Skip to main content

Pregnancy: Tolerance and Suppression of Immune Responses

  • Protocol
  • First Online:
Suppression and Regulation of Immune Responses

Abstract

Presence of foreign tissue in a host’s body would immediately lead to a strong immune response directed to destroy the alloantigens present in fetus and placenta. However, during pregnancy, the semiallogeneic fetus is allowed to grow within the maternal uterus due to multiple mechanisms of immune tolerance, which are discussed in this chapter.

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

Access this chapter

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 159.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Medawar PB (1953) Some immunological and endocrinological problems raised by evolution of viviparity in vertebrates. In: Symposia of the society for experimental biology, vol 7, Evolution, R. Brown and JF Danielli, Eds. Syndics of the Cambridge University Press, London, pp. 320–338

    Google Scholar 

  2. Yan Z, Lambert NC, Guthrie KA, Porter AJ, Loubiere LS et al (2005) Male microchimerism in women without sons: quantitative assessment and correlation with pregnancy history. Am J Med 118:899–906

    Article  PubMed  Google Scholar 

  3. Khosrotehrani K, Johnson KL, Guégan S, Stroh H, Bianchi DW (2005) Natural history of fetal cell microchimerism during and following murine pregnancy. J Reprod Immunol 66:1–12

    Article  PubMed  CAS  Google Scholar 

  4. Tan XW, Liao H, Sun L, Okabe M, Xiao ZC et al (2005) Fetal microchimerism in the maternal mouse brain: a novel population of fetal progenitor or stem cells able to cross the blood-brain barrier? Stem Cells 23:1443–1452

    Article  PubMed  CAS  Google Scholar 

  5. Elbe-Bürger A, Mommaas AM, Prieschl EE, Fiebiger E, Baumruker T, Stingl G (2000) Major histocompatibility complex class II – fetal skin dendritic cells are potent accessory cells of polyclonal T-cell responses. Immunol 101(2):242–253

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  7. Jiang SP, Vacchio MS (1998) Multiple mechanisms of peripheral T cell tolerance to the fetal “allograft”. J Immunol 160(7):3086–3090

    PubMed  CAS  Google Scholar 

  8. Moldenhauer LM, Diener KR, Thring DM, Brown MP, Hayball JD, Robertson SA (2009) Cross-presentation of male seminal fluid antigens elicits T cell activation to initiate the female immune response to pregnancy. J Immunol 182(12):8080–8093

    Article  PubMed  CAS  Google Scholar 

  9. Zenclussen ML, Thuere C, Ahmad N, Wafula PO, Fest S, Teles A, Leber A, Casalis PA, Bechmann I, Priller J, Volk HD, Zenclussen AC (2010) The persistence of paternal antigens in the maternal body is involved in regulatory T-cell expansion and fetal-maternal tolerance in murine pregnancy. Am J Reprod Immunol 63(3):200-208

    Article  PubMed  CAS  Google Scholar 

  10. Robertson SA, Guerin LR, Bromfield JJ, Branson KM, Ahlström AC, Care AS (2009) Seminal fluid drives expansion of the CD4+CD25+ T regulatory cell pool and induces tolerance to paternal alloantigens in mice. Biol Reprod 80(5):1036–1045

    Article  PubMed  CAS  Google Scholar 

  11. Tilburgs T, Roelen DL, van der Mast BJ, de Groot-Swings GM, Kleijburg C, Scherjon SA, Claas FH (2008) Evidence for a selective migration of fetus-specific CD4+CD25 bright regulatory T cells from the peripheral blood to the decidua in human pregnancy. J Immunol 180(8):5737–5745

    PubMed  CAS  Google Scholar 

  12. Ilarregui JM, Croci DO, Bianco GA, Toscano MA, Salatino M, Vermeulen ME, Geffner JR, Rabinovich GA (2009) Tolerogenic signals delivered by dendritic cells to T cells through a galectin-1-driven immunoregulatory circuit involving interleukin 27 and interleukin 10. Nat Immunol 10(9):981–991

