Skip to main content

Advertisement

SpringerLink
Log in

The Th1/Th2 paradigm: still important in pregnancy?

  • Review
  • Published:
Seminars in Immunopathology Aims and scope Submit manuscript

Abstract

The enunciation of the T helper 1/T helper 2 (Th1/Th2) paradigm in pregnancy has represented a major step forward in our understanding of physiological and pathologic materno–foetal relationship. However, recent developments in studies of the implantation process and in the emergence of the uterine vascular bed and its control by natural killer cells and cytokines suggest that one must go beyond this hitherto useful scheme. In this review, we replace the emergence of the paradigm in its historical context and then emphasises what it does explain and what it no longer account for. A final reappraisal of the paradigm is suggested.

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

Similar content being viewed by others

References

  1. Chaouat G, Assal Meliani A, Martal J, Raghupathy R, Elliot J, Mossmann T, Wegmann TG (1995) IL-10 prevents inflammatory cytokine-mediated fetal death and is inducible by tau interferon. J Immunol 152:2411–2420

    Google Scholar 

  2. Moffett A, Loke C (2006) Immunology of placentation in eutherian mammals. Nat Rev Immunol 6:584–594

    PubMed  CAS  Google Scholar 

  3. Boyson JE, Iwanaga KK, Golos TG, Watkins DI (1997) Identification of a novel MHC class I gene, Mamu-AG, expressed in the placenta of a primate with an inactivated G locus. J Immunol 159(7):3311–3321

    PubMed  CAS  Google Scholar 

  4. Vaidya SV, Mathew PA (2006) Of mice and men: different functions of the murine and human 2B4 (CD244) receptor on NK cells. Immunol Lett 15 105(2):180–184

    CAS  Google Scholar 

  5. Robillard PY, Dekker G, Chaouat G, Chaline J, Hulsey TC (2007) Possible role of eclampsia preeclampsia in the evolution of human reproduction. Evol Med. (in press)

  6. Hiby SE, Walker JJ, O’shaughnessy KM, Redman CW, Carrington M, Trowsdale J, Moffett A (2004) Combinations of maternal KIR and fetal HLA-C genes influence the risk of preeclampsia and reproductive success. J Exp Med 200(8):957–965

    PubMed  CAS  Google Scholar 

  7. Allen WR, Kydd JH, Antzack DF (1986) Successful application of immunotherapy to a model of pregnancy failure in equids. In: Clark DA, Croy BA (eds) Reproductive immunology. Elsevier, pp 253–261

  8. Redline RW, Lu CY (1988) Specific defects in the anti listerial immune response in discrete regions of the murine uterus and placenta account for the susceptibility to infection. J Immunol 140:3497–4005

    Google Scholar 

  9. Roth I, Corry DB, Locksley RM, Abrams JS, Litton MJ, Fisher SJ (1996) Human placental cytotrophoblasts produce the immunosuppressive cytokine interleukin 10. J Exp Med 184(2):539–548

    PubMed  CAS  Google Scholar 

  10. Kaliss N, Dagg MK (1964) Immune responses engendered in mice by multiparity. Transplantation 84:416–425

    Article  Google Scholar 

  11. Chaouat G, Voisin GA, Daeron M, Kanellopoulos J (1977) Enhancing antibodies and suppressive cells in maternal anti-fetal immune reaction. Ann Immunol (Paris) 128(1–2):21–24

    CAS  Google Scholar 

  12. Bell SC, Billington WD (1983) Anti-fetal allo-antibody in the pregnant female. Immunol Rev 75:5–30

    PubMed  CAS  Google Scholar 

  13. Dorman PJ, Searle RF (1988) Alloantigen presenting capacity of human decidual tissue. J Reprod Immunol 13(2):101–112; Jul

    PubMed  CAS  Google Scholar 

  14. Matthews CJ, Searle RF (1988) Antigen presenting capacity of murine decidual tissue in vivo. J Reprod Immunol 12(4):287–295

    PubMed  CAS  Google Scholar 

  15. Athanassakis-Vassiliadis I, Thanos D, Papamatheakis J (1989) Induction of class II major histocompatibility complex antigens in murine placenta by 5-azacytidine and interferon-gamma involves different cell populations. Eur J Immunol 2341–2348

  16. Ranella A, Vassiliadis S, Mastora C, Valentina M, Dionyssopoulou E, Athanassakis I (2005) Constitutive intracellular expression of human leukocyte antigen (HLA)-DO and HLA-DR but not HLA-DM in trophoblast cells. Hum Immunol 66(1):43–55

    PubMed  CAS  Google Scholar 

  17. Voisin GA, Chaouat G (1974) Demonstration, nature and properties of antibodies eluted from the placenta and directed against paternal antigens. J Reprod Fertil Suppl 21:89–108

    Google Scholar 

  18. Wegman TG, Mossman TR, Carlson G, Oling O, Singh B (1979) The ability of the murine placenta to absorb monoclonal anti fetal H-2 K antibody from the maternal circulation. J Immunol 122:270–277

    Google Scholar 

  19. Singh B, Raghupathy R, Anderson DJ, Wegman TG (1983) The murine placenta as an immunological barrier between the mother and the fetus. In: Wegmann TG, Gill TJ III (eds) Immunology of reproduction (1st Banff conference). Oxford University Press, New York, pp 229–251

    Google Scholar 

  20. Drake BL, Head JR (1989) Murine trophoblast cells can be killed by allospecific cytototoxic T lymphocytes generated in Gibco OPTI MEM medium. J Reprod Immunol 15:71–77

    PubMed  CAS  Google Scholar 

  21. Ellis SA, Sargent IL, Redman CW, McMichael AJ (1986) HLA-G: evidence for a novel HLA antigen found on human extravillous trophoblast and a choriocarcinoma cell line. Immunology 4:595–601

