Skip to main content

Advertisement

SpringerLink
Log in

The isolator piglet: a model for studying the development of adaptive immunity

  • Published:
Immunologic Research Aims and scope Submit manuscript

Abstract

The period from late gestation to weaning in neonatal mammals is a critical window when the adaptive immune system develops and replaces the protection temporarily provided by passive immunity and pre-adaptive antibodies. It is also when oral tolerance to dietary antigen and the distinction between commensal and pathogenic gut bacteria becomes established resulting in immune homeostasis. The reproductive biology of swine provides a unique model for distinguishing the effects of different factors on immune development during this critical period because all extrinsic factors are controlled by the experimenter. This chapter reviews this early stage of development and the usefulness of the piglet model for understanding events during this transitional stage. The review also describes the major features of the porcine immune system and the immune stimulatory and dysregulatory factors that act during this period. The value of the model to medical science in such areas as food allergy, organ transplantation, cystic fibrosis and the production of humanized antibodies for immuno-therapy is discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Butler JE, Leone CA. Antigenic changes during the life cycle of the beetle, Tenebrio molitor. Comp Biochem and Physiol 1966;19:699–711.

    CAS  Google Scholar 

  2. Ochsenbein AF, Zinkernagel R. Natural antibodies and complement link innate and acquired immunity. Immunol Today 2000;1:624–30.

    Google Scholar 

  3. Marchalonis JJ, Adelman MK, Schluter SF, Ramsland PA. The antibody repertoire in evolution: Chance, selection and continuity. Devel Comp Immunol 2006;30:223–47.

    CAS  Google Scholar 

  4. Butler JE, Sun J, Weber P, Francis D. Antibody repertoire development in fetal and neonatal piglets. III. Colonization of the gastrointestinal tracts results in preferential diversification of the pre-immune mucosal B-cell repertoire. Immunology (British) 2000;100:119–30.

    CAS  Google Scholar 

  5. Butler JE, Weber P, Sinkora M, Baker D, Schoenherr A, Mayer B, Francis D. Antibody repertoire development in fetal and neonatal piglets. VIII. Colonization is required for newborn piglets to make serum antibodies to T-dependent and type 2 T-independent antigens. J Immunol 2002;169:6822–30.

    PubMed  CAS  Google Scholar 

  6. Butler JE, Francis D, Freeling J, Weber P, Sun J, Krieg AM. Antibody repertoire development in fetal and neonatal piglets. IX. Three PAMPs act synergistically to allow germfree piglets to respond to TI-2 and TD antigens. J Immunol 2005;175:6772–85.

    PubMed  CAS  Google Scholar 

  7. Dighiero GP, Lymberi P, Holmberg D, Lundquist I, Coutinho A, Avrameas S. High frequency of natural autoantibodies in normal mice. J Immunol 1985;134:765–71.

    PubMed  CAS  Google Scholar 

  8. Lopez-Carvalho T, Foote J, Kearney JF. Marginal zone B cells in lymphocyte activation and regulation. Curr Opin Immunol 2005;17:244–50.

    Google Scholar 

  9. Fulton RJ, Nahm MH, Davie JM. Monoclonal antibodies to streptococcal group A carbohydrate. II. The Vk1GAC light chain is preferentially associated with serum IgG3. J Immunol 1983;131:1326–31.

    PubMed  CAS  Google Scholar 

  10. Matzinger P. The danger model: a renewed sense of self. Science 2002;296:301–5.

    PubMed  CAS  Google Scholar 

  11. Bach JF. The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med 2002;347:911–20.

    PubMed  Google Scholar 

  12. Elliott DE, Setiawan T, Metwali A, Blum A, Urban JF Jr, Weinstock JW. Heligmosomoides polygyrus inhibits established colitis in IL-10 deficient mice. Eur J Immunol 2004;34:2690–98.

    PubMed  CAS  Google Scholar 

  13. Butler JE. Immunoglobulins of the mammary secretions. In: Larson BL, Smith V, editors. Lactation a Comprehensive Treatise, Vol. III, Chapter V. New York: Academic Press; 1974. p. 217–55.

  14. Butler JE. Preface: why I agreed to do this. In: (Butler JE, Guest Ed). Antibody repertoire development. Dev Comp Immunol 2006;30:1–17.