    Article  PubMed  CAS  Google Scholar 

  13. Rémy S, Blancou P, Tesson L, Tardif V, Brion R, Royer PJ, Motterlini R, Foresti R, Painchaut M, Pogu S, Gregoire M, Bach JM, Anegon I, Chauveau C (2009) Carbon monoxide inhibits TLR-induced dendritic cell immunogenicity. J Immunol 182(4):1877–1884

    Article  PubMed  CAS  Google Scholar 

  14. Fest S, Aldo PB, Abrahams VM, Visintin I, Alvero A, Chen R, Chavez SL, Romero R, Mor G (2007) Trophoblast-macrophage interactions: a regulatory network for the protection of pregnancy. Am J Reprod Immunol 57(1):55–66

    Article  PubMed  Google Scholar 

  15. Karsten CM, Behrends J, Wagner AK, Fuchs F, Figge J, Schmudde I, Hellberg L, Kruse A (2009) DC within the pregnant mouse uterus influence growth and functional properties of uterine NK cells. Eur J Immunol 39(8):2203–2214

    Article  PubMed  CAS  Google Scholar 

  16. Murphy SP, Fast LD, Hanna NN, Sharma S (2005) Uterine NK cells mediate inflammation induced fetal demise in IL-10-null mice. J Immunol 175:4084–4090

    PubMed  CAS  Google Scholar 

  17. Peel S (1989) Granulated metrial gland cells. Adv Anat Embryol Cell Biol 115:1–112

    Article  PubMed  CAS  Google Scholar 

  18. Parr EL, Parr MB, Zheng LM, Young JD (1991) Mouse granulated metrial gland cells originate by local activation of uterine natural killer lymphocytes. Biol Reprod 44:834–841

    Article  PubMed  CAS  Google Scholar 

  19. Croy BA, Ashkar AA, Foster RA, DiSanto JP, Magram J, Carson D, Gendler SJ, Grusby MJ, Wagner N, Muller W, Guimond MJ (1997) Histological studies of geneablated mice support important functional roles for natural killer cells in the uterus during pregnancy. J Reprod Immunol 35:111–133

    Article  PubMed  CAS  Google Scholar 

  20. Sharma R, Bulmer D, Peel S (1986) Effects of exogenous progesterone following ovariectomy on the metrial glands of pregnant mice. J Anat 144:189–199

    PubMed  CAS  Google Scholar 

  21. Greenwood JD, Minhas K, Di Santo JP, Makita M, Kiso Y, Croy BA (2000) Ultrastructural studies of implantation sites from mice deficient in uterine natural killer cells. Placenta 21:693–702

    Article  PubMed  CAS  Google Scholar 

  22. Metzger H (1992) The receptor with high affinity for IgE. Immunol Rev 125:37–48

    Article  PubMed  CAS  Google Scholar 

  23. Gilfillan AM, Tkaczyk C (2006) Integrated signalling pathways for mast-cell activation. Nat Rev Immunol 6:218–230

    Article  PubMed  CAS  Google Scholar 

  24. Galli SJ, Nakae S, Tsai M (2005) Mast cells in the development of adaptive immune responses. Nat Immunol 6:135–142

    Article  PubMed  CAS  Google Scholar 

  25. Zaitsu M, Narita A, Lambert KC, Grady JJ, Estes DM, Curran EM, Brooks EG, Watson CS, Goldblum RM, Midoro-Horiuti T (2007) Estradiol activates mast cells via a non-genomic estrogen receptor-alpha and calcium influx. Mol Immunol 44(8):1977–1985

    Article  PubMed  CAS  Google Scholar 

  26. Grimbaldeston MA, Metz M, Yu M, Tsai, M, Galli SJ (2006) Effector and potential immunoregulatory roles of mast cells in IgE-associated acquired immune responses. Curr Opin Immunol 18:751–760

    Article  PubMed  CAS  Google Scholar 

  27. Theoharides TC, Kalogeromitros D (2006) The critical role of mast cells in allergy and inflammation. Ann N Y Acad Sci 1088:78–99