    Google Scholar 

  22. Geraghty DE, Koller BH, Orr HT (1987) A human major histocompatibility complex class I gene that encodes a protein with a shortened cytoplasmic segment. Proc Natl Acad Sci USA 24:9145–9149

    Google Scholar 

  23. King A, Boocock C, Sharkey AM, Gardner L, Beretta A, Siccardi AG, Loke YW (1996) Evidence for the expression of HLA A-C class I mRNA and protein by human first trimester trophoblast. J Immunol 156(6):2068–2076

    PubMed  CAS  Google Scholar 

  24. Bianchi DW, Flint AF, Pizzimenti MF, Knoll JH, Latt SA (1990) Isolation of fetal DNA from nucleated erythrocytes in maternal blood. Proc Natl Acad Sci USA 87(9):3279–3283

    PubMed  CAS  Google Scholar 

  25. Smith RN, Sternlicht M (1982) The alloantibody response in the allogeneically pregnant rat. III. The location of the alloantibody-forming cells. J Immunol 29(2):783–786

    Google Scholar 

  26. Beer AE, Scott JR, Billingham RE (1975) Histoincompatibility and maternal immunological status as determinants of fetoplacental weight and litter size in rodents. J Exp Med 142(1):180–196

    PubMed  CAS  Google Scholar 

  27. Chaouat G, Voisin GA, Escalier D, Robert P (1979) Facilitation reaction (enhancing antibodies and suppressor cells) and rejection reaction (sensitized cells) from the mother to the paternal antigens of the conceptus. Clin Exp Immunol 35:13–24

    PubMed  CAS  Google Scholar 

  28. Smith RN, Powell AE (1977) The adoptive transfer of pregnancy-induced unresponsiveness to male skin grafts with thymus-dependent cells. J Exp Med 146:899–904

    PubMed  CAS  Google Scholar 

  29. Simpson E, Chandler P, Pole D (1981) A model of T-cell unresponsiveness using the male-specific antigen, H-Y. Cell Immunol 2:251–257

    CAS  Google Scholar 

  30. Engleman EG, McMichael AJ, McDevitt HO (1978) Suppression of the mixed lymphocyte reaction in man by a soluble T-cell factor. Specificity of the factor for both responder and stimulator. J Exp Med 1 147(4):1037–1043

    CAS  Google Scholar 

  31. Monnot P, Chaouat G (1984) Systemic active suppression is not necessary for successful allopregnancy. Am J Reprod Immunol 6:5–8

    PubMed  Google Scholar 

  32. Clark DA, McDermott MR, Szewczuk MR (1980) Impairment of host-versus-graft reaction in pregnant mice. II. Selective suppression of cytotoxic T-cell generation correlates with soluble suppressor activity and with successful allogeneic pregnancy. Cell Immunol 1:106–118

    Google Scholar 

  33. Chaouat G, Kolb JP, Wegmann TG (1983) The murine placenta as an immunological barrier between the mother and the foetus. Immunol Rev iews 75:29–60

    Article  Google Scholar 

  34. Volumenie JL, Mognetti B, de Smedt D, Menu E, Chaouat G (1997) Induction of transient murine T cell anergy by a low molecular weight compound obtained from supernatants of human placental cultures is linked to defective phosphorylation of TCR CD3 chain. Am J Reprod Immunol 38(3):168–175

    PubMed  CAS  Google Scholar 

  35. Kvirkvelia N, Vojnovic I, Warner TD, Athie-Morales V, Free P, Rayment N, Chain BM, Rademacher TW, Lund T, Roitt IM, Delves PJ (2002) Placentally derived prostaglandin E2 acts via the EP4 receptor to inhibit IL-2-dependent proliferation of CTLL-2 T cells. Clin Exp Immunol 127/2:263–269

    Google Scholar 

  36. Clark DA, Flanders KC, Hirte H, Dasch JR, Coker R, McAnulty RJ, Laurent GJ (1995) Characterization of murine pregnancy decidua transforming growth factor beta. I. Transforming growth factor beta 2-like molecules of unusual molecular size released in bioactive form. Biol Reprod 6:1380–1388

    Google Scholar 

  37. Chaouat G, Kiger N, Wegmann TG (1983) Vaccination against spontaneous abortion in mice. J Reprod Immunol 8:389–394

    Google Scholar 

  38. Chaouat G, Kolb JP, Kiger N, Stanislawski M, Wegmann TG (1985) Immunological concomitants of vaccination against abortion in mice. J Immunol 134:1594–1598

    PubMed  CAS  Google Scholar 

  39. Chaouat G, Clark DA, Wegmann TG (1988) Genetics aspects of the CBA/J DBA/2 J and B10 B10.A models of murine spontaneous abortions and prevention by leukocyte immunisation. In:18th R.C.O.G. study group. Early Pregnancy loss. Mechanisms and treatment. Allen WR, Clark DA, Gill TJ III, Mowbray JF, Robertson WF RCOG London, pp 89–105

  40. Baines MG, Gendron RL (1993) Natural and experimental animal models of reproductive failure. In: Chaouat G (ed) Immunology of pregnancy. CRC, Boca Raton, pp 173–203

    Google Scholar 

  41. Chaouat G, Kiger N, Chaouat G, Kolb JP, Wegmann TG, Guenet JL (1985) Immunogenetic studies of spontaneous abortion in mice. I. Preimmunisation of the mother with allogeneic spleen cells. J Immunol 134:2966–2972

    PubMed  Google Scholar 

  42. Schumacher A, Wollenberg I, Zambon Bertoja AC, Thure C, Gerlof K, Zenclussen ML, Sollwedel A, Leber J, Wafula P, Volk HD, Zenclussen AC (2006) Pregnancy-protective regulatory T cells act in an antigen-specific manner. Am J Reprod Immunol 56:7

    Google Scholar 

  43. Wegmann TG (1984) Fetal protection against abortion: is it immuno suppression or immuno stimulation? Ann Immuno. Inst Pasteur 135D:309–311

