Macaques used for immune function studies – experiment highlights significant interspecies differences

Trist HM, Tan PS, Wines BD, Ramsland PA, Orlowski E, Stubbs J, Gardiner EE, Pietersz GA, Kent SJ, Stratov I, Burton DR, & Hogarth PM 2014. ‘Polymorphisms and Interspecies Differences of the activating and inhibitory FcγRII of Macaque nemestrina Influence the Binding of Human IgG Subclasses,’ Journal of Immunology, 192: 792-803.

Associated Institutions: The University of Melbourne, CSIRO, The Burnet Institute

The Experiment

Macaques are widely used in research, and pig-tailed macaques (Macaca nemestrina) are used in particular for preclinical evaluation of vaccines (Trist et al. 2014, 792; 800).

This experiment used 3 to 5 year old pig-tailed macaques, sourced from the Australian national Macaque Breeding Facility (Churchill, VIC), in an attempt to investigate interspecies differences between immune function of humans and macaques, in particular relating to Immunoglobulin G(IgG), a type of antibody.

The macaques were first sedated with ketamine, and then whole venous blood was collected from them. Blood of four of the macaques then underwent flow cytometric analysis. Ten of the macaques had their DNA analysed.

In order to analyse key interspecies sequence differences between macaque and human receptors, a molecular model of antibody interaction, using the x-ray structure, was also generated.

The fate of the macaques is not described in the experiment publication.

Results

The experiment publication states that ‘significant structural difference between humans and macaques’ were identified (Trist et al. 2014, 797), including ‘considerable interspecies differences of IgG binding’ (Trist et al. 2014, 799).

The sequence analysis conducted, comparing the macaques with humans, revealed amino aciddifferences between macaques and humans in all animals used, and also identified polymorphic sequence variation even between individual macaques (Trist et al. 2014, 794).

The authors state that their findings have ‘implications for the structural and functional analysis of IgG FcR interactions, not only in M. nemestrina [pig-tailed macaques] but also in the widely used rhesus and cynomolgus macaques and other NHP [non-human primates]‘ (Trist et al. 2014, 800).

The authors conclude that their data ‘highlight that the activities of mAbs designed to alter interactions between human Abs and huFcRs may not be faithfully recapitulated in preclinical studies in nonhuman primates, or at least in macaques‘ (Trist et al. 2014, 801). They also suggest that these differences may apply to viral pathogenesis studies in macaques of human infections, such as dengue or HIV infection (Trist et al. 2014, 801).

Relevance to Humans

There are major anatomical, genetic, dietetic, environmental, toxic, and immune differences between animals – including macaques – and humans(1), making them inappropriate for use in studying human immune function and other human disease. Many studies and systematic reviews show that there is discordance between animal and human studies, and that animal ‘models’ fail to mimic clinical disease adequately(2)(3).

In fact, within the research publication itself, the authors note that ‘clear differences exist between species [macaques and humans]‘, and bring into question ‘the use of NHPs as a model of human immunity or preclinical model for the evaluation of AbFcR interactions’ (Trist et al. 2014, 802).

The authors also state that the ‘interspecies and polymorphic differences we describe in this study may translate to alterations of … outcomes in vivo in NHPs that are distinct from those in humans” and that “differences in cell distribution may also confound the interpretation of in vivo studies of Ab function’ (Trist et al. 2014, 801).

Also of concern is the use of fetal bovine serum in this study. Aside from the cruel nature in which this product is obtained, fbs is a major source of viral contaminants which once present, are almost impossible to remove from cultures. It can contain viruses, prions (a protein that can transform into a rogue agent) and mycoplasma, each of which can skew the outcome of scientific experiments. It can also interfere with genotypic and phenotypic cell stability, which can also influence experimental outcome. Such concerns were raised by researchers themselves at CSIRO back in 2006 during discussion with HRA and suggestions of alternative non-animal mediums were provided.

Funding

The experiment was funded by the National Health and Medical Research Council of Australia (NHMRC) through fellowships and project grants (1002270; $655,074), NHMRC program grant 510448 ($18,744,238.25), and by the Victorian Operational Infrastructure Support Program.

What You Can Do

Please use the form below to encourage the University of Melbourne and CSIRO to cease their use of non-human primates for research. You can use the text provided or compose your own (remember personalised messages carry more weight).

Your message will be sent via email to the Vice-Chancellor of The University of Melbourne, and the CEO of CSIRO.

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References

(1) Pound P, Ebrahim S, Sandercock P, Bracken MB, Roberts I; on behalf of the Reviewing Animal Trials Systematically Group. 2004. ‘Where is the evidence that animal research benefits humans?’, BMJ, 328, 514-7.

(2) Perel P, Roberts I, Sena E, Wheble P, Briscoe C, Sandercock P, et al. 2007. ‘Comparison of treatment effects between animal experiments and clinical trials: systemic review’, BMJ, 334:197.

(3) Van der Worp H, Howells DV, Sena ES, Porritt MJ, Rewell S, O”Collins V, et al. 2010. ‘Can animal models of disease reliably inform human studies?’, PLoS Med.

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