    Article  PubMed  CAS  Google Scholar 

  28. Boesiger J, Tsai M, Maurer M, Yamaguchi M, Brown LF, Claffey KP, Dvorak HF, Galli SJ (1998) Mast cells can secrete vascular permeability factor/vascular endothelial cell growth factor and exhibit enhanced release after immunoglobulin E-dependent upregulation of Fcε receptor I expression. J Exp Med 188:1135–1145

    Article  PubMed  CAS  Google Scholar 

  29. Baram D, Vaday GG, Salamon P, Drucker I, Hershkoviz R, Mekori YA (2001) Human mast cells release metalloproteinase-9 on contact with activated T cells: juxtacrine regulation by TNF-alpha. J Immunol 167(7):4008–4016

    PubMed  CAS  Google Scholar 

  30. Jeziorska M, Salamonsen LA, Woolley DE (1995) Mast cell and eosinophil distribution and activation in human endometrium throughout the menstrual cycle. Biol Reprod 53(2):312–320

    Article  PubMed  CAS  Google Scholar 

  31. Mori A, Zhai YL, Toki T, Nikaido T, Fujii S (1997) Distribution and heterogeneity of mast cells in the human uterus. Hum Reprod 12(2):368–372

    Article  PubMed  CAS  Google Scholar 

  32. Cabanillas-Saez A, Schalper JA, Nicovani SM, Rudolph MI (2002) Characterization of mast cells according to their content of tryptase and chymase in normal and neoplastic human uterine cervix. Int J Gynecol Cancer 12(1):92–98

    Article  PubMed  CAS  Google Scholar 

  33. Padilla L, Reinicke K, Montesino H, Villena F, Asencio H, Cruz M, Rudolph MI (1990) Histamine content and mast cells distribution in mouse uterus: the effect of sexual hormones, gestation and labor. Cell Mol Biol 36(1):93–100

    PubMed  CAS  Google Scholar 

  34. Rudolph MI, de los Angeles García M, Sepulveda M, Brandan E, Reinicke K, Nicovani S, Villan L (1997) Ethodin: pharmacological evidence of the interaction between smooth muscle and mast cells in the myometrium. J Pharmacol Exp Ther 282(1):256–261

    PubMed  CAS  Google Scholar 

  35. Harvey EB (1964) Mast cell distribution in the uterus of cycling and pregnant hamsters. Anat Rec 148:507–516

    Article  PubMed  CAS  Google Scholar 

  36. Tabb NT (1994) Immune control of myometrial contractility: Role of mast cells. In: Control of uterine contractility, RE Garfield, NT Tabb, Eds. CRC Press, Boca de Raton, FL, pp. 355–373

    Google Scholar 

  37. Varayoud J, Ramos JG, Bosquiazzo VL, Muñoz-de-Toro M, Luque EH (2004) Mast cells degranulation affects angiogenesis in the rat uterine cervix during pregnancy. Reproduction 127(3):379–387

    Article  PubMed  CAS  Google Scholar 

  38. Bosquiazzo VL, Ramos JG, Varayoud J, Muñoz-de-Toro M, Luque EH (2007) Mast cell degranulation in rat uterine cervix during pregnancy correlates with expression of vascular endothelial growth factor mRNA and angiogenesis. Reproduction 133(5):1045–1055

    Article  PubMed  CAS  Google Scholar 

  39. Widayati DT, Ohmori Y, Fukuta KJ (2004) Distribution patterns of immunocompetent cells in the pregnant mouse uteri carrying allogeneic mouse and xenogeneic vole embryos. J Anat 205(1):45–55

    Article  PubMed  Google Scholar 

  40. Garfield RE, Irani AM, Schwartz LB, Bytautiene E, Romero R (2006) Structural and functional comparison of mast cells in the pregnant versus nonpregnant human uterus. Am J Obstet Gynecol 194(1):261–267

    Article  PubMed  CAS  Google Scholar 

  41. Bytautiene E, Vedernikov YP, Saade GR, Romero R, Garfield RE (2008) IgE-independent mast cell activation augments contractility of nonpregnant and pregnant guinea pig myometrium. Int Arch Allergy Immunol 147(2):140–146

