FREE SHIPPING over $40
OVER 9000 FIVE-STAR REVIEWS
5% OFF ALL SUBSCRIPTIONS
100% HAPPINESS GUARANTEE
Analyze Diet
0
Home / Equine Research Bank / Biol Reprod / Ectopic Trophoblast Allografts in the Horse Resist Destructi...
Biology of reproduction2016; 95(6); 135; doi: 10.1095/biolreprod.115.137851

Ectopic Trophoblast Allografts in the Horse Resist Destruction by Secondary Immune Responses.

Abstract: Invasive trophoblast from Day 34 horse conceptuses survives in extrauterine sites in allogeneic recipients that are immunologically naive to donor major histocompatibility complex class I antigens. The ectopic trophoblast retains its in utero characteristics, including similar lifespan, physiologic effect of its secreted product (equine chorionic gonadotropin) upon the recipient's ovaries, and induction of host immune responses. Immunologic memory has not been considered previously in this experimental system. We hypothesized that primary exposure to ectopic trophoblast would affect the recipient's immune status such that the survival time of subsequent transplants would be altered. Secondary transplant lifespans could be shortened by destructive memory responses, as has been observed in ectopic trophoblast studies in rodents, or lengthened, as occurs when male skin grafts follow multiple syngeneic pregnancies in mice. Eight mares received two closely spaced trophoblast transplants. Both grafts for each recipient were obtained from conceptuses sired by the same stallion to provide consistency in histocompatibility antigen exposure. Donor stallions were major histocompatibility complex class I homozygotes. Cytotoxic antibody production was tracked to monitor recipients' immune responses to the transplants. Detection of serum equine chorionic gonadotropin was used as a proxy for transplant lifespan. There was no significant difference between the distributions of primary and secondary transplant lifespans, despite evidence of immunologic memory. These data demonstrate that secondary ectopic trophoblast transplants in horses do not experience earlier destruction or prolonged survival following immune priming of recipients. Mechanisms responsible for the eventual demise of the transplants remain unperturbed by secondary immune responses or chronic antigenic exposure.
© 2016 by the Society for the Study of Reproduction, Inc.
Get Full Text
Publication Date: 2016-10-19 PubMed ID: 27760752PubMed Central: PMC5315430DOI: 10.1095/biolreprod.115.137851Google Scholar: Lookup
The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
LinkedInCopy
  • Journal Article
  • Research Support
  • Non-U.S. Gov't
  • Research Support
  • N.I.H.
  • Extramural

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research explores how invasive trophoblast from horse embryos manages to survive outside the uterus, resisting destruction by the host’s immune responses and retaining its original characteristics, even upon secondary exposure.

Primary Hypothesis and Object of Study

  • The primary hypothesis of this study revolved around how primary exposure to ectopic trophoblast – that is, trophoblast cells growing outside the uterus in an unrelated (allogeneic) recipient – may influence the recipient’s immune status, altering the survival time of subsequent transplants.
  • The study examined whether secondary transplant lifespans would be shortened due to destructive immune responses, similar to previous findings in rodent studies, or lengthened, as seen when male skin grafts follow multiple pregnancies in mice.

Methodology

  • Eight mares were used for the experiment, each undergoing two closely spaced trophoblast transplants.
  • Consistency was ensured by obtaining both grafts for each recipient from embryos sired by the same stallion, and the donor stallions all shared the same characteristic of being major histocompatibility complex (MHC) class I homozygotes.
  • The production of cytotoxic antibodies was tracked to monitor the mare’s immune responses to the transplants.
  • The lifespan of the transplants was estimated based on the detection of serum equine chorionic gonadotropin (eCG), a hormone secreted by the trophoblast.

Results and Conclusion

  • The results showed no significant difference between the survival times of the first and second transplants, inspite of evidence of immune memory, indicating resistance to ‘destructive’ secondary immune responses.
  • The research concluded that secondary ectopic trophoblast transplants in horses do not face earlier destruction or extended survival following the immune preparation (“priming”) of the recipients.
  • Whatever mechanisms lead to the eventual failure of the transplants seem unaffected by secondary immune responses or long-term antigen exposure.

