Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Opinion
  • Published:

A road less travelled: large animal models in immunological research

Nature Reviews Immunology volume 3, pages 79–84 (2003)Cite this article

Abstract

The main advances in immunology have been forged or underpinned by animal experiments. However, animal research now focuses excessively on one laboratory species, and there is too much redundant repetition and too few transfers from basic discovery to successful clinical application. These features can be improved markedly by placing more emphasis on biological relevance when evaluating animal models and by taking greater advantage of the unique experimental opportunities that are offered by large animals.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: A diagram showing how lymphatic cannulation can be used to sample cells and serum components that participate in regional immune responses.
Figure 2: Schematic representation of surgically created 'intestinal segments' and 'loops'.
Figure 3: The capacity to clone elite individuals enhances the experimental utility of large animal models.

Similar content being viewed by others

References

  1. Tang, D. -C., DeVit, M. & Johnston, S. A. Genetic immunisation is a simple method for eliciting an immune response. Nature 356, 152–154 (1992).

    Article  CAS  Google Scholar 

  2. MacGregor, R. R. et al. First human trial of a DNA-based vaccine for treatment of human immunodeficiency virus type 1 infection: safety and host response. J. Infect. Dis. 178, 92–100 (1998).

    Article  CAS  Google Scholar 

  3. Robinson, H. L. New hope for an AIDS vaccine. Nature Rev. Immunol. 2, 239–250 (2002).

    Article  CAS  Google Scholar 

  4. Babiuk, L. A., Babiuk, S. L., Loehr, B. I. & van Drunnen Littel-van den Hurk, S. Nucleic acid vaccines: research tool or commercial reality. Vet. Immunol. Immunopathol. 76, 1–23 (2000).

    Article  CAS  Google Scholar 

  5. Eynon, E. E. & Flavell, R. A. Walking through the forest of transgenic models of human disease. Immunol. Rev. 169, 5–10 (1999).

    Article  CAS  Google Scholar 

  6. Billingham, R. E., Brent, L. & Medawar, P. B. 'Actively acquired tolerance' of foreign cells. Nature 172, 603–606 (1953).

    Article  CAS  Google Scholar 

  7. Griebel, P. J. & Hein, W. R. Expanding the role of Peyer's patches in B-cell ontogeny. Immunol. Today 17, 30–38 (1996).

    Article  CAS  Google Scholar 

  8. Mutwiri, G., Bateman, C., Baca-Estrada, M. E., Snider, M. & Griebel, P. J. Immunocompetence of gut-associated lymphoid tissue in newborn lambs. Vaccine 19, 1284–1293 (2000).

    Article  CAS  Google Scholar 

  9. Meeusen, E. N., Bishof, R. J. & Lee, C. S. Comparative T-cell responses during pregnancy in large animals and humans. Am. J. Reprod. Immunol. 46, 169–179 (2001).

    Article  CAS  Google Scholar 

  10. Swasdipan, S., McGowan, M., Phillips, N. & Bielefeldt-Ohmann, H. Pathogenesis of transplacental virus infection: pestivirus replication in the placenta and fetus following respiratory infection. Microb. Pathog. 32, 49–60 (2002).

    Article  CAS  Google Scholar 

  11. Hecht, S. J., Stedman, K. E., Carlson, J. O. & DeMartini, J. C. Distribution of endogenous type B and type D sheep retrovirus sequences in ungulates and other mammals. Proc. Natl Acad. Sci. USA 93, 3297–3302 (1996).

    Article  CAS  Google Scholar 

  12. Gerdts, V., Babiuk, L. A., van Drunen Littel-van den Hurk, S. & Griebel, P. J. Fetal immunization by a DNA vaccine delivered into the oral cavity. Nature Med. 6, 929–932 (2000).

    Article  CAS  Google Scholar 

  13. Gerdts, V., Snider, M., Brownlie, R., Babiuk, L. A. & Griebel, P. J. Oral DNA vaccination in utero induces mucosal immunity and immune memory in the neonate. J. Immunol. 168, 1877–1885 (2002).

    Article  CAS  Google Scholar 

  14. Hein, W. R. Sheep as experimental animals for immunological research. The Immunologist 3, 12–18 (1995).

    Google Scholar 

  15. Pirenne, J. Contribution of large animal models to the development of clinical intestinal transplantation. Acta Gastroenterol. Belg. 62, 221–225 (1999).