    CAS  Google Scholar 

  44. Szekeres-Bartho J, Wegmann TG (1996) A progesterone-dependent immunomodulatory protein alters the Th1/Th2 balance. J Reprod Immunol 31(1-2):81–95

    PubMed  CAS  Google Scholar 

  45. Athanassakis I, Bleackley RC, Paetkau V, Guibert LL, Barrp J, Wegmann TG (1987) The immunostimulatory effects of T cells and T cell lymphokines on murine fetally derived placental cells. J Immunol 138:37–44

    PubMed  CAS  Google Scholar 

  46. Chaouat G, Menu E, Dy M, Minkowski M, Clark DA, Wegmann TG (1990) Control of fetal survival in CBA × DBA/2 mice by lymphokine therapy. J Fertil Steril 89:447–458

    CAS  Google Scholar 

  47. Pollard JW (1997) Role of colony-stimulating factor-1 in reproduction and development. Mol Reprod Dev 46(1):54–60

    PubMed  CAS  Google Scholar 

  48. Robertson SA, Mau VJ, Hudson SN, Tremellen KP (1997) Cytokine leukocyte networks and the establishment of pregnancy. Am J Reprod Immunol 37:438–443

    PubMed  CAS  Google Scholar 

  49. Tangri S, Raghupathy R (1993) Expression of cytokines in placenta of mice undergoing immunologically mediated fetal resorption. Biol Reprod 49:840–850

    Google Scholar 

  50. Tangri S, Wegmann TG, Lin H, Raghupathy R (1994) Maternal anti-placental activity in natural, immunologically mediated foetal resorption. J Immunol 152:4903–4910

    PubMed  CAS  Google Scholar 

  51. Wegmann TG, Lin H, Guilbert L, Mossman TH (1993) Bidirectional cytokine interactions in the materno fetal relationship: successful allopregnancy is a Th2 phenomenon. Immunol Today 14:353–355

    PubMed  CAS  Google Scholar 

  52. Lin H, Mossmann TR, Guibert L, Tuntipopat S, Wegmann TG (1993) Synthesis of T helper-2 cytokines at the maternal fetal interface. J Immunol 151:4562–4573

    PubMed  CAS  Google Scholar 

  53. Delassus S, Couthino A, Saucier C, Darche S, Kourilsky P (1994) Differential cytokine expression in maternal blood and placenta during murine gestation. J Immunol 152:2411–2420

    PubMed  CAS  Google Scholar 

  54. Krishnan Guilbert LJ, Russell AS, Wegmann TG, Mosmann TR, Belosevic M (1996) Pregnancy impairs resistance of C57Bl/6 mice to Leishmania major infection and causes decreased antigen-specific IFN-γ response and increased production of T helper 2 cytokines. J Immunol 156:644–653

    Google Scholar 

  55. Krishnan L, Guilbert LJ, Wegmann TG, Belosevic M, Mossman TR (1996) Helper 1 response against Leishmania major in pregnant C57BL/6 mice increases implantation failure and fetal resorption: correlation with increased IFN-γ and TNF and reduced IL-10 production by placental cells. J Immunol 156:653–662

    PubMed  CAS  Google Scholar 

  56. Buendia A, Fallon PG, Del Rio L, Ortega N, Caro MR, Gallego MC, Salinas J (2002) Previous infection with the nematode Nippostrongylus brasiliensis alters the immune specific response against Chlamydophila abortus infection. Microb Pathog 33/1:7–15

    Google Scholar 

  57. Kinsky R, Delage G, Rosin N, Thang MN, Hoffman M, Chaouat G (1990) A murine model of NK mediated fetal resorption. Am J Reprod Immunol 123(3):73–78

    Google Scholar 

  58. Clark DA, Chaouat G, Arck PC, Mittruecker HW, Levy GA (1998) Cytokine dependent abortion in CBA DBA/2 mice is mediated by the procoagulant fgl/2 prothrombinase. J Immunol 160(2):550–555

    Google Scholar 

  59. Brunda MJ (1994) Interleukin-12. J Leukoc Biol 55(2):280–288

    PubMed  CAS  Google Scholar 

  60. Zurawski G, de Vries JE (1994) Interleukin 13, an interleukin 4-like cytokine that acts on monocytes and B cells, but not on T cells. Immunol Today 15(1):19–26

    PubMed  CAS  Google Scholar 

  61. Zourbas S, Dubanchet S, Martal J, Chaouat G (2001) Localization of pro-inflammatory (IL-12, IL-15) and anti-inflammatory (IL-11, IL-13) cytokines at the feto maternal interface during murine pregnancy. Clin Exp Immunol 126(3):519–528

    PubMed  CAS  Google Scholar 

  62. Ostojic S, Dubanchet S, Mjihdi A, Truyens C, Capron F, Chaouat G (2003) Demonstration of the presence of IL-16, IL-17 and IL-18 at the murine fetomaternal interface during murine pregnancy. Am J Reprod Immunol 49:101–113

    PubMed  CAS  Google Scholar 

  63. Kapsenberg ML, Hilkens CM, Wierenga EA, Kalinski P (1999) The paradigm of type 1 and type 2 antigen-presenting cells. Implications for atopic allergy. Clin Exp Allergy Suppl 2:33–36

    Google Scholar 

  64. Kadowaki N, Ho S, Antonenko S, Malefyt RW, Kastelein RA, Bazan F, Liu YJ (2001) Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens. J Exp Med 194(6):863–869

    PubMed  CAS  Google Scholar 

  65. Arpinati M, Green CL, Heimfeld S, Heuser JE, Anasetti C (2000) Granulocyte-colony stimulating factor mobilizes T helper 2-inducing dendritic cells. Blood 95(8):2484–2490

    PubMed  CAS  Google Scholar 

  66. Tsuda H, Sakai M, Michimata T, Tanebe K, Hayakawa S, Saito S (2001) Characterization of NKT cells in human peripheral blood and decidual lymphocytes. Am J Reprod Immunol 45(5):295–302

