Title:
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The fate and effects of a naturally-occurring double-stranded RNA in mice
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Interferons are a group of inducible proteins with antiviral,
anticancer and immunomodulatory activities. Difficulties involved in
the production and purification of large quantities of interferon
prevented their clinical use in man, and prompted investigations into
the possible use of interferon inducers in man. The advent of DNA
recombinant technology has largely overcome this problem with large
quantities of pure recombinant interferon now being available,
however, the successful use of these recombinant interferons in man
will be delayed until the biological properties of each type of
interferon are unravelled. The use of interferon inducers in man
therefore could have practical advantages over the use of preparations
of exogenous interferon.
A naturally occurring ds RNA isolated and purified from a
mycophage grown in Penicillium chrysoqenum has been shown to be a
potent inducer of interferon. In view of the possible therapeutic use
of ds RNA, toxicity studies were carried out with ds RNA in mice.
Toxic side effects of ds RNA treatment include a reduction in
nucleated bone marrow cell numbers and circulating lymphocyte numbers,
a loss of lymphocytes from the thymus and severe mucosal damage to the
ileum. Possible mechanisms of ds RNA induced toxicity are discussed.
A more detailed investigation into the effect of ds RNA on
mouse bone marrow indicated that ds RNA was toxic to both the stem
cell population and the maturing/mature population of the bone marrow
following administration to mice. Interferon was found to be toxic tog administration to mice.
Interferon was found to be toxic to
haemopoietic stem cells when incubated i£ vitro with mouse bone marrow
cells, however, incubation of ds RNA with mouse bone marrow cells in
vitro had no effect on stem cell numbers. DNA, RNA and protein
synthesis in mouse bone marrow cells were similarly unaffected
following in vitro incubation with ds RNA.
Entrapment of ds RNA within liposomes was examined as a
possible means of reducing ds RNA induced toxicity. It was also
believed that liposome entrapment of ds RNA might result in enhanced
interferon production. Unfortunately, entrapment of ds RNA within
liposomes neither reduced ds RNA toxicity nor enhanced interferon
production.
The effect of ds RNA on non-specific immunity in the mouse
was studied. Double-stranded RNA treatment of mice resulted in
enhanced natural killer activity and enhanced phagocytic function of
the reticuloendothelial system (RES). Possible mechanisms are
discussed.
The distribution and fate of i.p. administered free and
liposome-entrapped ds RNA was studied in the mouse. Both free and
liposome-entrapped ds RNA became localised in the liver and spleen,
although proportionally more ds RNA was found in these organs when
administered within liposomes. Double-stranded RNA was rapidly
degraded in the liver, spleen, kidneys, lungs and heart, whilst
degradation occurred at a much slower rate in the bone marrow, thymus
and ileum. These organs were most affected by ds RNA treatment of
mice, indicating an assocation between ds RNA toxicity and the
persistence of undegraded ds RNA.
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