  15. Butler JE, Kehrle ME. Immunocytes and immunoglobulins in milk. In: Mestecky J, Lamm ME, Strober W, McGhee JR, Mayer L, Bienenstock J, editors. Mucosal Immunology. 3rd ed. Academic Press, NY; 2005. p. 1763–93.

  16. Butler JE, Sun J, Wertz N, Sinkora M. Antibody repertoire development in swine. Dev Comp Immunol 2006;30:199–221.

    PubMed  CAS  Google Scholar 

  17. Murphy WJ, Eizirik E, Johnson WE, Zhang YP, Ryder OA, Obrien SJ. Molecular phylogenetics and the origins of placental mammals. Nature 2001;409:614–18.

    PubMed  CAS  Google Scholar 

  18. Waddell PJ, Shelley S. Evaluating inter-ordinal phylogenies with novel sequences including RAG1, g-fibrinogen, NDG and mt-tRNA plus MCMC driven nucleotide, amino acid and codon models. Mol Phylogeny and Evol 2003;28:197–224.

    CAS  Google Scholar 

  19. Madsen O, Scally M, Douady CJ. Parallel adaptive radiations in two major clades of placental mammals. Nature 2001;409:610–14.

    PubMed  CAS  Google Scholar 

  20. Lesser TD, Amenuvor JZ, Jensen TK, Lindecrona RH, Boye M, Møller K. Culture-independent analysis of gut bacteria: the pig gastrointestinal tract microbiota revisited. Appl Environ Microbiol 2002;68(2):673–90.

    Google Scholar 

  21. Butler JE. Immunoglobulin gene organization and the mechanism of repertoire development. Scand J Immunol 1997;45:455–62.

    PubMed  CAS  Google Scholar 

  22. Sinkora M, Sinkora J, Rehakova Z, Splichal I, Yang H, Parkhouse RME, Trebichavsky I. Prenatal ontogeny of lymphocyte supoulations in pigs. Immunology 1998;95:595–603.

    PubMed  CAS  Google Scholar 

  23. Yang H, Parkhouse RM. Phenotypic classification of porcine lymphocyte subpopulations in blood and lymphoid tissues. Immunology 1996;89:76–83.

    PubMed  CAS  Google Scholar 

  24. Hein WR, Mackay CR. Prominence of γδ T cells in the ruminant immune system. Immunol Today 1991;12:30–4.

    PubMed  CAS  Google Scholar 

  25. Appleyard GD, Wilkie BN. Characterization of porcine CD5 and CD5+ B cells. Clin Exp Immunol 1998;111:225–30.

    PubMed  CAS  Google Scholar 

  26. Sinkora J, Rehakova Z, Sinkora M, Cukrowska B, Tlaskalova-Hogenova H, Bianchi AT, De Geus B. Expression of CD2 on porcine B lymphocytes. Immunology 1998;95:443–49.

    PubMed  CAS  Google Scholar 

  27. Uenishi H, Hiraiwa H, Yamamoto R, Yasue H, Takagaki Y, Shiina T, Kikkawa E, Inoko H, Awata T. Genomic structure around joining segments and constant regions of swine T-cell receptor αβ (TRA/TRD) locus. Immunology 2003;109:515–26.

    PubMed  CAS  Google Scholar 

  28. Lefranc M-P, Giudicelli V, Kaas Q, Duprat E, Jabado-Michaloud J, Scaviner D, Ginestoux C, Clément O, Chaume D, Lefranc G. IMGT, the international ImMunoGeneTics information system®. Nucl Acids Res 2005;33:D593–97.

    PubMed  CAS  Google Scholar 

  29. Yang YG, Hota S, Yamada S, Shimizu M, Takagaki Y. Diversity of T cell receptor δ-chain cDNA in the thymus of a one-month-old pig. J Immunol 1995;155:1981–93.

    PubMed  CAS  Google Scholar 

  30. Holtmeier W, Geisel W, Bernert K, Butler JE, Sinkora M, Rehakova Z, Sinkora J, Caspary WF. Prenatal development of the porcine TCRδ repertoire: dominant expression of an invariant T cell receptor Vδ3-Jδ3 chain, Eur. J Immunol 2004;34:1941–9.