    PubMed  CAS  Google Scholar 

  67. Bendelac A, Schwartz RH (1991) Th0 cells in the thymus: the question of T-helper lineages. Immunol Rev 123:169–188

    PubMed  CAS  Google Scholar 

  68. Mitchison A, Sieper J (1995) Immunological basis of oral tolerance. Z Rheumatol 54(3):141–144

    PubMed  CAS  Google Scholar 

  69. Bach JF (2001) Non-Th2 regulatory T-cell control of Th1 autoimmunity. Scand J Immunol 1–2:21–29

    Google Scholar 

  70. Raghupathy R (2001) Pregnancy: success and failure within the Th1/Th2/Th3 paradigm. Semin Immunol 13(4):219–227

    PubMed  CAS  Google Scholar 

  71. Saito S, Tsukaguchi N, Hasegawa T, Michimata T, Tsuda H, Narita N (1999) Distribution of Th1, Th2, and Th0 and the Th1/Th2 cell ratios in human peripheral and endometrial T cells. Am J Reprod Immunol 42(4):240–245

    PubMed  CAS  Google Scholar 

  72. Nagaeva O, Jonsson L, Mincheva-Nilsson L (2002) Dominant IL-10 and TGF-beta mRNA expression in gamma delta T cells of human early pregnancy decidua suggests immunoregulatory potential. Am J Reprod Immunol 48(1):9–17

    PubMed  Google Scholar 

  73. Sanford TR, De M, Wood G (1992) Expression of colony stimulating factors and inflammatory cytokines in the uterus if CD1 mice during days 1 to days 3 of pregnancy. J Reprod Fertil 94(1):213–220

    Article  PubMed  CAS  Google Scholar 

  74. Mac Master MT, Newton RC, Dey SK, Andrews GK (1992) Activation and distribution of inflammatory cells in the mouse uterus during the preimplantation period. J Immunol 148:1699–1705

    Google Scholar 

  75. Colloque Université Paris Sud. Inserm Fondation Mérieux. Early embryo development, uterine preparation and role of cytokines in implantation and labour. May 12–14 1994. Chaouat G (ed) Fondation Mérieux Ed Lyon. 1995

  76. Head JR, Billingham RE (1981) Immunobiological aspects of the feto maternal relationship. In: Lachman P, Peters D (eds) Clinical aspects of Immunology. Blackwell Scientific, Oxford

    Google Scholar 

  77. Hogarth PJ (1982) Immunological aspects of mammalian reproduction. Blackie, Glasgow

    Google Scholar 

  78. Claman HN (1993) Immunology of human pregnancy. Humana, Totowa, NJ

    Google Scholar 

  79. Woodruff M (1985) The immunology of host–tumour relationships. Nature 317(6038):582

    PubMed  CAS  Google Scholar 

  80. El-Roeiy A, Shoenfeld Y (1985) Autoimmunity and pregnancy. Am J Reprod Immunol Microbiol 9(1):25–32

    PubMed  CAS  Google Scholar 

  81. Draca S (2002) Is pregnancy a model how we should control some autoimmune diseases? Autoimmunity 35(5):307–312

    PubMed  CAS  Google Scholar 

  82. Ostensen M, Villiger PM (2002) Immunology of pregnancy–pregnancy as a remission inducing agent in rheumatoid arthritis. Transpl Immunol 2–4:155–160

    Google Scholar 

  83. Furukawa K, Itoh K, Okamura K, Kumagai K, Suzuki M (1984) Changes in NK cell activity during the estrous cycle and pregnancy in mice. J Reprod Immunol 6:353–363

    PubMed  CAS  Google Scholar 

  84. Loke YW, King A (1995) Human implantation. Cell Biology and Immunology. Cambridge University Press

  85. Clarke AG (1979) Pregnancy-induced involution of the thymus can be prevented by immunizing with paternal skin grafts: a strain-dependent effect. Clin Exp Immunol 35(3):421–424

    PubMed  CAS  Google Scholar 

  86. Maroni ES, de Sousa MA (1973) The lymphoid organs during pregnancy in the mouse. A comparison between a syngeneic and an allogeneic mating. Clin Exp Immunol 13(1):107–124

    PubMed  CAS  Google Scholar 

  87. Adelstein S, Pritchard-Briscoe H, Loblay RH, Basten A (1990) Suppressor T-cell memory. Curr Top Microbiol Immunol 159:123–138

    PubMed  CAS  Google Scholar 

  88. Tafuri A, Alferink J, Moller P, Hammerling GJ, Arnold B (1995) T cell awareness of paternal alloantigens during pregnancy. Science 270(5236):630–633

    PubMed  CAS  Google Scholar 

  89. Jiang SP, Vacchio MS (1998) Multiple mechanisms of peripheral T cell tolerance to the foetal ‘allograft’. J Immunol 160:3086–3090

    PubMed  CAS  Google Scholar 

  90. Eblen AC, Gercel-Taylor C, Nakajima ST, Taylor DD (2002) Modulation of T-cell CD3-zeta chain expression in early pregnancy. Am J Reprod Immunol 47(3):167–173

    PubMed  Google Scholar 

  91. Taylor DD, Akyol S, Gercel-Taylor C (2006) Pregnancy-associated exosomes and their modulation of T cell signalling. J Immunol 176(3):1534–1542

    PubMed  CAS  Google Scholar 

  92. Vacchio MS, Hodes RJ (2005) Fetal expression of Fas ligand is necessary and sufficient for induction of CD8 T cell tolerance to the fetal antigen H-Y during pregnancy. J Immunol 174(8):4657–4661

    PubMed  CAS  Google Scholar 

  93. Hunt JS, Vasmer D, Ferguson TA, Miller L (1997) Fas ligand is positioned in mouse uterus and placenta to prevent trafficking of activated leukocytes between the mother and the conceptus. J Immunol 158:4122–4128