This study provides invaluable insights into the resilience of ectopic trophoblast transplants in horses against secondary immune responses and signifies potential avenues for further research into reproductive biology and immunology.

Cite This Article

APA
Brosnahan MM, Silvela EJ, Crumb J, Miller DC, Erb HN, Antczak DF. (2016). Ectopic Trophoblast Allografts in the Horse Resist Destruction by Secondary Immune Responses. Biol Reprod, 95(6), 135. https://doi.org/10.1095/biolreprod.115.137851

Publication

Biology of reproduction
ISSN: 1529-7268
NlmUniqueID: 0207224
Country: United States
Language: English
Volume: 95
Issue: 6
Pages: 135
PII: 135

Researcher Affiliations

Brosnahan, Margaret M
  • Baker Institute for Animal Health, Cornell University College of Veterinary Medicine, Ithaca, New York.
Silvela, Emily J
  • Baker Institute for Animal Health, Cornell University College of Veterinary Medicine, Ithaca, New York.
Crumb, Jessica
  • Baker Institute for Animal Health, Cornell University College of Veterinary Medicine, Ithaca, New York.
Miller, Donald C
  • Baker Institute for Animal Health, Cornell University College of Veterinary Medicine, Ithaca, New York.
Erb, Hollis N
  • Department of Population Medicine and Diagnostic Sciences, Cornell University College of Veterinary Medicine, Ithaca, New York.
Antczak, Douglas F
  • Baker Institute for Animal Health, Cornell University College of Veterinary Medicine, Ithaca, New York DFA1@cornell.edu.

MeSH Terms

  • Allografts
  • Animals
  • Female
  • Graft Survival / immunology
  • Horses
  • Immunity, Active / immunology
  • Trophoblasts / immunology
  • Trophoblasts / transplantation