    CAS  Google Scholar 

  31. Holtmeier W, Käller J, Geisel W, Pabst R, Caspary WF, Rothkötter HJ. Development and compartmentalization of the porcine TCRδ repertoire at mucosal and extraintestinal sites: The pig as a model for analyzing the effect of age and microbial factors. J Immunol 2002;169:1993–2002.

    PubMed  CAS  Google Scholar 

  32. Havran WL, Carbone A, Allison JP. Murine T cells with invariant γδ antigen receptors: origin, repertoire, and specificity. Semin Immunol 1991;3:89–97.

    PubMed  CAS  Google Scholar 

  33. Butler JE, Wertz N, Sun J, Sacco R. Characterization of the porcine Vβ repertoire in thymocytes versus peripheral T-cells. Immunology 2005;114:184–93.

    PubMed  CAS  Google Scholar 

  34. Baron C, Sachs DH, LeGuerin C. A particular TCRβ variable used by T-cells infiltrating kidney transplants. J Immunol 2001;166:2589–96.

    PubMed  CAS  Google Scholar 

  35. Rast JP, Anderson MK, Strong SJ, Luer C, Litman RT, Litman GW. αβγ and δ T-cell antigen receptor genes arose early in vertebrate phylogeny. Immunity 1997;6:1–12.

    PubMed  CAS  Google Scholar 

  36. Marchalonis JJ, Schluter SF, Bernstein RM, Shanxiang S, Edmundson AB. Phylogenetic emergence and molecular evolution of the immunoglobulin family. Adv Immunol 1996;70:417–506.

    Google Scholar 

  37. Zhao Y, Pan-Hammarstrom Q, Yu S, Wertz N, Zhang X, Li N, Butler JE. Hammarstrom L. Identification of IgF, a hinge-region containing Ig class and IgD in Xenopus tropicalis. Proc Natl Acad Sci (USA) 2006;103:12087–92.

    CAS  Google Scholar 

  38. Butler JE, Sinkora M, Wertz N, Holtmeier W, Lemke CD. Development of the neonatal B- and T-cell repertoire in swine: Implications for comparative and veterinary immunology. Vet Res 2006;37:417–41.

    PubMed  CAS  Google Scholar 

  39. Nguyen VK. Generation of heavy chain antibodies in camelids, Ph.D., Thesis, Free University of Brussels 2001. p. 109–11.

  40. Butler JE, Wertz N. Antibody repertoire development in fetal and neonatal piglets. XVII. Fetal IgG subclass transcription re-visited. J Immunol 2006;177:5480–9.

    PubMed  CAS  Google Scholar 

  41. Kehoe JM, Capra JD. Nature and significance of immunoglobulin subclasses. N Y State J Med 1974;74:489–91.

    PubMed  CAS  Google Scholar 

  42. Zhao Y, Pan-Hammarstrom Q, Kacskovics I, Hammarstrom L. The porcine Ig δ gene: Unique chimeric splicing of the first constant region domain in its heavy chain transcripts. J Immunol 2003;171:1312–8.

    PubMed  CAS  Google Scholar 

  43. Brown WR, Kacskovics I, Amendt B, Shinde R, Blackmore N, Rothschild M, Butler JE. The hinge deletion variant of porcine IgA results from a mutation at the splice acceptor site in the first Cα intron. J Immunol 1995;154:3836–42.

    PubMed  CAS  Google Scholar 

  44. Navarro P, Christenson R, Ekhardt G, Lunney JK, Rothschild M, Bosworth B, Lemke J, Butler JE. Genetic differences in the frequency of the hinge variants of porcine IgA is breed dependent. Vet Immunol Immunopath 2000;73:287–95.

    CAS  Google Scholar 

  45. Butler JE, Weber P, Wertz N. Antibody repertoire development in fetal and neonatal pigs. XIII. “Hybrid VH genes” and the pre-immune repertoire revisited. J Immunol 2006;177:5459–70.

    PubMed  CAS  Google Scholar 

  46. Gallarda JL, Gleason KS, Knight KL. Organization of rabbit immunoglobulin genes. I. Structure and multiplicity of germ-line VH genes. J Immunol 1985 135:4222–8.

    PubMed  CAS  Google Scholar 

  47. Butler JE, Sun J, Navarro P. The swine immunoglobulin heavy chain locus has a single JH, no identifiable IgD. Int Immunol 1996;8:1897–904.