    PubMed  CAS  Google Scholar 

  94. Uckan D, Steele A, Chery BY, Chamizo W, Koutsonikolos A, Gilbert-Barnes E, Good RA (1997) Trophoblasts express Fas ligand. A proposed mechanism for immune privilege in placenta and maternal invasion. Mol Hum Reprod 3:655–662

    PubMed  CAS  Google Scholar 

  95. Chaouat G, Clark DA (2001) FAS/FAS ligand interaction at the placental interface is not required for the success of allogeneic pregnancy in anti-paternal MHC preimmunized mice. Am J Reprod Immunol 2:108–115

    Google Scholar 

  96. Munn DH, Zhou M, Attwood JT, Bondarev I, Conway SJ, Marshall B, Brown C, Mellor AL (1998) Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 281(5380):1191–1993

    PubMed  CAS  Google Scholar 

  97. Clark DA, Blois S, Kandil J, Handjiski B, Manuel J, Arck PC (2005) Reduced uterine indoleamine 2,3-dioxygenase versus increased Th1/Th2 cytokine ratios as a basis for occult and clinical pregnancy failure in mice and humans. Am J Reprod Immunol 54(4):203–216

    PubMed  CAS  Google Scholar 

  98. Comiskey M, Goldstein CY, De Fazio SR, Mammolenti M, Newmark JA, Warner CM (2003) Evidence that HLA-G is the functional homolog of mouse Qa-2, the Ped gene product. Hum Immunol 64(11):999–1004

    PubMed  CAS  Google Scholar 

  99. Roth I, Corry DB, Locksley RM, Anrams JS, Litton MJ, Fisher SJ (1996) Human placental cytotrophoblasts produce the immunosuppressive cytokine interleukin 10. J Exp Med 184:539–548

    PubMed  CAS  Google Scholar 

  100. Hill JA (1995) T helper 1 immunity to trophoblast: evidence for a new immunological mechanism for recurrent abortion in women. Hum Reprod 10:114–120

    PubMed  CAS  Google Scholar 

  101. Tranchot Diallo J, Gras G, Parnet Mathieru F, Benveniste O, Marcé D, Roques P, Milliez J, Chaouat G, Dormont D (1996) Modulation of cytokine expression in pregnant women. Am J Reprod Immunol 37/3:215–227

    Google Scholar 

  102. Raghupathy R, Makhseed M, Azizieh F, Hassan N, Al-Azemi M, Al-Shamali E (1999) Maternal Th1-and Th2-type reactivity to placental antigens in normal human pregnancy and unexplained recurrent spontaneous abortions. Cell Immunol 196/2:122–130

    Google Scholar 

  103. Jenkins C, Roberts J, Wilson R, MacLean MA, Shilito J, Walker JJ (2000) Evidence of a T(H) 1 type response associated with recurrent miscarriage. Fertil Steril 73:1206–1208

    PubMed  CAS  Google Scholar 

  104. Piccinni MP, Scaletti C, Vultaggio A, Maggi E, Romagnani S (2001) Defective production of LIF, M-CSF and Th2-type cytokines by T cells at fetomaternal interface is associated with pregnancy loss. J Reprod Immunol 52/1–2:35–43

    Google Scholar 

  105. Stewart C, Kaspar P, Brunet LJ, Bhatt H, Gadi I, Köntgen F, Abbondanzo S (1992) Blastocyst implantation depends on maternal expression of leukemia inhibitory factor. Nature 359:76–79

    PubMed  CAS  Google Scholar 

  106. Delage G, Moreau J-F, Taupin J-L, Freitas S, Hambartsoumian E, Olivennes F, Fanchin R, Letut-Körnish H, Fydman R, Chaouat G (1995) In vitro endometrial secretion of human interleukin for DA cells/leukaemia inhibitory factor by explant cultures from fertile and infertile women. Hum Reprod 10:2483–2488

    PubMed  CAS  Google Scholar 

  107. Laird SM, Tuckerman EM, Dalton CF, Dunphy BC, LiI TC, Zhang X (1997) The production of leukemia inhibitory factor by human endometrium: presence in uterine flushings and production by cells in culture. Hum Reprod 12:569–574

    PubMed  CAS  Google Scholar 

  108. Giess R, Tanasescu I, Steck T, Sendtner M (1999) Leukaemia inhibitory factor gene mutations in infertile women. Mol Hum Reprod 6:581–586

    Google Scholar 

  109. Laird SM, Tuckerman EM, Li TC (2006) Cytokine expression in the endometrium of women with implantation failure and recurrent miscarriage. Reprod Biomed Online 1:13–23

    Article  Google Scholar 

  110. Ntrivalas EI, Kwak-Kim JY, Gilman-Sachs A, Chung-Bang H, Ng SC, Beaman KD, Mantouvalos HP, Beer AE (2001) Status of peripheral blood natural killer cells in women with recurrent spontaneous abortions and infertility of unknown aetiology. Hum Reprod 16:855–861

    PubMed  CAS  Google Scholar 

  111. Kwak-Kim JY, Chung-Bang HS, Ng SC, Ntrivalas EI, Mangubat CP, Beaman KD, Beer AE, Gilman-Sachs A (2003) Increased T helper 1 cytokine responses by circulating T cells are present in women with recurrent pregnancy losses and in infertile women with multiple implantation failures after IVF. Hum Reprod 18:767–773

    PubMed  CAS  Google Scholar 

  112. Ng SC, Gilman-Sachs A, Thaker P, Beaman KD, Beer AE, Kwak-Kim J (2002) Expression of intracellular Th1 and Th2 cytokines in women with recurrent spontaneous abortion, implantation failures after IVF/ET or normal pregnancy. Am J Reprod Immunol 48/2:77–86

    Google Scholar 

  113. Saito S, Umekage H, Sakamoto Y, Sakai M, Tanebe K, Sasaki Y, Morikawa H (1999) Increased T-helper-1-type immunity and decreased T-helper-2-type immunity in patients with preeclampsia. Am J Reprod Immunol 41/5:297–306