    Article  PubMed  CAS  Google Scholar 

  42. Walsh LJ, Trinchieri G, Waldorf HA, Whitaker D, Murphy GF (1991) Human dermal mast cells contain and release tumor necrosis factor alpha, which induces endothelial leukocyte adhesion molecule 1. Proc Natl Acad Sci USA 88(10):4220–4224

    Article  PubMed  CAS  Google Scholar 

  43. Schmith A, Goepfert C, Feitsma K, Buddecke E (2002) Lovastatin-stimulated superinduction of E-selectin, ICAM-1 and VCAM in TNF alpha-activated human vascular endothelial cells. Atherosclerosis 164(1):57–64

    Article  Google Scholar 

  44. Worobec AS, Akin C, Scott LM, Metcalfe DD (2000) Mastocytosis complicating pregnancy. Obstet Gynecol 95(3):391–395

    Article  PubMed  CAS  Google Scholar 

  45. Waldmann H (2006) Immunology: protection and privilege. Nature 442(7106):987–988

    Article  PubMed  CAS  Google Scholar 

  46. Lu L-F, Lind EF, Gondek DC, Bennett KA, Gleeson MW, Pino-Lagos K, Scott ZA, Coyle AJ, Reed JL, Snick JV, Strom TB, Zheng XX, Noelle RJ (2006) Mast cells are essential intermediaries in regulatory T-cell tolerance. Nature 31:997–1002

    Article  CAS  Google Scholar 

  47. Mowbray JF, Underwood JL (1985) Immunology of abortion. Clin Exp Immunol 60:1–7

    PubMed  CAS  Google Scholar 

  48. Innes A, Cunningham C, Power DA, Catto GRD (1989) Fetus as an allograft: noncytotoxic maternal antibodies to HLA-linked paternal antigens. Am J Reprod Immunol 19(4):146–150

    PubMed  CAS  Google Scholar 

  49. Malan Borel I, Gentile T, Angelucci J, Pividori J, Margni R (1991) IgG asymmetric molecules with anti-paternal activity isolated from sera and placenta of pregnant human. J Reprod Immunol 20(2):129–140

    Article  PubMed  CAS  Google Scholar 

  50. Jalali GR, Rezai A, Underwood JL, Mowbray JF, Surridge SH, AllenWR, Matthias S (1995) An 80-kDa syncytiotrophoblast alloantigen bound to maternal alloantibody in term placenta. Am J Reprod Immunol 33:213–220

    PubMed  CAS  Google Scholar 

  51. Jalali GR, Arck P, Surridge S, Markert U, Chaouat G, Clark DA, Underwood JL, Mowbray JF (1996) Immunosuppressive properties of monoclonal antibodies and human polyclonal alloantibodies to the R80K protein of trophoblast. Am J Reprod Immunol 36:129–134

    Article  PubMed  CAS  Google Scholar 

  52. Margni RA, Malan Borel I (1998) Paradoxical behavior of asymmetric IgG antibodies. Immunol Rev 163:77–87

    Article  PubMed  CAS  Google Scholar 

  53. Malan Borel I, Gentile T, Angelucci J, Pividori J, Guala MC, Binaghi RA, Margni RA (1991) IgG asymmetric molecules with antipaternal activity isolated from sera and placenta of pregnant human. J Reprod Immunol 20(2):129–140

    Article  PubMed  CAS  Google Scholar 

  54. Zenclussen AC, Gentile T, Kortebani G, Mazzolli A, Margni R (2001) Asymmetric antibodies and pregnancy. Am J Reprod Immunol 45(5):289–294

    Article  PubMed  CAS  Google Scholar 

  55. Gentile T, Malan Borel I, Angelucci J, Miranda S, Margni R (1992) Preferential synthesis of asymmetric antibodies in rat immunized with paternal particulate antigens. Effects on pregnancy. J Reprod Immunol 22:173–183

    Article  PubMed  CAS  Google Scholar 

  56. Gentile T, Llambias P, Dokmetjian J, Margni RA (1998) Effect of pregnancy and placental factors on the quality of humoral immune response. Immunol Lett 62:151–157