Grant Funding

  • K08 HD065914 / NICHD NIH HHS
  • R01 HD049545 / NICHD NIH HHS

References

This article includes 57 references
  1. Erlebacher A. Immunology of the maternal-fetal interface.. Annu Rev Immunol 2013;31:387-411.
    pubmed: 23298207doi: 10.1146/annurev-immunol-032712-100003google scholar: lookup
  2. Erlebacher A. Mechanisms of T cell tolerance towards the allogeneic fetus.. Nat Rev Immunol 2013 Jan;13(1):23-33.
    pubmed: 23237963doi: 10.1038/nri3361google scholar: lookup
  3. Petroff MG. Review: Fetal antigens--identity, origins, and influences on the maternal immune system.. Placenta 2011 Mar;32 Suppl 2(Suppl 2):S176-81.
    pmc: PMC3258439pubmed: 21211836doi: 10.1016/j.placenta.2010.12.014google scholar: lookup
  4. Medawar PB. Some immunological and endocrinological problems raised by the evolution of viviparity in vertebrates.. Symp Soc Exp Biol 1952;7:320–338.
  5. Medawar PB. The behaviour and fate of skin autografts and skin homografts in rabbits: A report to the War Wounds Committee of the Medical Research Council.. J Anat 1944 Oct;78(Pt 5):176-99.
    pmc: PMC1272490pubmed: 17104960
  6. Moffett A, Loke C. Immunology of placentation in eutherian mammals.. Nat Rev Immunol 2006 Aug;6(8):584-94.
    pubmed: 16868549doi: 10.1038/nri1897google scholar: lookup
  7. Hemberger M. Immune balance at the foeto-maternal interface as the fulcrum of reproductive success.. J Reprod Immunol 2013 Mar;97(1):36-42.
    pubmed: 23432870doi: 10.1016/j.jri.2012.10.006google scholar: lookup
  8. Ristich V, Liang S, Zhang W, Wu J, Horuzsko A. Tolerization of dendritic cells by HLA-G.. Eur J Immunol 2005 Apr;35(4):1133-42.
    pubmed: 15770701doi: 10.1002/eji.200425741google scholar: lookup
  9. Apps R, Gardner L, Moffett A. A critical look at HLA-G.. Trends Immunol 2008 Jul;29(7):313-21.
    pubmed: 18538632doi: 10.1016/j.it.2008.02.012google scholar: lookup
  10. Madeja Z, Yadi H, Apps R, Boulenouar S, Roper SJ, Gardner L, Moffett A, Colucci F, Hemberger M. Paternal MHC expression on mouse trophoblast affects uterine vascularization and fetal growth.. Proc Natl Acad Sci U S A 2011 Mar 8;108(10):4012-7.
    pmc: PMC3053985pubmed: 21300875doi: 10.1073/pnas.1005342108google scholar: lookup
  11. Donaldson WL, Zhang CH, Oriol JG, Antczak DF. Invasive equine trophoblast expresses conventional class I major histocompatibility complex antigens.. Development 1990 Sep;110(1):63-71.
    pubmed: 2081471doi: 10.1242/dev.110.1.63google scholar: lookup
  12. Donaldson WL, Oriol JG, Pelkaus CL, Antczak DF. Paternal and maternal major histocompatibility complex class I antigens are expressed co-dominantly by equine trophoblast.. Placenta 1994 Feb-Mar;15(2):123-35.
    pubmed: 8008728doi: 10.1016/s0143-4004(05)80449-7google scholar: lookup
  13. Kydd JH, Butcher GW, Antczak DF, Allen WR. Expression of major histocompatibility complex (MHC) class 1 molecules on early trophoblast.. J Reprod Fertil Suppl 1991;44:463-77.
    pubmed: 1795291
  14. Allen WR. Immunological aspects of the endometrial cup reaction and the effect of xenogeneic pregnancy in horses and donkeys.. J Reprod Fertil Suppl 1982 Nov;31:57-94.
    pubmed: 6962845
  15. Antczak DF, Miller JM, Remick LH. Lymphocyte alloantigens of the horse. II. Antibodies to ELA antigens produced during equine pregnancy.. J Reprod Immunol 1984 Aug;6(5):283-97.
    pubmed: 6481697doi: 10.1016/0165-0378(84)90028-7google scholar: lookup
  16. Grünig G, Triplett L, Canady LK, Allen WR, Antczak DF. The maternal leucocyte response to the endometrial cups in horses is correlated with the developmental stages of the invasive trophoblast cells.. Placenta 1995 Sep;16(6):539-59.