    PubMed  CAS  Google Scholar 

  48. Sun J, Hayward C, Shinde R, Christenson R, Ford SP, Butler JE. Antibody repertoire development in fetal and neonatal piglets. I. Four VH genes account for 80% of VH usage during 84 days of fetal life. J Immunol 1998;161:5070–8.

    PubMed  CAS  Google Scholar 

  49. Butler JE, Wertz N, Wang H, Sun J, Chardon P, Piumi F, Wells K. Antibody repertoire in fetal and neonatal pigs. VII. Characterization of the pre-immune kappa light chain repertoire. J Immunol 2004;173:6794–805.

    PubMed  CAS  Google Scholar 

  50. Sinkora M, Sun J, Sinkorova J, Christenson RK, Ford SP, Butler JE. Antibody repertoire development in fetal and neonatal piglets. VI. B-cell lymphogenesis occurs at multiple sites with differences in the frequency of in-frame rearrangements. J Immunol 2003;170:1781–8.

    PubMed  CAS  Google Scholar 

  51. Sinkora M, Sinkora J, Rehakova Z, Butler JE. Early ontogeny of thymocytes in pigs: sequential colonization of the thymus by T cell progenitors. J Immunol 2000;165:1832–9.

    PubMed  CAS  Google Scholar 

  52. Sinkora M, Sun J, Butler JE. Antibody repertoire development in fetal and neonatal piglets. V. VDJ gene chimeras resembling gene conversion products are generated at high frequency by PCR in vitro. Mol Immunol 2000;37:1025–34.

    PubMed  CAS  Google Scholar 

  53. Butler JE, Weber P, Sinkora M, Sun J, Ford SJ, Christenson R. Antibody repertoire development in fetal and neonatal piglets. II. Characterization of heavy chain CDR3 diversity in the developing fetus. J Immunol 2000;165:6999–7011.

    PubMed  CAS  Google Scholar 

  54. Becker RS, Knight KL. Somatic diversification of immunoglobulin heavy chain VDJ genes: Evidence for somatic gene conversion in rabbits. Cell 1990;63:987–97.

    PubMed  CAS  Google Scholar 

  55. Butler JE, Wertz N, Sun J, Wang H, Lemke C, Chardon P, Puimi F, Wells K. The pre-immune variable kappa repertoire of swine is selectively generated from certain subfamilies of Vκ2 and one Jκ gene. Vet Immunol Immunopath 2005;108:127–37.

    CAS  Google Scholar 

  56. Butler JE, Sun J, Weber P, Ford SP, Rehakova Z, Sinkora J, Lager K. Antibody repertoire development in fetal and neonatal piglets. IV. Switch recombination, primarily in fetal thymus occurs independent of environmental antigen and is only weakly associated with repertoire diversification. J Immunol 2001;167:3239–49.

    PubMed  CAS  Google Scholar 

  57. Cukrowska B, Sinkora J, Mandel L, Splichal I, Bianchi ATJ, Kovaru F, Tlaskalova-Hogenova H. Thymic B cells of pig fetuses, germ free pigs spontaneiously produce IgM, IgG and IgA: detection of ELISPOT method. Immunology 1996;87:487–94.

    PubMed  CAS  Google Scholar 

  58. McAleer J, Weber P, Sun J, Butler JE. Antibody repertoire development in fetal and neonatal piglets. XI. The thymic B cell repertoire develops independently from that in blood and mesenteric lymph nodes. Immunology 2005;114:171–83.

    PubMed  CAS  Google Scholar 

  59. Deenick EK, Hasbold J, Hodgkins PD. Switching to IgG3, IgG2b and IgA is division linked and independent revealing a stochastic framework for describing differentiation. J Immunol 1999;163:4707–17.

    PubMed  CAS  Google Scholar 

  60. Sinkora M, Sinkorova J, Cimburek Z, Holtmeier W. Two groups of porcine TCRγδ+ thymocytes behave and diverge differently. J Immunol 2007;178:711–19.

    PubMed  CAS  Google Scholar 

  61. Sinkora M, Sinkorova J, Holtmeier W. Development of γδ thymocyte subsets during prenatal and postnatal ontogeny. Immunology 2005;115:544–55.