    Article  PubMed  CAS  Google Scholar 

  57. Margni RA, Malan Borel I (1999) Role of asymmetric antibodies in fetal maintenance. Curr Trends Immunol 2:53–163

    Google Scholar 

  58. Canellada A, Färber A, Zenclussen AC, Gentile T, Dokmetjian J, Keil A, Blois S, Miranda S, Berod L, Gutiérrez G, Markert UR, Margni RA (2002) Interleukin regulation of asymmetric antibody synthesized by isolated placental B cells. Am J Reprod Immunol 48(4):275–282

    Article  PubMed  CAS  Google Scholar 

  59. Gutierrez G,Malan Borel I, Margni RA (2001) The placental regulatory factor involved in the asymmetric IgG antibody synthesis responds to IL-6 features. J Reprod Immunol 49:21–32

    Article  PubMed  CAS  Google Scholar 

  60. Margni RA, Zenclussen AC (2001) During pregnancy, in the context of a Th2-type cytokine profile, serum IL-6 levels might condition the quality of the synthesized antibodies. Am J Reprod Immunol 46(3):181–187

    Article  PubMed  CAS  Google Scholar 

  61. Zenclussen AC, Kortebani G, Mazzolli A, Margni R, Malan Borel I (2000) Interleukin-6 and soluble interleukin-6 receptor serum levels in recurrent spontaneous abortion women immunized with paternal white cells. Am J Reprod Immunol 44(1):22–29

    Article  PubMed  CAS  Google Scholar 

  62. Piccinni MP, Beloni L, Livi C, Maggi E, Scarselli G, Romagnani S (1998) Defective production of both, leukemia inhibitory factor and type 2 T-helper cytokines by decidual T cells in unexplained recurrent abortions. Nat Med 4:1020–1024

    Article  PubMed  CAS  Google Scholar 

  63. Lin H, Mossmann TR, Guilbert L, Tuntipopipat S, Wegmann TG (1993) Synthesis of T helper 2-type cytokines at the feto–maternal interface. J Immunol 151:4562–4573

    PubMed  CAS  Google Scholar 

  64. 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 196:122–130

    Article  PubMed  CAS  Google Scholar 

  65. Saito S (2001) Cytokine network at the feto–maternal interface. J Reprod Immunol 47:87–103

    Article  Google Scholar 

  66. 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 51:3–7

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  68. Dealtry GB, O’Farrell MK, Fernandez N (2000) The Th2 cytokine environment of the placenta. Int Arch Allergy Immunol 123(2):107–119

    Article  PubMed  CAS  Google Scholar 

  69. White CA, Johansson M, Roberts CT, Ramsay AJ, Robertson SA (2003) Effect of interleukin-10 null mutation on maternal immune response and reproductive outcome in mice. Biol Reprod 70(1):123–131

    Article  PubMed  CAS  Google Scholar 

  70. Gorivodsky M, Torchinsky A, Zemliak I, Savion S, Fein A, Toder V (1999) TGF beta 2 mRNA expression and pregnancy failure in mice. Am J Reprod Immunol 42(2):124–133

    PubMed  CAS  Google Scholar 

  71. Dünker N, Krieglstein K (2002) Tgfbeta2−/− Tgfbeta3−/− double knockout mice display severe midline fusion defects and early embryonic lethality. Anat Embryol (Berl) 206(1–2):73–83

    Google Scholar 

  72. Kruse A, Merchant MJ, Hallmann R, Butcher EC (1999) Evidence of specialized leukocyte-vascular homing interactions at the maternal/fetal interface. Eur J Immunol 29(4):1116–1126

    Article  PubMed  CAS  Google Scholar 

  73. Zambon Bertoja A, Zenclussen ML, Wollenberg I, Paeschke S, Sollwedel K, Gerlof K, Woiciechosky C, Volk HD, Zenclussen AC (2005) Upregulation of Bcl-2 at the fetal–maternal interface from mice undergoing abortion. Scand J Immunol 61:492–502

    Article  PubMed  Google Scholar 

  74. Tangri S, Raghupathy R (1993) Expression of cytokines in placentas of mice undergoing immunologically mediated spontaneous fetal resorptions. Biol Reprod 49(4):850–856