    Google Scholar 

  114. Dong M, He J, Wang Z, Xie X, Wang H (2005) Placental imbalance of Th1- and Th2-type cytokines in preeclampsia. Acta Obstet Gynecol Scand 84(8):788–793

    PubMed  Google Scholar 

  115. Azizieh F, Raghupathy R, Makhseed M (2005) Maternal cytokine production patterns in women with pre-eclampsia. Am J Reprod Immunol 54(1):30–37

    PubMed  CAS  Google Scholar 

  116. Darmochwal-Kolarz D, Leszczynska-Gorzelak B, Rolinski J, Oleszczuk J (1999) T helper 1- and T helper 2-type cytokine imbalance in pregnant women with pre-eclampsia. Eur J Obstet Gynecol Reprod Biol 86(2):165–170

    PubMed  CAS  Google Scholar 

  117. Kelsö A (1995) Th1 and Th2 subsets: paradigms lost? Immunol Today 16:374–379

    PubMed  Google Scholar 

  118. Allen JE, Maizels RM (1997) Th1–Th2: reliable paradigm or dangerous dogma? Immunol Today 18:387–389

    PubMed  CAS  Google Scholar 

  119. Vince GS, Johnson PM (1996) Is there a Th2 bias in human pregnancy? J Reprod Immunol 32/2:101–104

    Google Scholar 

  120. Dosiou C, Giudice LC (2005) Natural killer cells in pregnancy and recurrent pregnancy loss: endocrine and immunologic perspectives. Endocr Rev 26(1):44–62

    PubMed  CAS  Google Scholar 

  121. Moffett A, Regan L, Braude P (2004) Natural killer cells, miscarriage, and infertility. Br Med J (BMJ) 329(7477):1283–1285

    Google Scholar 

  122. Hess AP, Dosiou C, Hamilton AE, Talbi S, Nyegaard M, Nayak N, Genbecev-Krtolica O, Mavrogianis P, Ferrer K, Kruessel J, Fazleabas AT, Fisher SJ, Giudice LC (2007) Decidual stromal cell response to paracrine signals from the trophoblast: amplification of immune and angiogenic modulators. Biol Reprod 76(1):102–117

    PubMed  CAS  Google Scholar 

  123. Mohamed OA, Jonnaert M, Labelle-Dumais C, Kuroda K, Clarke HJ, Dufort D (2005) Uterine Wnt/beta-catenin signaling is required for implantation. Proc Natl Acad Sci USA 102(24):8579–8584

    PubMed  CAS  Google Scholar 

  124. Sengupta J, Lalitkumar PG, Najwa AR, Ghosh D (2006) Monoclonal anti-leukemia inhibitory factor antibody inhibits blastocyst implantation in the rhesus monkey. Contraception 74(5):419–425

    PubMed  CAS  Google Scholar 

  125. Kralickova M, Sima R, Vanecek T, Sima P, Rokyta Z, Ulcova-Gallova Z, Sucha R, Uher P, Hes O (2006) Leukemia inhibitory factor gene mutations in the population of infertile women are not restricted to nulligravid patients. Eur J Obstet Gynecol Reprod Biol 127(2):231–235

    PubMed  CAS  Google Scholar 

  126. Takamoto N, Kurihara I, Lee K, Demayo FJ, Tsai MJ, Tsai SY (2005) Haploinsufficiency of chicken ovalbumin upstream promoter transcription factor II in female reproduction. Mol Endocrinol 19(9):2299–2308

    PubMed  CAS  Google Scholar 

  127. Bilinski P, Roopenian D, Gossler A (1998) Maternal IL-11R alpha function is required for normal decidua and fetoplacental development in mice. Genes Dev 12:2234–2243

    PubMed  CAS  Google Scholar 

  128. Robb L, Li R, Hartley L, Nandurkar H, Koetgen F, Begley CG (1998) Infertility in female mice lacking the receptor for interleukin-11 is due to a defective uterine response to implantation. Nat Med 4:303–308

    PubMed  CAS  Google Scholar 

  129. White CA, Robb L, Salamonsen LA (2004) Uterine extracellular matrix components are altered during defective decidualization in interleukin-11 receptor alpha deficient mice. Reprod Biol Endocrinol 2004 10:2:76

    Google Scholar 

  130. Ain R, Trinh ML, Soares MJ (2004) Interleukin-11 signaling is required for the differentiation of natural killer cells at the maternal–fetal interface. Dev Dyn 231(4):700–708

    PubMed  CAS  Google Scholar 

  131. Pollard JW, Hunt JW, Wiktor Jedrzejczack W, Stanley ER (1991) A pregnancy defect in the osteopetrotic (op/op) mouse demonstrates the requirement for CSF-1 in female fertility. Dev Biol 148:273–283

    PubMed  CAS  Google Scholar 

  132. Cohen PE, Chisholm O, Arceci RJ, Stanley ER, Pollard JW (1996) Abscence of CSF1 in osteopetrotic (csfmop/csfmop) mice results in male fertility defects. Biol Reprod 55:310–317

    PubMed  CAS  Google Scholar 

  133. Makrigiannakis A, Minas V, Kalantaridou SN, Nikas G, Chrousos GP (2006) Hormonal and cytokine regulation of early implantation. Trends Endocrinol Metab 17(5):178–185

    PubMed  CAS  Google Scholar 

  134. Simon C, Frances A, Piquette GN, Danasouri IE, Zurawski G, Dang W, Polan ML (1994) IL-1 receptor antagonist prevents successful implantation in mice. Endocrinology 134:521–528

    PubMed  CAS  Google Scholar 

  135. Simon C, Mercader A, Gimeno MJ, Pellicer A (1997) The interleukin 1 system and human implantation. Am J Reprod Immunol 37/1:64–72

    Google Scholar 

  136. Abbondanzo SJ, Cullinan EB, McIntyre K, Labow MA, Stewart CL (1996) Reproduction in mice lacking a functional type 1 IL-1 receptor. Endocrinology 137:3598–3601