    PubMed  CAS  Google Scholar 

  62. Jenne CN, Kennedy LJ, Reynolds JD. Antibody repertoire development in the sheep. Dev Comp Immunol 2006;30:165–74.

    PubMed  CAS  Google Scholar 

  63. Reynaud CA, MacKay CR, Miller RG, Weill JC. Somatic generation of diversity in a mammalian primary lymphoid organ: the sheep ileal Peyers patches. Cell 1991;64:995–1005.

    PubMed  CAS  Google Scholar 

  64. Reynolds JD, Morris B. The evolution and involution of Peyer’s patches in fetal and postnatal sheep, Eur. J Immunol 1983;13:627–35.

    CAS  Google Scholar 

  65. Pabst R, Geist M, Rothkötter HJ, Fritz FJ. Postnatal development and lymphocyte production of jejunal and ileal Peyers patches in normal and gnotobiotic pigs. Immunology 1988;64:539–44.

    PubMed  CAS  Google Scholar 

  66. Hardy RR. B-1 B cell development. J Immunol 2006;177:2749–54.

    PubMed  CAS  Google Scholar 

  67. Snapper CM, Marcu KB, Zelazowski P. The immunoglobulin class switch: beyond “accessibility”. Immunity 1997;6:217–23.

    PubMed  CAS  Google Scholar 

  68. Wostmann BS. Germfree and gnotobiotic animal models. Boca Raton: CRC Press; 1996. p. 19–35.

    Google Scholar 

  69. Kenworthy R, Allen WD. Influence of diet and bacteria on small intestinal morphology with special reference to early weaning and Escherichia coli. Studies with germfree and gnotobiotic pigs. J Comp Path 1966;76:291–6.

    PubMed  CAS  Google Scholar 

  70. Bry L, Falk P, Huttner K, Quellette A, Midtvedt T, Gordon JI. Paneth cell differentiation in the developing intestine of normal and transgenic mice. Proc Natl Acad Sci (USA) 1994;91:10335–9.

    CAS  Google Scholar 

  71. Heneghan JB. Enterocyte kinetics, mucosal surface area and mucus in gnotobiotes. In: Fliedner T et al, editors. Clinical and experimental gnotobiotics. Proceedings of VIth International Symposium on Gnotobiology. NY: Gustav. Fisher, 1979. p. 19–31.

  72. Stokes CR, Miller BG, Bourne FJ. Animal models of food sensitivity. In: Brostoff J, Challacombe SJ, editors. Food allergy and intolerance. London: Bailliere Tindall, 1987. p. 286–300.

  73. Hooper LV, Wong MH, Thelin A, Hanson L, Falk PG, Gordon JI. Molecular analysis of commensal host-microbial relationship in the intestine. Science 2001;29:881–4.

    Google Scholar 

  74. Sudo N, Sawamura SA, Tanaka K, Alba Y, Kulo C, Koga K. The requirement of intestinal flora for the development of an IgE production system fully susceptible to oral tolerance induction. J Immunol 1997;1549:1739–45.

    Google Scholar 

  75. Christen U, van Herrath MG. Infection and autoimmunity-good or bad? J Immunol 2005;174:7481–6.

    PubMed  CAS  Google Scholar 

  76. Wang Y, McCusker CM. Neonatal exposure with LPS and/or allergen prevents experimental airway disease: development of tolerance using environmental antigen. J Allergy Clin Immunol 2006;118:143–51.

    PubMed  CAS  Google Scholar 

  77. Knight KL, Becker RS. Molecular basis of allelic inheritance of rabbit immunoglobulin VH allotypes: Implications for the generation of antibody diversity. Cell 1990;60:963–70.

    PubMed  CAS  Google Scholar 

  78. Reynaud CA, Dahan A, Anquez V, Weill JC. Somatic hyperconversion diversifies the single VH gene of the chicken with a high incidence in the D region. Cell 1989;59:171–83.

    PubMed  CAS  Google Scholar 

  79. Zuckermann FA, Husmann RJ. Functional and phenotypic analysis of porcine peripheral blood CD4/CD8 double-positive T cells. Immunology 1996;87:500–12.

    PubMed  CAS  Google Scholar 

  80. Saalmuller A, Hirt A, Reddehase MJ. Phenotypic discrimination between thymic and extrathymic CD4−CD8− and CD4+CD8+ porcine T lymphocytes. Eur J Immunol 1989;19:2011–6.