    Article  PubMed  CAS  Google Scholar 

  75. Zenclussen AC, Gerlof K, Zenclussen ML, Sollwedel A, Zambon Bertoja A, Ritter T, Kotsch K, Leber J, Volk HD (2005) Abnormal T cell reactivity against paternal antigens in spontaneous abortion: adoptive transfer of pregnancy-induced CD4+CD25+ T regulatory cells prevents fetal rejection in a murine abortion model. Am J Pathol 166:811–822

    Article  PubMed  Google Scholar 

  76. Zenclussen AC, Fest S, Joachim R, Klapp BF, Arck PC (2004) Introducing a mouse model for pre-eclampsia: adoptive transfer of activated Th1 cells leads to pre-eclampsia-like symptoms exclusively in pregnant mice. Eur J Immunol 34(2):377–387

    Article  PubMed  CAS  Google Scholar 

  77. Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, Weaver CT (2005) Interleukin 17-producing CD4 + effector T cells develop in a lineage distinct from the T helper type 1 and 2 lineages. Nat Immun 6:1123–1132

    Article  CAS  Google Scholar 

  78. Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, Wang Y, Hood L, Zhu Z, Tian Q, Dong C (2005) A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immun 6:1133–1141

    Article  CAS  Google Scholar 

  79. Moller G (1988) Do suppressor T cells exist? Scand J Immunol 27:247–250

    Article  PubMed  CAS  Google Scholar 

  80. Arruvito L, Billordo A, Capucchio M, Prada ME, Fainboim L (2009) IL-6 trans-signaling and the frequency of CD4+FOXP3+ cells in women with reproductive failure. J Reprod Immunol 82(2):158–165

    Article  PubMed  CAS  Google Scholar 

  81. Albanesi C, Cavani A, Girolomoni G (1999) IL-17 is produced by nickelspecific T lymphocytes and regulates ICAM-1 expression and chemokine production in human keratinocytes: synergistic or antagonist effects with IFN-gamma and TNF-alpha. J Immunol 162:494–502

    PubMed  CAS  Google Scholar 

  82. Loong CC, Hsieh HG, Lui WY, Chen A, Lin CY (2002) Evidence for the early involvement of interleukin 17 in human and experimental renal allograft rejection. J Pathol 197:322–332

    Article  PubMed  CAS  Google Scholar 

  83. Vanaudenaerde BM, Dupont LJ, Wuyts WA Verbeken EK, Meyts I, Bullens DM, Dilissen E, Luyts L, Van Raemdonck DE, Verleden GM (2006) The role of interleukin-17 during acute rejection after lung transplantation. Eur Respir J 27:779–787

    Article  PubMed  CAS  Google Scholar 

  84. Yoshida S, Haque A, Mizobuchi T, Iwata T, Chiyo M, Webb TJ, Baldridge LA, Heidler KM, Cummings OW, Fujisawa T, Blum JS, Brand DD, Wilkes DS (2006) Anti-type V collagen lymphocytes that express IL-17 and IL-23 induce rejection pathology in fresh and well-healed lung transplants. Am J Transplant 6:724–735

    Article  PubMed  CAS  Google Scholar 

  85. Del Prete G, De Carli M, Almerigogna F, Giudizi MG, Biagiotti R, Romagnani S (1993) Human IL-10 is produced by both type 1 helper (Th1) and type 2 helper (Th2) T cell clones and inhibits their antigen-specific proliferation and cytokine production. J Immunol 150:353–360

    PubMed  Google Scholar 

  86. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M (1995) Immunological self-tolerance maintained by activated T-cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various auto-immune diseases. J Immunol 155:1151–1164

    PubMed  CAS  Google Scholar 

  87. Kingsley CL, Karim M, Bushell AR, Wood K (2002) CD25+CD4+ regulatory T cells prevent graft rejection: CTLA4- and IL-10-dependent immunoregulation of alloresponses. J Immunol 168:1080–1086