    CAS  PubMed  Google Scholar 

  16. Goodman, S. & Check, E. Animal experiments: the great primate debate. Nature 417, 684–687 (2002).

    Article  CAS  Google Scholar 

  17. Tran, N. D. et al. In utero transfer and expression of exogenous genes in sheep. Exp. Hematol. 28, 17–30 (2000).

    Article  CAS  Google Scholar 

  18. Tsai, E. J. et al. Retroviral transduction of IL2RG into CD34+ cells from X-linked severe combined immunodeficiency patients permits human T- and B-cell development in sheep chimeras. Blood 100, 72–79 (2002).

    Article  CAS  Google Scholar 

  19. Lewis, I. D. et al. Umbilical cord blood cells capable of engrafting in primary, secondary, and tertiary xenogeneic hosts are preserved after ex vivo culture in a noncontact system. Blood 97, 3441–3449 (2001).

    Article  CAS  Google Scholar 

  20. Costa, C. et al. Transgenic pigs designed to express human CD59 and H-transferase to avoid humoral xenograft rejection. Xenotransplantation 9, 45–57 (2002).

    Article  Google Scholar 

  21. Luo, Y. et al. HDAF transgenic pig livers are protected from hyperacute rejection during ex vivo perfusion with human blood. Xenotransplantation 9, 36–44 (2002).

    Article  Google Scholar 

  22. Fogg, M. H., Parsons, K. R., Thomas, L. H. & Taylor, G. Identification of CD4+ T-cell epitopes on the fusion (F) and attachment (G) proteins of bovine respiratory syncytial virus (BRSV). Vaccine 19, 3226–3240 (2001).

    Article  CAS  Google Scholar 

  23. Karol, M. H. Animal models of occupational asthma. Eur. Respir. J. 7, 555–568 (1994).

    Article  CAS  Google Scholar 

  24. Bice, D. E., Seagrave, J. & Green, F. H. Animal models of asthma: potential usefulness for studying health effects of inhaled particles. Inhal. Toxicol. 12, 829–862 (2000).

    Article  CAS  Google Scholar 

  25. Buddle, B. M. Vaccination of cattle against Mycobacterium bovis. Tuberculosis 81, 125–132 (2001).

    Article  CAS  Google Scholar 

  26. Orme, I. M. Immunology and vaccinology of tuberculosis: can lessons from the mouse be applied to the cow? Tuberculosis 81, 109–113 (2001).

    Article  CAS  Google Scholar 

  27. Buddle, B. M., Wards, B. J., Aldwell, F. E., Collins, D. M. & de Lisle, G. W. Influence of sensitisation to environmental mycobacteria on subsequent vaccination against bovine tuberculosis. Vaccine 20, 1126–1133 (2002).

    Article  Google Scholar 

  28. Fine, P. E. M. Variation in protection by BCG: implications of and for heterologous immunity. Lancet 346, 1339–1345 (1995).

    Article  CAS  Google Scholar 

  29. Heggebo, R., Press, C. M., Gunnes, G., Gonzalez, L. & Jeffrey, M. Distribution and accumulation of PrP in gut-associated and peripheral lymphoid tissue of scrapie-affected Suffolk sheep. J. Gen. Virol. 83, 479–489 (2002).

    Article  CAS  Google Scholar 

  30. Bauer, S. et al. Human TLR9 confers responsiveness to bacterial DNA via species-specific CpG motif recognition. Proc. Natl Acad. Sci. USA 98, 9237–9242 (2001).

    Article  CAS  Google Scholar 

  31. Rankin, R. et al. Identification of a stimulatory CpG motif for veterinary and laboratory species demonstrates that sequence recognition is highly conserved. Antisense Nucleic Acid Drug Dev. 11, 333–340 (2001).

    Article  CAS  Google Scholar 

  32. Ceretti, D. P. et al. The murine homologue of the human interleukin-8 type receptor type-B maps near the Ity-Lsh-Bcg disease resistance locus. Genomics 18, 410–413 (1993).

    Article  Google Scholar 

  33. Pastoret, P. -P., Griebel, P., Bazin, H. & Govaerts, A. (eds) Handbook of Vertebrate Immunology (Academic Press, London, 1998).

    Google Scholar 

  34. Li, F., Zhang, X. & Gordon, J. R. CXCL8((3-73))K11R/G31P antagonizes ligand binding to the neutrophil CXCR1 and CXCR2 receptors and cellular responses to CXCL8/IL-8. Biochem. Biophys. Res. Commun. 293, 939–944 (2002).

    Article  CAS  Google Scholar 

  35. Brayden, D. J. Oral vaccination in man using antigens in particles: current status. Eur. J. Pharm. Sci. 14, 183–189 (2001).