    PubMed  CAS  Google Scholar 

  81. Yang H, Parkhouse RME. Differential expression of CD8 epitopes amongst porcine CD8-positive functional lymphocyte subsets. Immunology 1997;92:45–52.

    PubMed  CAS  Google Scholar 

  82. Reddehase MJ, Saalmuller A, Hirt W. γδ T-lymphocyte subsets in swine. Curr Top Microbiol Immunol 1991;173:113–7.

    PubMed  CAS  Google Scholar 

  83. Sinkora J, Rehakova Z, Sinkora M, Cukrowska B, Tlaskalova-Hogenova H. Early development of immune system in pigs. Vet Immunol Immunopathol 2002;87:301–6.

    PubMed  CAS  Google Scholar 

  84. Neumann EJ, Kliebenstein JB, Johnson CD, Mabry JW, Bush EJ, Seitzinger AH, Green AL, Zimmerman JJ. Assessment of the economic impact of porcine reproductive and respiratory syndrome on swine production in the United States. J Am Vet Med Assoc 2005;227:385–92.

    PubMed  Google Scholar 

  85. Lemke CD, Haynes JS, Spaete R, Adolphson D, Vorwald A, Lager K, Butler JE. Lymphoid hyperplasia resulting in immune dysregulation is caused by PRRSV infection in pigs. J Immunol 2004;172:1916–25.

    PubMed  CAS  Google Scholar 

  86. Lemke CD. PRRSV infection of neonatal piglets induces immune dysregulation and modulation. Ph D. Thesis. University of Iowa; 2006.

  87. Butler JE, Lemke CD, Weber P, Sinkora M, Lager KM. Antibody repertoire development in fetal and neonatal piglets. XIX. Undiversified B cells with hydrophobic HCDR3s preferentially proliferate in PRRS. J Immunol 2007;178:6320–31.

    PubMed  CAS  Google Scholar 

  88. Hunziker L, Recher M, Macpherson AJ, Ciurea A, Freigand S, Hengartner H. Hypergammaglobulinemia and autoantibody induction mechanisms in viral infection. Nat Immunol 2003;4:343–9.

    PubMed  CAS  Google Scholar 

  89. Casali P, Schettino EW. Structure and function of natural antibodies. In: Rose N, Potter M, editors. Immunology of silicones. Springer Verlag, 1996. p. 167–79.

  90. Blutt SE, Crawford SE, Warfield KL, Lewis DE, Estes MK, Conner ME. The VP7 outer capsid protein of rotavirus induces polyclonal B-cell activation. J Virol 2004;78:6974–81.

    PubMed  CAS  Google Scholar 

  91. Kim SH, Shin YK, Lee IS, Bae YM, Shon HW, Suh YH, Ree HJ, Rowe M, Park SH. Viral latent membrane protein 1 (LMP-1) induced CD99 down regulation in B cells leads to the generation of cells with Hodgkin’s and Reed-Sternberg phenotype. Blood 2000;95:294–300.

    PubMed  CAS  Google Scholar 

  92. Coutelier J-P, Coulie G, Wauters P, Heremans H, der Logt JT. In vivo polyclonal B-lymphocyte activation elicted by murine viruses. J Virol 1990;64:5383–8.

    PubMed  CAS  Google Scholar 

  93. Stevenson PG, Doherty PC. Non-speecific B cell activation following murine gammaherpesvirus infection is CD4 indepednet in vitro but CD4 dependent in vivo. J Virol 1999;73:1075–9.

    PubMed  CAS  Google Scholar 

  94. Karupiah G, Sacks TE, Klinman DM, Frederickson TN, Hartley JW, Chen JH, Morse HC. Murine cytomegalovirus infection-induced polyclonal B cell activation is independent of CD4+ T cells and CD40. Virology 1998;240:12–26.

    PubMed  CAS  Google Scholar 

  95. Scholtissek C. Pigs as the “mixing vessel” for the creation of new pandemic influenza A viruses. Med Princ Pract 1990;2:65–71.

    Google Scholar 

  96. Patience C, Takeuchi Y, Weiss RA. Infection of human cells by an endogenous retrovirus of pig. Nat Med 1997;3:282–6.

    PubMed  CAS  Google Scholar 

  97. Wood JC, Quinn G, Suling KM, Oldmixon BA, van Tine BA, Cina R, Arn S, Huang CA, Scobie L, Onions DE, Sachs DH, Schuurman H, Fishman JA, Patience C. Identification of exogenous forms of human-tropic porcine endogenous retrovirus in minature swine. J Virol 2004;78:2494–501.