    PubMed  CAS  Google Scholar 

  88. Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299:1057–1061

    Article  PubMed  CAS  Google Scholar 

  89. Fontenot JD, Rudensky AY (2005) A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3. Nat Immunol 6:331–337

    Article  PubMed  CAS  Google Scholar 

  90. Fontenot JD, Gavin MA, Rudensky AY (2003) Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 4:330–336

    Article  PubMed  CAS  Google Scholar 

  91. Sakaguchi S (2004) Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 22:531–562

    Article  PubMed  CAS  Google Scholar 

  92. Apostolou I, Sarukhan A, Klein L, von Boehmer H (2002) Origin of regulatory T cells with known specificity for antigen. Nat Immunol 3:756–763

    PubMed  CAS  Google Scholar 

  93. Somerset DA, Zheng Y, Kilby MD, Sansom DM, Drayson MT (2004) Normal human pregnancy is associated with an elevation in the immune suppressive CD25+ CD4+ regulatory T-cell subset. Immunology 112:38–43

    Article  PubMed  CAS  Google Scholar 

  94. Aluvihare V, Kallikourdis M, Betz A (2004) Regulatory T cells mediate maternal tolerance to the fetus. Nat Immunol 3:266–271

    Article  CAS  Google Scholar 

  95. Schumacher A, Wafula PO, Bertoja AZ, Sollwedel A, Thuere C, Wollenberg I, Yagita H, Volk HD, Zenclussen AC (2007) Mechanisms of action of regulatory T cells specific for paternal antigens during pregnancy. Obstet Gynecol 110:1137–1145

    Article  PubMed  CAS  Google Scholar 

  96. Bulmer JN, Johnson PM (1986) The T-lymphocyte population in first trimester human decidua does not express the interleukin-2 receptor. Immunology 58:685–687

    PubMed  CAS  Google Scholar 

  97. Athanassakis I, Iconomidou B (1996) Cytokine production in the serum and spleen of mice from day 6 to 14 of gestation: cytokines/placenta/spleen/serum. Dev Immunol 4:247–255

    Article  PubMed  CAS  Google Scholar 

  98. Zhu XY, Zhou YH, Wang MY, Jin LP, Yuan MM, Li DJ (2005) Blockade of CD86 signaling facilitates a Th2 bias at the maternal–fetal interface and expands peripheral CD4+CD25+ regulatory T cells to rescue abortion-prone fetuses. Biol Reprod 72:338–345

    Article  PubMed  CAS  Google Scholar 

  99. Schumacher A, Brachwitz N, Sohr S, Engeland K, Langwisch S, Dolaptchieva M, Alexander T, Taran A, Malfertheiner SF, Costa SD, Zimmermann G, Nitschke C, Volk HD, Alexander H, Gunzer M, Zenclussen AC (2009) Human chorionic gonadotropin attracts regulatory T cells into the fetal–maternal interface during early human pregnancy. J Immunol 182(9):5488–5497

    Article  PubMed  CAS  Google Scholar 

  100. Groux H, O’Garra A, Bigler M, Rouleau M, Antonenko S, de Vries JE, Roncarolo MG (1997) A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389:737–742

    Article  PubMed  CAS  Google Scholar 

  101. Weiner HL (2001) Induction and mechanism of action of transforming growth factor-beta-secreting Th3 regulatory cells. Immunol Rev 182:207–214

    Article  PubMed  CAS  Google Scholar 

  102. Wafula PO, Teles A, Schumacher A, Pohl K, Yagita H, Volk HD, Zenclussen AC (2009) PD-1 but not CTLA-4 blockage abrogates the protective effect of regulatory T cells in a pregnancy murine model. Am J Reprod Immunol 62(5):283–292

    Article  PubMed  CAS  Google Scholar 

  103. Zenclussen AC, Gerlof K, Zenclussen ML, Ritschel S, Zambon Bertoja A, Fest S, Hontsu S, Ueha S, Matsushima K, Leber J, Volk HD (2006) Regulatory T cells induce a privileged tolerance microenvironment at the fetal–maternal interface. Eur J Immunol 36:82–94

    Article  PubMed  CAS  Google Scholar 

  104. Bhatt H, Brunet LJ, Stewart CL (1991) Uterine expression of leukemia inhibitory factor coincides with the onset of blastocyst implantation. Proc Natl Acad Sci USA 88(24):11408–11412