    PubMed  CAS  Google Scholar 

  137. Paulesu L, Romagnoli R, Bigliardi E (2005) Materno–fetal immunotolerance: is interleukin-1 a fundamental mediator in placental viviparity? Dev Comp Immunol 29(5):409–415

    PubMed  CAS  Google Scholar 

  138. Mas A E, Dubanchet S, Fay S, Ledée N, Chaouat G (2006) Immune regulation at the interface during early steps of murine implantation: involvement of new IL-12 family cytokines (IL-23 and IL-27) and TWEAK. Submitted for publication and presentation at the Banff JRI/Elsevier conference on Reproductive Immunology. Banff. November 15–18 2006

  139. Clark DA, Chaouat G (2005) Loss of surface CD200 on stored allogeneic leukocytes may impair anti-abortive effect in vivo. Am J Reprod Immunol 53(1):13–20

    PubMed  CAS  Google Scholar 

  140. Somigliana E, Vigano P, Rossi G, Carinelli S, Vignali M, Panina-Bordignon P (1999) Endometrial ability to implant in ectopic sites can be prevented by interleukin-12 in a murine model of endometriosis. Hum Reprod 12:2944–2950

    Google Scholar 

  141. Svensson L, Arvola M, Sallstrom MA, Holmdahl R, Mattsson R (2001) The Th2 cytokines IL-4 and IL-10 are not crucial for the completion of allogeneic pregnancy in mice. J Reprod Immunol 51(1):3–7

    PubMed  CAS  Google Scholar 

  142. Fallon PG, Jolin HE, Smith P, Emson CL, Townsend MJ, Fallon R, Smith P, Mc Kenzie AN (2002) IL-4 induces characteristic Th2 responses even in the combined absence of IL-5, IL-9, and IL-13. Immunity 17(1):7–17

    PubMed  CAS  Google Scholar 

  143. White CA, Johansson M, Roberts CT, Ramsay AJ, Robertson SA (2004) Effect of interleukin-10 null mutation on maternal immune response and reproductive outcome in mice. Biol Reprod 70(1):123–131

    PubMed  CAS  Google Scholar 

  144. Robertson SA, Skinner RJ, Care AS (2006) Essential role for IL-10 in resistance to lipopolysaccharide-induced preterm labor in mice. J Immunol 177(7):4888–4896

    PubMed  CAS  Google Scholar 

  145. Guimond MJ, Wang B, Croy BA (1998) Engraftment of bone marrow from severe combined immunodeficiency (SCID) mice reverses the reproductive deficit in natural killer cells deficient TgE26 mice. J Exp Med 187:217–223

    PubMed  CAS  Google Scholar 

  146. Barber EM, Pollard JW (2003) The uterine NK cell population requires IL-15 but these cells are not required for pregnancy nor the resolution of a Listeria monocytogenes infection. J Immunol 171/1:37–46

    Google Scholar 

  147. Miyazaki S, Tanebe K, Sakai M, Michimata T, Tsuda H, Fujimura M, Nakamura M, Kiso Y, Saito S (2002) Interleukin 2 receptor gamma chain (gamma(c)) knockout mice show less regularity in estrous cycle but achieve normal pregnancy without fetal compromise. Am J Reprod Immunol 47/4:222–230

    Google Scholar 

  148. Ashkar AA, Black GP, Wei Q, He H, Liang L, Head JR, Croy BA (2003) Assessment of requirements for IL-15 and IFN regulatory factors in uterine NK cell differentiation and function during pregnancy. J Immunol 171(6):2937–2944

    PubMed  CAS  Google Scholar 

  149. Leonard S, Murrant C, Tayade C, van den Heuvel M, Watering R, Croy BA (2006) Mechanisms regulating immune cell contributions to spiral artery modification—facts and hypotheses—a review. Placenta Suppl A:S40–S46

  150. Li XF, Charnock-Jones DS, Zhang E, Hiby S, Malik S, Day K, Licence D, Bowen JM, Gardner L, King A, Loke YW, Smith SK (2001) Angiogenic growth factor messenger ribonucleic acids in uterine natural killer cells. J Clin Endocrinol Metab 86(4):1823–1834

    PubMed  CAS  Google Scholar 

  151. Lash GE, Schiessl B, Kirkley M, Innes BA, Cooper A, Searle RF, Robson SC, Bulmer JN (2006) Expression of angiogenic growth factors by uterine natural killer cells during early pregnancy. J Leukoc Biol 80(3):572–580

    PubMed  CAS  Google Scholar 

  152. Xie X, He H, Colonna M, Seya T, Takai T, Croy BA (2005) Pathways participating in activation of mouse uterine natural killer cells during pregnancy. Biol Reprod 73(3):510–518

    PubMed  CAS  Google Scholar 

  153. Sacks GP, Redman CW, Sargent IL (2003) Monocytes are primed to produce the Th1 type cytokine IL-12 in normal human pregnancy: an intracellular flow cytometric analysis of peripheral blood mononuclear cells. Clin Exp Immunol 131:490–497

    PubMed  CAS  Google Scholar 

  154. Zenclussen AC, Fest S, Busse P, Joachim R, Klapp BF, Arck PC (2002) Questioning the Th1/Th2 paradigm in reproduction: peripheral levels of IL-12 are down-regulated in miscarriage patients. Am J Reprod Immunol 48/4:245–251

    Google Scholar 

  155. Ledee-Bataille N, Bonnet-Chea K, Hosny G, Dubanchet S, Frydman R, Chaouat G (2005) Role of the endometrial tripod interleukin-18, -15, and -12 in inadequate uterine receptivity in patients with a history of repeated in vitro fertilization-embryo transfer failure. Fertil Steril 83(3):598–605