    PubMed  CAS  Google Scholar 

  98. Blusch JH, Patience C, Martin U. Pig endogenous retroviruses and xenotransplantation. Xenotransplantation 2002;9:242–51.

    PubMed  Google Scholar 

  99. Jonsson SR, Hache G, Stenglein MD, Fahrenkrug SC, Andresdottir V, Harris RS. Evolutionarily conserved and non-conserved retrovirus restriction activities of artiodactyl APOBEC3F proteins. Nucleic Acid Res 2006;34:5683–94.

    PubMed  CAS  Google Scholar 

  100. Yuan L, Ward LA, Rosen BI, To TL, Saif LJ. Systemic and intestinal antibody-secreting cell responses and corrletaes of protective immunity to human rotavirus in a gnotobiotic pig model of disease. J Virol 1996;70:3075–83.

    PubMed  CAS  Google Scholar 

  101. Ventor C, Pereira B, Grundy J, Clayton CB, Arshad SH, Dean T. Prevalence of sensitization reported and objectively assessed food hypersensitivity amongst six-year-old children: a population-based study. Pediatr Allergy Immunol 2006;17:356–63.

    Google Scholar 

  102. Allen KJ, Hill DJ, Heine RG. Food allergy in children. MJA Pract Essent 2006;185:394–400.

    Google Scholar 

  103. Kletter B, Gery I, Freier S, Davies AM. Immune responses of normal infants to cow’s milk. I. Antibody type and kinetics of production. Int Archives Allergy Appl Immunol 1971;40:656–66.

    CAS  Google Scholar 

  104. Gunther M, Aschaffenburg R, Matthews RH, Parish WE, Coombs RRA. The level of antibodies to the proteins of cow’s milk in the serum of normal human infeants. Immunology 1960;3:296–306.

    PubMed  CAS  Google Scholar 

  105. Anderson AF, Schloss OM. Allergy to cow’s milk in infants with nutritional disorders. Amer J Dis Children 1923;26:451–74.

    CAS  Google Scholar 

  106. Cunningham-Rundles C, Brandeis W, Good RA, Day NK. Milk precipitins, circulating immune complexes and IgA deficiency. Proc Natl Acad Sci (USA) 1978;75:3387–89.

    CAS  Google Scholar 

  107. Butler JE, Oskig R. Cancer, autoimmunity and IgA-deficiency related by a common antigen-antibody system. Nature (London) 1974;249:830–3.

    CAS  Google Scholar 

  108. Paronen J, Knip M, Savilahti E, Virtanen SM, Ilonen J, Akerblom HS, Vaarala O. Effect of cow’s milk exposure and maternal type 1 diabetes on cellular and humoral immunization to dietary insulin in infants at genetic risk for type 1 diabetes. Diabetes 2000;49:1657–65.

    PubMed  CAS  Google Scholar 

  109. Reeds P, Odle J. Pigs as models for nutrient functional interaction. In: Tumbleson ME, Schook LB, editors. Avd. Swine Biomedical Res. Plenum Press, Vol. 2, 1996. p. 709–12.

  110. Sicherer SH, Munoz-Furlong A, Sampon HA. Prevalence of peanut and tree nut allergy in the United States determined by means of randon digit dial telephone survey: a 5-year follow-up study. J Allergy Clin Immunol 2003;112:1203–7.

    PubMed  Google Scholar 

  111. Fischer R, McGhee JR, Vu HL, Atkinson TP, Jackson RJ, Tome D, Boyaka PN. Oral and nasal sensitization promote distinct immune responses and lung reactivity in a mouse model of peanut allergy. Am J Path 2005;167:1621–30.

    PubMed  CAS  Google Scholar 

  112. Sampson HA, Mendelson L, Rosen JR. Fatal and near-fatl anaphylactic reactions to food in children and adolescents. N Eng J Med 1992;327:380–4.

    Article  CAS  Google Scholar 

  113. Rhee KJ, Sethupathi P, Driks A, Lanning DK, Knight KL. Role of commensal bacteria in development of gut-associated lymphoid tissues and preimmune antibody repertoire. J Immunol 2004;172:1118–24.