    pubmed: 8570575doi: 10.1016/s0143-4004(05)80005-0google scholar: lookup
  17. Adams AP, Antczak DF. Ectopic transplantation of equine invasive trophoblast.. Biol Reprod 2001 Mar;64(3):753-63.
    pubmed: 11207188doi: 10.1095/biolreprod64.3.753google scholar: lookup
  18. de Mestre AM, Hanlon D, Adams AP, Runcan E, Leadbeater JC, Erb HN, Costa CC, Miller D, Allen WR, Antczak DF. Functions of ectopically transplanted invasive horse trophoblast.. Reproduction 2011 Jun;141(6):849-56.
    pmc: PMC5181105pubmed: 21389079doi: 10.1530/rep-10-0462google scholar: lookup
  19. Hulka JF, Mohr K. Trophoblast antigenicity demonstrated by altered challenge graft survival.. Science 1968 Aug 16;161(3842):696-8.
    pubmed: 5664509doi: 10.1126/science.161.3842.696google scholar: lookup
  20. Smith RN, Powell AE. The adoptive transfer of pregnancy-induced unresponsiveness to male skin grafts with thymus-dependent cells.. J Exp Med 1977 Sep 1;146(3):899-904.
    pmc: PMC2180788pubmed: 330791doi: 10.1084/jem.146.3.899google scholar: lookup
  21. Rowe JH, Ertelt JM, Xin L, Way SS. Pregnancy imprints regulatory memory that sustains anergy to fetal antigen.. Nature 2012 Oct 4;490(7418):102-6.
    pmc: PMC3465465pubmed: 23023128doi: 10.1038/nature11462google scholar: lookup
  22. Aurich C, Weber J, Nagel C, Merkl M, Jude R, Wostmann S, Ollech D, Baron U, Olek S, Jansen T. Low levels of naturally occurring regulatory T lymphocytes in blood of mares with early pregnancy loss.. Reprod Fertil Dev 2014;26(6):827-33.
    pubmed: 23787006doi: 10.1071/rd13012google scholar: lookup
  23. de Mestre A, Noronha L, Wagner B, Antczak DF. Split immunological tolerance to trophoblast.. Int J Dev Biol 2010;54(2-3):445-55.
    pmc: PMC2879498pubmed: 19876828doi: 10.1387/ijdb.082795adgoogle scholar: lookup
  24. Schietinger A, Greenberg PD. Tolerance and exhaustion: defining mechanisms of T cell dysfunction.. Trends Immunol 2014 Feb;35(2):51-60.
    pmc: PMC3946600pubmed: 24210163doi: 10.1016/j.it.2013.10.001google scholar: lookup
  25. Lazary S, Antczak DF, Bailey E, Bell TK, Bernoco D, Byrns G, McClure JJ. Joint Report of the Fifth International Workshop on Lymphocyte Alloantigens of the Horse, Baton Rouge, Louisiana, 31 October-1 November 1987.. Anim Genet 1988;19(4):447-56.
    pubmed: 2466424doi: 10.1111/j.1365-2052.1988.tb00836.xgoogle scholar: lookup
  26. Tseng CT, Miller D, Cassano J, Bailey E, Antczak DF. Identification of equine major histocompatibility complex haplotypes using polymorphic microsatellites.. Anim Genet 2010 Dec;41 Suppl 2(Suppl 2):150-3.
    pmc: PMC3289534pubmed: 21070289doi: 10.1111/j.1365-2052.2010.02125.xgoogle scholar: lookup
  27. Antczak DF, Oriol JG, Donaldson WL, Poleman C, Stenzler L, Volsen SG, Allen WR. Differentiation molecules of the equine trophoblast.. J Reprod Fertil Suppl 1987;35:371-8.
    pubmed: 3479591
  28. Antczak DF, Bright SM, Remick LH, Bauman BE. Lymphocyte alloantigens of the horse. I. Serologic and genetic studies.. Tissue Antigens 1982 Sep;20(3):172-87.
    pubmed: 6182639doi: 10.1111/j.1399-0039.1982.tb00343.xgoogle scholar: lookup
  29. Jiang TT, Chaturvedi V, Ertelt JM, Kinder JM, Clark DR, Valent AM, Xin L, Way SS. Regulatory T cells: new keys for further unlocking the enigma of fetal tolerance and pregnancy complications.. J Immunol 2014 Jun 1;192(11):4949-56.
    pmc: PMC4030688pubmed: 24837152doi: 10.4049/jimmunol.1400498google scholar: lookup
  30. Kinder JM, Jiang TT, Clark DR, Chaturvedi V, Xin L, Ertelt JM, Way SS. Pregnancy-induced maternal regulatory T cells, bona fide memory or maintenance by antigenic reminder from fetal cell microchimerism?. Chimerism 2014 Jan-Mar;5(1):16-9.
