The ethics of research involving animals - Nuffield Council on ...
The ethics of research involving animals - Nuffield Council on ...
The ethics of research involving animals - Nuffield Council on ...
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T h e e t h i c s o f r e s e a r c h i n v o l v i n g a n i m a l s<br />
(TNFα). 6 Enhanced TNF producti<strong>on</strong> in the affected joints results in release <str<strong>on</strong>g>of</str<strong>on</strong>g> other cytokines<br />
and <str<strong>on</strong>g>of</str<strong>on</strong>g> growth factors that cause abnormal growth <str<strong>on</strong>g>of</str<strong>on</strong>g> new blood vessels, increased blood<br />
flow and destructi<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> cartilage. Once the crucial role <str<strong>on</strong>g>of</str<strong>on</strong>g> TNF became clear, it was proposed<br />
that neutralising TNF or switching <str<strong>on</strong>g>of</str<strong>on</strong>g>f its producti<strong>on</strong> in the joint might reverse joint<br />
inflammati<strong>on</strong>. Researchers were able to test the usefulness <str<strong>on</strong>g>of</str<strong>on</strong>g> neutralising TNF with anti-TNF<br />
antibodies, 7 both in in vitro studies with human joint tissue and in an arthritis model in<br />
rodents. In both cases, the antibodies reduced inflammati<strong>on</strong> in joint tissue by binding<br />
specifically to the TNF molecules. 8 Thus, <str<strong>on</strong>g>research</str<strong>on</strong>g>ers used in vivo studies <str<strong>on</strong>g>of</str<strong>on</strong>g> rodent arthritis<br />
models to complement in vitro studies <str<strong>on</strong>g>of</str<strong>on</strong>g> human RA joint tissue to understand the<br />
pathogenesis <str<strong>on</strong>g>of</str<strong>on</strong>g> immune arthritis.<br />
<str<strong>on</strong>g>The</str<strong>on</strong>g> rodent model for arthritis<br />
6.7 <str<strong>on</strong>g>The</str<strong>on</strong>g> rodent arthritis model is produced by the injecti<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> bovine or chicken collagen, 9<br />
together with a chemical that increases the resulting immune reacti<strong>on</strong>, into inbred strains <str<strong>on</strong>g>of</str<strong>on</strong>g><br />
mice or rats. Swollen joints and arthritis appear within 20–40 days. Although collageninduced<br />
arthritis in the mouse does not exactly mimic RA in humans, it has a number <str<strong>on</strong>g>of</str<strong>on</strong>g><br />
similarities. For example, the model allowed the primary role <str<strong>on</strong>g>of</str<strong>on</strong>g> TNF in joint inflammati<strong>on</strong><br />
to be examined, as it is comm<strong>on</strong> to both forms <str<strong>on</strong>g>of</str<strong>on</strong>g> arthritis. <str<strong>on</strong>g>The</str<strong>on</strong>g> mouse model for arthritis<br />
played a significant role in the development <str<strong>on</strong>g>of</str<strong>on</strong>g> the current and successful therapeutic<br />
interventi<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> blocking TNF to alleviate RA in humans.<br />
6.8 Once arthritis develops, a painful swelling <str<strong>on</strong>g>of</str<strong>on</strong>g> the paws occurs, accompanied by erosi<strong>on</strong>s <str<strong>on</strong>g>of</str<strong>on</strong>g><br />
the joint cartilage. In humans, painful swelling is accompanied by pain in the extremities.<br />
Similar effects resulting from the inflammati<strong>on</strong> occur in mice, which may affect the welfare<br />
<str<strong>on</strong>g>of</str<strong>on</strong>g> the animal c<strong>on</strong>siderably since rodents use their fr<strong>on</strong>t feet extensively for grooming,<br />
holding food, eating and moving around. Severely affected <str<strong>on</strong>g>animals</str<strong>on</strong>g> are usually euthanised<br />
before the end <str<strong>on</strong>g>of</str<strong>on</strong>g> the experiments.<br />
Human clinical trials<br />
6.9 It had been dem<strong>on</strong>strated in vitro that antibodies against TNF (anti-TNF) reduced the<br />
producti<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> other cytokines involved in the inflammatory resp<strong>on</strong>se. 10 Subsequent<br />
animal experiments established that anti-TNF could be used to reduce the symptoms <str<strong>on</strong>g>of</str<strong>on</strong>g><br />
inflammatory joint disease without seriously impairing the functi<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> other tissues and<br />
organs. Clinical trials to assess the effect <str<strong>on</strong>g>of</str<strong>on</strong>g> anti-TNF reagents in humans began in 1992.<br />
Infliximab, a m<strong>on</strong>ocl<strong>on</strong>al antibody against human TNF, was used in a series <str<strong>on</strong>g>of</str<strong>on</strong>g> trials in<br />
patients to test the safety, efficacy and pharmocokinetics <str<strong>on</strong>g>of</str<strong>on</strong>g> anti-TNF therapy. <str<strong>on</strong>g>The</str<strong>on</strong>g><br />
therapeutic dose used for the human trials was based <strong>on</strong> the mouse studies. 11 <str<strong>on</strong>g>The</str<strong>on</strong>g> clinical<br />
results in RA patients treated with infliximab dem<strong>on</strong>strated substantial benefits: patients<br />
reported alleviati<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> symptoms such as swelling, pain, stiffness, tiredness and lethargy<br />
CHAPTER 6 THE USE OF ANIMALS IN THE STUDY OF HUMAN DISEASE<br />
6 <str<strong>on</strong>g>The</str<strong>on</strong>g> abnormal synthesis <str<strong>on</strong>g>of</str<strong>on</strong>g> TNF by cells invading the joint capsule amplifies the inflammatory cell cascade, triggering the release<br />
<str<strong>on</strong>g>of</str<strong>on</strong>g> other inflammatory cytokines which cause tissue damage when present in excess.<br />
7 Anti-TNF antibodies bind specifically to TNF molecules. For a descripti<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> the functi<strong>on</strong> <str<strong>on</strong>g>of</str<strong>on</strong>g> antibodies, see paragraphs 5.24-5.25.<br />
8 Williams RO, Feldmann M and Maini RN (1992) Anti-tumor necrosis factor ameliorates joint disease in murine collagen-induced<br />
arthritis Proc Natl Acad Sci USA 89: 9784–8. For a review and references to simultaneous work, see Vilcek and Feldmann M<br />
(2004) Historical review: cytokines as therapeutics and targets <str<strong>on</strong>g>of</str<strong>on</strong>g> therapeutics Trends Pharmacol Sci 25: 201–9.<br />
9 Collagen is a tough, fibrous protein that forms a major comp<strong>on</strong>ent <str<strong>on</strong>g>of</str<strong>on</strong>g> skin, tend<strong>on</strong>s, b<strong>on</strong>es, cartilage and other c<strong>on</strong>nective<br />
tissues. It helps to hold cells and tissues together.<br />
10 Brennan FM, Chantry D, Jacks<strong>on</strong> A, Maini R and Feldmann M (1989) Inhibitory effect <str<strong>on</strong>g>of</str<strong>on</strong>g> TNF alpha antibodies <strong>on</strong> synovial cell<br />
interleukin-1 producti<strong>on</strong> in rheumatoid arthritis Lancet 2: 244–7.<br />
11 Vilcek and Feldmann M (2004) Historical review: cytokines as therapeutics and targets <str<strong>on</strong>g>of</str<strong>on</strong>g> therapeutics Trends Pharmacol Sci 25:<br />
201–9.<br />
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