    PubMed  CAS  Google Scholar 

  156. Cohen M, Meisser A, Haenggeli L, Bischof P (2006) Involvement of MAPK pathway in TNF-alpha-induced MMP-9 expression in human trophoblastic cells. Mol Hum Reprod 12(4):225–232

    PubMed  CAS  Google Scholar 

  157. Bell E (2006) TWEAK and TNF: Yin and Yang in innate immunity. Nat Rev Immunol 6:91

    Google Scholar 

  158. Devergne O, Coulomb-L’Hermine A, Capel F, Moussa M, Capron F (2001) Expression of Epstein–Barr virus-induced gene 3, an interleukin-12 p40-related molecule, throughout human pregnancy: involvement of syncytio trophoblasts and extra villous trophoblasts. Am J Pathol 159(5):1763–1776

    PubMed  CAS  Google Scholar 

  159. Haddad EK, Duclos AJ, Baines MG (1995) Early embryo loss is associated with local production of nitric oxide by activated macrophages. J Exp Med 182:1143–1152

    PubMed  CAS  Google Scholar 

  160. Jerzak M, Bischof P (2002) Apoptosis in the first trimester human placenta: the role in maintaining immune privilege at the maternal–foetal interface and in the trophoblast remodelling. Eur J Obstet Gynecol Reprod Biol 100(2):138–142

    PubMed  CAS  Google Scholar 

  161. Girardi G, Yarilin D, Thurman JM, Holers VM, Salmon JE (2006) Complement activation induces dysregulation of angiogenic factors and causes fetal rejection and growth restriction. J Exp Med 203(9):2165–2175

    PubMed  CAS  Google Scholar 

  162. Paldi A (1991) Genomic imprinting and feto maternal relationship. In: Chaouat G (ed) Biologie cellulaire et moléculaire de la relation materno fetale. Colloque INSERM 254. INSERM John Libbey, Paris, pp 61–66

    Google Scholar 

  163. Tartakovsky B, Ben-Yair E (1991) Cytokines modulate preimplantation development and pregnancy. Dev Biol 146(2):345–352

    PubMed  CAS  Google Scholar 

  164. Du MR, Dong L, Zhou WH, Yan FT, Li DJ (2006) Cyclosporin A improves pregnant outcome by promoting functions of trophoblasts and inducing maternal tolerance to the allogeneic fetus. Biol Reprod 2007 Jan 17; (in press)

  165. Xu C, Mao D, Holmers M, Palanca B, Cheng AM, Molina H (2000) A critical role for complement regulatory Crry in feto maternal tolerance. Science 287:498–499

    PubMed  CAS  Google Scholar 

  166. Girardi G, Bulla R, Salmon JE, Tedesco F (2006) The complement system in the pathophysiology of pregnancy. Mol Immunol 43(1–2):68–77

    PubMed  CAS  Google Scholar 

  167. Berman J, Girardi G, Salmon JE (2005) TNF-alpha is a critical effector and a target for therapy in antiphospholipid antibody-induced pregnancy loss. J Immunol 174(1):485–490

    PubMed  CAS  Google Scholar 

  168. Holmes CH, Simpson KL, Wainwright SD, Tate CG, Houlihan JM, Sawyer JH, Roger IP, Spring FA, Amstee DJ, Tanner MJ (1990) Preferential expression of the complement regulatory protein decay accelerating factor at the foetomaternal interface during human pregnancy. J Immunol 144:3099–3115

    PubMed  CAS  Google Scholar 

  169. Baban B, Chandler P, McCool D, Marshall B, Munn DH, Mellor AL (2004) Indoleamine 2,3-dioxygenase expression is restricted to fetal trophoblast giant cells during murine gestation and is maternal genome specific. J Reprod Immunol (2):67–77

    Google Scholar 

  170. Lokki ML, Laitinen T (2001) Role of major histocompatibility complex class III genes in recurrent spontaneous abortions. Front Biosci 1(6):E23

    Google Scholar 

  171. Aluvihare VR, Kallikourdis M, Betz AG (2004) Regulatory T cells mediate maternal tolerance to the fetus. Nat Immunol 5:266–271

    PubMed  CAS  Google Scholar 

  172. Saito S, Sasaki Y, Sakai M (2005) CD4(+)CD25 high regulatory T cells in human pregnancy. J Reprod Immunol 65(2):111–120

    PubMed  CAS  Google Scholar 

  173. Zhang C, Zhang J, Tian Z (2006) The regulatory effect of natural killer cells: do “NK-reg cells” exist? Cell Mol Immunol 3(4):241–254

    PubMed  CAS  Google Scholar 

  174. Shao L, Jacobs AR, Johnson VV, Mayer L (2005) Activation of CD8+ regulatory T cells by human placental trophoblasts. J Immunol 174(12):7539–7547

    PubMed  CAS  Google Scholar 

  175. Fourth International Workshop on Immunology of Pre-eclampsia, December 2004, Reunion, France. J Reprod Immunol 2005 67(1–2):103–111

  176. Sargent IL, Borzychowski AM, Redman CW (2006) NK cells and human pregnancy—an inflammatory view. Trends Immunol 27(9):399–404

    PubMed  CAS  Google Scholar 

  177. Chaouat G (2003) Opinion: should we re-examine the status of lymphocyte allo-immunisation therapy for recurrent spontaneous abortion? Am J Reprod Immunol 50(6):433–438

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Unité 782 Inserm, Equipe implantation et dialogue cytokinique mère conceptus (Endocrinologie et génétique de la reproduction et du développement), Université Paris Sud, 32 rue des Carnets et Hôpital Antoine Béclère, Maternité, Pavillon Jean Dalsace, 92141, Clamart Cedex, France

    Gérard Chaouat

Authors
  1. Gérard Chaouat
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gérard Chaouat.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chaouat, G. The Th1/Th2 paradigm: still important in pregnancy?. Semin Immunopathol 29, 95–113 (2007). https://doi.org/10.1007/s00281-007-0069-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00281-007-0069-0

Keywords

Search

Navigation