    pmc: PMC3988116pubmed: 24553046doi: 10.4161/chim.28241google scholar: lookup
  31. Rosenblum MD, Way SS, Abbas AK. Regulatory T cell memory.. Nat Rev Immunol 2016 Feb;16(2):90-101.
    pmc: PMC5113825pubmed: 26688349doi: 10.1038/nri.2015.1google scholar: lookup
  32. Zhang J, Patel G. Partner change and perinatal outcomes: a systematic review.. Paediatr Perinat Epidemiol 2007 Jul;21 Suppl 1:46-57.
    pubmed: 17593197doi: 10.1111/j.1365-3016.2007.00837.xgoogle scholar: lookup
  33. Erlebacher A, Lukens AK, Glimcher LH. Intrinsic susceptibility of mouse trophoblasts to natural killer cell-mediated attack in vivo.. Proc Natl Acad Sci U S A 2002 Dec 24;99(26):16940-5.
    pmc: PMC139248pubmed: 12486249doi: 10.1073/pnas.222652199google scholar: lookup
  34. Borland R, Loke YW, Oldershaw PJ. Sex difference in trophoblast behaviour on transplantation.. Nature 1970 Nov 7;228(5271):572.
    pubmed: 5472483doi: 10.1038/228572a0google scholar: lookup
  35. Epple-Farmer J, Debeb BG, Smithies O, Binas B. Gender-dependent survival of allogeneic trophoblast stem cells in liver.. Cell Transplant 2009;18(7):769-76.
    pmc: PMC3464099pubmed: 19523327doi: 10.3727/096368909x470856google scholar: lookup
  36. Hunt CV, Avery GB. The development and proliferation of the trophoblast from ectopic mouse embryo allografts of increasing gestational age.. J Reprod Fertil 1976 Mar;46(2):305-11.
    pubmed: 1255559doi: 10.1530/jrf.0.0460305google scholar: lookup
  37. Vandeputte M, Sobis H. Histocompatibility antigens on mouse blastocysts and ectoplacental cones.. Transplantation 1972 Sep;14(3):331-8.
    pubmed: 4637812doi: 10.1097/00007890-197209000-00008google scholar: lookup
  38. Allen WR. The immunological measurement of pregnant mare serum gonadotrophin.. J Endocrinol 1969 Apr;43(4):593-8.
    pubmed: 5767691doi: 10.1677/joe.0.0430593google scholar: lookup
  39. Allen WR, Kydd J, Miller J, Antczak DF. Immunological studies on feto-maternal relationships in early pregnancy.. 1984;pp. 183–193.
  40. Adams AP, Oriol JG, Campbell RE, Oppenheim YC, Allen WR, Antczak DF. The effect of skin allografting on the equine endometrial cup reaction.. Theriogenology 2007 Jul 15;68(2):237-47.
    pmc: PMC2259290pubmed: 17559923doi: 10.1016/j.theriogenology.2007.04.058google scholar: lookup
  41. Somerset DA, Zheng Y, Kilby MD, Sansom DM, Drayson MT. Normal human pregnancy is associated with an elevation in the immune suppressive CD25+ CD4+ regulatory T-cell subset.. Immunology 2004 May;112(1):38-43.
    pmc: PMC1782465pubmed: 15096182doi: 10.1111/j.1365-2567.2004.01869.xgoogle scholar: lookup
  42. Santner-Nanan B, Peek MJ, Khanam R, Richarts L, Zhu E, Fazekas de St Groth B, Nanan R. Systemic increase in the ratio between Foxp3+ and IL-17-producing CD4+ T cells in healthy pregnancy but not in preeclampsia.. J Immunol 2009 Dec 1;183(11):7023-30.
    pubmed: 19915051doi: 10.4049/jimmunol.0901154google scholar: lookup
  43. Tilburgs T, Roelen DL, van der Mast BJ, de Groot-Swings GM, Kleijburg C, Scherjon SA, Claas FH. Evidence for a selective migration of fetus-specific CD4+CD25bright regulatory T cells from the peripheral blood to the decidua in human pregnancy.. J Immunol 2008 Apr 15;180(8):5737-45.
    pubmed: 18390759doi: 10.4049/jimmunol.180.8.5737google scholar: lookup
  44. Tilburgs T, Roelen DL, van der Mast BJ, van Schip JJ, Kleijburg C, de Groot-Swings GM, Kanhai HH, Claas FH, Scherjon SA. Differential distribution of CD4(+)CD25(bright) and CD8(+)CD28(-) T-cells in decidua and maternal blood during human pregnancy.. Placenta 2006 Apr;27 Suppl A:S47-53.