    Article  CAS  Google Scholar 

  36. Gerdts, V. et al. Multiple intestinal 'loops' provide an in vivo model to analyze mucosal immune responses. J. Immunol. Methods 256, 19–33 (2001).

    Article  CAS  Google Scholar 

  37. Mutwiri, G. et al. Induction of mucosal immune responses following enteric immunisation with antigen delivered in alginate microspheres. Vet. Immunol. Immunopathol. 87, 269–276 (2002).

    Article  CAS  Google Scholar 

  38. Hammond, S. A., Guebre-Xabier, M., Yu, J. & Glenn, G. M. Transcutaneous immunization: an emerging route of immunization and potent immunostimulation strategy. Crit. Rev. Ther. Drug Carrier Syst. 18, 503–526 (2001).

    Article  CAS  Google Scholar 

  39. Glenn, G. M. et al. Transcutaneous immunization: a human vaccine delivery strategy using a patch. Nature Med. 6, 1403–1406 (2000).

    Article  CAS  Google Scholar 

  40. Hammond, S. A. et al. Transcutaneous immunisation of domestic animals: opportunities and challenges. Adv. Drug Delivery Rev. 43, 45–55 (2000).

    Article  CAS  Google Scholar 

  41. Lunney, J. K., Fossum, C., Alm, G. V., Steinbach, F. & Wattrang, E. Veterinary immunology: opportunities and challenges. Trends Immunol. 23, 4–6 (2002).

    Article  CAS  Google Scholar 

  42. Hein, W. R. & Mackay, C. R. Prominence of γδ T cells in the ruminant immune system. Immunol. Today 12, 30–34 (1991).

    Article  CAS  Google Scholar 

  43. Zuckermann, F. A. Extrathymic CD4/CD8 double positive T cells. Vet. Immunol. Immunopathol. 72, 55–66 (1999).

    Article  CAS  Google Scholar 

  44. Binns, R. M. & Pabst, R. Lymphoid tissue structure and lymphocyte trafficking in the pig. Vet. Immunol. Immunopathol. 43, 79–87 (1994).

    Article  CAS  Google Scholar 

  45. Check, E. Priorities for genome sequencing leave macaques out in the cold. Nature 417, 473–474 (2002).

    Article  CAS  Google Scholar 

  46. Tatlow, D., Brownlie, R., Babiuk, L. A. & Griebel. P. Differential display analysis of gene expression during the induction of mucosal immunity. Immunogenetics 52, 73–80 (2000).

    Article  CAS  Google Scholar 

  47. Campbell, K. H., McWhir, J., Ritchie, W. A. & Wilmut, I. Sheep cloned by nuclear transfer from a cultured cell. Nature 380, 64–66 (1996).

    Article  CAS  Google Scholar 

  48. Dinnyes, A., De Sousa, P., King, T. & Wilmut, I. Somatic cell nuclear transfer: recent progress and challenges. Cloning Stem Cells 4, 81–90 (2002).

    Article  CAS  Google Scholar 

  49. Campbell, K. H. Transgenic sheep from cultured cells. Methods Mol. Biol. 180, 289–301 (2002).

    PubMed  Google Scholar 

  50. Denning, C. et al. Deletion of the α(1,3)galactosyl transferase (GGTA1) gene and the prion protein (PrP) gene in sheep. Nature Biotechnol. 19, 559–562 (2001).

    Article  CAS  Google Scholar 

  51. Zinkernagel, R. M. What is missing in immunology to understand immunity? Nature Immunol. 1, 181–185 (2001).

    Article  Google Scholar 

  52. Marozin, S. et al. Antigenic and genetic diversity among swine influenza A H1N1 and H1N2 viruses in Europe. J. Gen. Virol. 83, 735–745 (2002).

    Article  CAS  Google Scholar 

  53. Olsen, C. W. DNA vaccination against influenza viruses: a review with emphasis on equine and swine influenza. Vet. Microbiol. 22, 149–164 (2000).

    Article  Google Scholar 

  54. Griffin, J. F., Chinn, D. N., Rodgers, C. R. & Mackintosh, C. G. Optimal models to evaluate the protective efficacy of tuberculosis vaccines. Tuberculosis 81, 133–139 (2001).

    Article  CAS  Google Scholar 

  55. Bradley, R. Bovine spongiform encephalopathy and its relationship to the new variant form of Creutzfeldt–Jakob disease. Contrib. Microbiol. 7, 105–144 (2001).