    PubMed  CAS  Google Scholar 

  114. Talham GL, Jiang H-Q, Bos NA, Cebra JJ. Segmented filamentous bacteria are potent stimuli of a physiological noram state of the murine gut mucosal immune system. Infect Immun 1990;67:1992–2000.

    Google Scholar 

  115. Adlerberth I, Jahil F, Carlsson B, Mellander L, Hanson LA, Larson P, Khahil K, Wold AE. High orunover rate of Escherichia coli strains in the intestinal flora of infants in Pakistan. Epidemiol Infect 1998;121:587–98.

    PubMed  CAS  Google Scholar 

  116. Walker R, Buckley M. Probiotic microbes: the scientific basis. Am. Academy of Sciences Colloquium Report. Am. Academy of Microbiology. 2006; 22.

  117. Blum S, Alvarez S, Haller D, Perez P, Schiffrin EJ. Intestinal microflora and the interaction with immunocompetent cells. Antonei van Leeuwenhock 1999;76:199–205.

    CAS  Google Scholar 

  118. Jaeger MA, Lamar CH, Bottoms GD, Cline TR. Growth-stimulating substances in porcine milk. Amer J Vet Res 1987;48:1531–3.

    PubMed  CAS  Google Scholar 

  119. Jin Y, Cox DA, Kenecht R, Raschdorf S, Cerletti N. Separation, purification and sequence identification of TGF-β1 and TGF-β2 from bovine milk. J Prot Chem 1991;10:565–75.

    CAS  Google Scholar 

  120. Miettinen PJ. Transforming growth factor β and epithelial growth factor expression in the human fetal gastrointestinal tract. Pediatr Res 1993;33:481–6.

    PubMed  CAS  Google Scholar 

  121. Wheeler MB, Walters EM. Transgenic technology and applications in swine. Theriogenology 2001;56:1345–69.

    PubMed  CAS  Google Scholar 

  122. Niemann H, Rath D, Wrenzycki C. Advances in biotechnology: new tools in future pig production for agriculture and biomedicine. Reprod Domest Anim 2003;38:82–9.

    PubMed  CAS  Google Scholar 

  123. Sachs DH, Sykes M, Robson SC, Cooper DK. Xenotransplantation. Adv Immunol 2001;79:129–223.

    Article  PubMed  CAS  Google Scholar 

  124. Waltz E. Polyclonal antibodies step out of the shadow. Nature Biotechnology 2006;24:1181–81.

    PubMed  CAS  Google Scholar 

  125. Kuriowa Y, Kasinathan P, Choi YJ, Naem R, Tomizuka K, Sullivan EJ, Knott JG, Duteau A, Goldsby RA, Osborne BA, Ishida I, Robl JM. Cloned transchromosomic calves producing human immunoglobulin Nat. Biotechnol 2002;20:889–94.

    Google Scholar 

  126. Rodgers C, Hao Y, Rokhlina T, Yan Z, Engelhardt J, Prather R, Welsh M. Gene targeting of pig CFTR: progress toward a large animal model of cystic fibrosis. Pediatr Pulmonol 2006;Suppl 29. Abstract 231.

Download references

Acknowledgments

This work was supported by Grant Agency of the Czech Republic Grant 524/07/0087 and 523/07/0088 and Grant Agency of Academy of Sciences of the Czech Republic Grant A5020303 and by a grant from the National Porkboard and by the Carver Trust of the University of Iowa.

Author information

Authors and Affiliations

  1. Department of Microbiology and Interdisciplinary Graduate Immunology Program, University of Iowa, 3-550 BSB, 51 Newton Rd, Iowa City, IA, 52242, USA

    J. E. Butler

  2. Department of Immunology and Gnotobiology, Institute of Microbiology, Academy of Science of the Czech Republic, Doly 183, Novy Hradek, Czech Republic

    Marek Šinkora

Authors
  1. J. E. Butler
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marek Šinkora
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J. E. Butler.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Butler, J.E., Šinkora, M. The isolator piglet: a model for studying the development of adaptive immunity. Immunol Res 39, 33–51 (2007). https://doi.org/10.1007/s12026-007-0062-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12026-007-0062-7

Keywords

Search

Navigation