    pubmed: 16442616doi: 10.1016/j.placenta.2005.11.008google scholar: lookup
  45. Noronha LE, Antczak DF. Modulation of T-cell reactivity during equine pregnancy is antigen independent.. Am J Reprod Immunol 2012 Aug;68(2):107-15.
    pubmed: 22587222doi: 10.1111/j.1600-0897.2012.01154.xgoogle scholar: lookup
  46. Baker JM, Bamford AI, Antczak DF. Modulation of allospecific CTL responses during pregnancy in equids: an immunological barrier to interspecies matings?. J Immunol 1999 Apr 15;162(8):4496-501.
    pubmed: 10201987
  47. Tilburgs T, Crespo ÂC, van der Zwan A, Rybalov B, Raj T, Stranger B, Gardner L, Moffett A, Strominger JL. Human HLA-G+ extravillous trophoblasts: Immune-activating cells that interact with decidual leukocytes.. Proc Natl Acad Sci U S A 2015 Jun 9;112(23):7219-24.
    pmc: PMC4466754pubmed: 26015573doi: 10.1073/pnas.1507977112google scholar: lookup
  48. Lee JH, Lydon JP, Kim CH. Progesterone suppresses the mTOR pathway and promotes generation of induced regulatory T cells with increased stability.. Eur J Immunol 2012 Oct;42(10):2683-96.
    pmc: PMC3668644pubmed: 22740122doi: 10.1002/eji.201142317google scholar: lookup
  49. Schumacher A, Heinze K, Witte J, Poloski E, Linzke N, Woidacki K, Zenclussen AC. Human chorionic gonadotropin as a central regulator of pregnancy immune tolerance.. J Immunol 2013 Mar 15;190(6):2650-8.
    pubmed: 23396945doi: 10.4049/jimmunol.1202698google scholar: lookup
  50. Schumacher A, Costa SD, Zenclussen AC. Endocrine factors modulating immune responses in pregnancy.. Front Immunol 2014;5:196.
    pmc: PMC4021116pubmed: 24847324doi: 10.3389/fimmu.2014.00196google scholar: lookup
  51. Hunt JS, Miller L, Platt JS. Hormonal regulation of uterine macrophages.. Dev Immunol 1998;6(1-2):105-10.
    pmc: PMC2276012pubmed: 9716911doi: 10.1155/1998/87527google scholar: lookup
  52. Hansen PJ. Regulation of uterine immune function by progesterone--lessons from the sheep.. J Reprod Immunol 1998 Oct;40(1):63-79.
    pubmed: 9862257doi: 10.1016/s0165-0378(98)00035-7google scholar: lookup
  53. Leposavić G, Nanut MP, Pilipović I, Kosec D, Arsenović-Ranin N, Stojić-Vukanić Z, Djikić J, Nacka-Aleksić M. Reshaping of T-lymphocyte compartment in adult prepubertaly ovariectomised rats: a putative role for progesterone deficiency.. Immunobiology 2014 Feb;219(2):118-30.
    pubmed: 24054944doi: 10.1016/j.imbio.2013.08.004google scholar: lookup
  54. Ferreira-Dias G, Claudino F, Carvalho H, Agrícola R, Alpoim-Moreira J, Robalo Silva J. Seasonal reproduction in the mare: possible role of plasma leptin, body weight and immune status.. Domest Anim Endocrinol 2005 Jul;29(1):203-13.
    pubmed: 15927774doi: 10.1016/j.domaniend.2005.02.006google scholar: lookup
  55. Wilsher S, Allen WR. Factors influencing equine chorionic gonadotrophin production in the mare.. Equine Vet J 2011 Jul;43(4):430-8.
    pubmed: 21496079doi: 10.1111/j.2042-3306.2010.00309.xgoogle scholar: lookup
  56. Crabtree JR, Chang Y, de Mestre AM. Clinical presentation, treatment and possible causes of persistent endometrial cups illustrated by two cases.. Equine Vet Educ 2012;5:251–259.
  57. Baker JM, Bamford AI, Carlson ML, Mcculloch CE, Antczak DF. Equine trophoblast as an immunological target.. J Reprod Fertil Suppl 2000;(56):635-44.
    pubmed: 20681179

Citations

This article has been cited 1 times.
  1. Antczak DF, Allen WRT. Placentation in Equids. Adv Anat Embryol Cell Biol 2021;234:91-128.
    doi: 10.1007/978-3-030-77360-1_6pubmed: 34694479google scholar: lookup
Subscribe to our newsletter
Join 99,344 horse owners like you who receive our email updates on horse health and nutrition.