    Article  CAS  Google Scholar 

  56. Shanahan, F. Crohn's disease. Lancet 359, 62–69 (2002).

    Article  CAS  Google Scholar 

  57. Lefebvre, L. et al. Oncoviral leukaemia virus G4 and human T-cell leukaemia virus type 1 p13(II) accessory proteins interact with farnesyl pyrophosphate synthetase. J. Virol. 76, 1400–1414 (2002).

    Article  CAS  Google Scholar 

  58. Abraham, W. M. et al. A small-molecule tight-binding inhibitor of the integrin α4β1 blocks antigen-induced airway responses and inflammation in experimental asthma in sheep. Am. J. Respir. Crit. Care Med. 162, 603–611 (2000).

    Article  CAS  Google Scholar 

  59. Yuan, L. & Saif, L. J. Induction of mucosal immune responses and protection against enteric viruses: rotavirus infection of gnotobiotic pigs as a model. Vet. Immunol. Immunopathol. 87, 147–160 ( 2002).

    Article  CAS  Google Scholar 

  60. Ijaz, M. K. et al. Inhibition of rotavirus infection in vitro and in vivo by a synthetic peptide from VP4. Vaccine 16, 916–920 (1998).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank A. Pernthaner, B. Buddle, H. Townsend, V. Gerdts and P. Atkinson for constructive comments and suggestions during the preparation of this manuscript.

Author information

Authors and Affiliations

  1. AgResearch Limited, Wallaceville Animal Research Centre, Ward Street, PO Box 40063, Upper Hutt, New Zealand

    Wayne R. Hein

  2. the Veterinary Infectious Disease Organization, 120 Veterinary Road, Saskatoon, S7N 5E3, Saskatchewan, Canada

    Philip J. Griebel

Authors
  1. Wayne R. Hein
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Philip J. Griebel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wayne R. Hein.

Related links

Related links

DATABASES

LocusLink

IL-8

TLR9

FURTHER INFORMATION

Celentis

National Center for Biotechnology Information

National Human Genome Research Institute

World Health Organisation

Glossary

CLOSED ANALYSIS OF GENE EXPRESSION

An analysis in which the number and identity of genes that can be detected is predetermined by the probe set used for detection, such as microarray hybridization.

CpG MOTIFS

Unmethylated CpG dinucleotides flanked by specific nucleotide sequences that can bind to TLR9 or other surface receptors and activate various immune cells (B cells, monocytes, macrophages and dendritic cells). The flanking nucleotide sequences that confer optimal immunostimulatory activity to CpG dinucleotides vary between species. These motifs are known also as CpG-oligodeoxynucleotides (CpG-ODNs).

DIFFERENTIAL DISPLAY

A method that is used to identify genes that are expressed differentially by different sets of cells. Messenger RNA species are amplified by polymerase chain reaction using sets of degenerate primers, resolved by denaturing polyacrylamide gel electrophoresis and cloned as complementary DNA.

EST DATABASE

An annotated collection of ESTs (expressed sequence tags). ESTs are pieces of RNA of varying length isolated from cells and cloned as cDNA. The template RNA might be transcribed from either the coding or non-coding parts of the genome, and the relative abundance of a particular EST is a measure of transcriptional activity.

MICROARRAY HYBRIDIZATION

A procedure in which the messenger RNA isolated from cells is labelled and hybridized to a large number of nucleic-acid probes — complementary DNA or oligonucleotides — that are printed as arrays of small spots on a solid surface that is usually similar in size to a microscope slide.

OPEN ANALYSIS OF GENE EXPRESSION

An analysis in which there is no constraint on the number or identity of genes that can be detected, such as differential display or subtracted cDNA libraries.

SOMATIC CLONING

A procedure in which the nucleus from a differentiated cell is transferred to the cytoplasm of an oocyte from which the pronucleus has been removed. The genome of the transferred nucleus directs the future development of the cloned individual.

SUBTRACTED cDNA LIBRARY

A collection of complementary DNA clones corresponding to the messenger RNA species that are present in one cell or tissue type and that are not present in another type.

TOLL-LIKE RECEPTORS

(TLRs). A diverse family of type 1 transmembrane proteins, the extracellular domains of which contain leucine-rich repeat motifs. The cytoplasmic domains of TLRs are structurally similar to the mammalian interleukin-1 receptor family. TLRs are important in innate immune recognition — their ligands include a range of molecules that are found only in prokaryotes.

ZOONOTIC DISEASE

An infectious disease that is transferred from animals to humans.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hein, W., Griebel, P. A road less travelled: large animal models in immunological research. Nat Rev Immunol 3, 79–84 (2003). https://doi.org/10.1038/nri977

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri977

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing