukocyte interferon (IFNox) from buffy coats provided by the Finnish Red
Cross. With this interferon most of the clinical trials done so far were performed. In particular, because the amounts of interferon produced steadily increased, it was eventually possible to do trials showing that typical virus infections of man could be prevented or treated: for example, the studies at the Common Cold Unit on rhinovirus infections, and at Stanford University on varicella and zoster in patients immunosuppressed by disease and treatment.
Also during the 1970s the first results emerged of the studies of osteogenic sarcoma in Sweden, Which seemed to show that recurrence of the disease after primary treatment was less in patients given regular intramuscular interferon. These trials could be criticized and were, but they emphasized the importance of experimental work on the wide-ranging effects of interferon.
In particular Gresser, in Paris, showed how tumours of mice, not caused by viruses, might be inhibited by a direct reduction of the rate of growth of the cells, or more likely by effects on the host defence mechanism. There was widespread work showing that interferon could modulate the immune system, particularly by an effect on T lymphocytes, but also stimulated other systems, such as natural killer (NK) cells.
In fact, it became clear that interferon is one of the lymphokines responsible for regulation of cellular responses. Reference has not been made to the long-continued studies on the biochemistry of interferon, which has recently shown in some detail how the synthesis of viral protein is impaired without general danger to the cell.
It is interesting, though, that the interest in dsRNA and the way interferon synthesis might be regulated led to the development of large scale production of human fibroblast interferon (IFNJ). The clinical potential of this is only now being evaluated.
The first efforts to purify interferon began immediately after 1957 and were carried on in
many laboratories using chicken, mouse and human interferon.
In the last few years, almost exactly twenty years later, success has been achieved, and with modern technology the very small amounts available have been used to obtain preliminary evidence on the amino acid sequence of the molecule. DNA for interferon has now been cloned into bacteria and sequenced (Mantei et al. 1980, Taniguchi et al. 1980) and the amino acid sequences deduced from that are now being checked.
Furthermore, human interferon has now been produced in bacteria and we can expect useful amounts for clinical study to become available in the next few years. Once this technique is developed we shall not be constrained by lack of material for either research or clinical use.
Thus there has been an explosion of knowledge about the chemical and molecular basis of
the interferons, but there is still much more to be learned in this field and in the biological
significance and clinical application of these substances. An exciting period lies ahead.
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References
Gresser I ed (1979) Interferon 1, 1979. Academic Press, London
Isaacs A & Lindemann J (1957) Proceedings of the Royal Society B 147, 258-267
Mantei N, Schwarzstein M, Streuli M, Panem S, Nagata S & Weissmann C (1980) Gene 10, 1-10
Taniguchi T, Ohno S, Fujii-Kuriyama Y & Maramatsu M (1980) Gene 10, 11-15
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