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  106. Cheng JG, Rodriguez CI, Stewart CL (2002) Control of uterine receptivity and embryo implantation by steroid hormone regulation of LIF production and LIF receptor activity: Towards a molecular understanding of “the window of implantation”. Rev Endocr Metab Disord 3:119–126

    Article  PubMed  CAS  Google Scholar 

  107. Mikołajczyk M, Skrzypczak J, Szymanowski K, Wirstlein P (2003) The assessment of LIF in uterine flushing: a possible new diagnostic tool in states of impaired fertility. Reprod Biol 3(3):259–270

    PubMed  Google Scholar 

  108. Hu W, Feng Z, Teresky AK, Levine AJ (2007) p53 regulates maternal reproduction through LIF. Nature 450(7170):721–724

    Article  PubMed  CAS  Google Scholar 

  109. Robertson SA (2005) Seminal plasma and male factor signaling in the female reproductive tract. Cell Tissue Res 322(1):43–52

    Article  PubMed  Google Scholar 

  110. Zhao H, Wong RJ, Kalish FS, Nayak NR, Stevenson DK (2009) Effect of heme oxygenase-1 deficiency on placental development. Placenta 30(10):861–868

    Article  PubMed  CAS  Google Scholar 

  111. Wise CD, Drabkin DL (1964) Degradation of haemoglobin and hemin to biliverdin by a new cell-free system obtained from the hemophagous organ of dog placenta. Fed Proc 23:323

    Google Scholar 

  112. Tenhunen R, Marver HS, Schmid R (1968) The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase. Proc Natl Acad Sci USA 61(2):748–755

    Article  PubMed  CAS  Google Scholar 

  113. Tenhunen R, Marver HS, Schmid R (1969) Microsomal heme oxygenase – characterization of the enzyme. J Biol Chem 244(23):6388–6394

    PubMed  CAS  Google Scholar 

  114. Tenhunen R, Marver H, Pimstone NR, Trager WF, Cooper DY, Schmid R (1972) Enzymatic degradation of heme. Oxygenative cleavage requiring cytochrome P-450. Biochemistry 11(9):1716–1720

    Article  PubMed  CAS  Google Scholar 

  115. Ryter SW, Otterbein LE, Morse D, Choi AM (2002) Heme oxygenase/carbon monoxide signaling pathways: regulation and functional significance. Mol Cell Biochem 234–235(1–2):249–263

    Article  PubMed  Google Scholar 

  116. Montellano PR (2000) The mechanism of heme oxygenase. Curr Opin Chem Biol 4(2):221–227

    Article  PubMed  CAS  Google Scholar 

  117. Otterbein LE, Choi AM (2000) Heme oxygenase: colors of defense against cellular stress. Am J Physiol Lung Cell Mol Physiol 279(6):L1029–L1037

    PubMed  CAS  Google Scholar 

  118. Morse D, Choi AM (2002) Heme oxygenase-1: the “Emerging Molecule” has arrived. Am J Respir Cell Mol Biol 27(1):8–16

    PubMed  CAS  Google Scholar 

  119. Maines MD (1997) The heme oxygenase system: a regulator of second messenger gases. Annu Rev Pharmacol Toxico 37:517–554

    Article  CAS  Google Scholar 

  120. Soares MP, Lin Y, Anrather J, Csizmadia E, Takigami K, Sato K, Grey ST, Colvin RB, Choi AM, Poss KD, Bach FH (1998) Expression of heme oxygenase-1 can determine cardiac xenograft survival. Nat Med 4(9):1073–1077

    Article  PubMed  CAS  Google Scholar 

  121. Coito AJ, Buelow R, Shen XD, Amersi F, Moore C, Volk HD, Busuttil RW, Kupiec-Weglinski JW (2002) Heme oxygenase-1 gene transfer inhibits inducible nitric oxide synthase expression and protects genetically fat zucker rat livers from ischemia-reperfusion injury. Transplantation 74(1):96–102

    Article  PubMed  CAS  Google Scholar 

  122. Tullius SG, Nieminen-Kelha M, Buelow R, Reutzel-Selke A, Martins PN, Pratschke J, Bachmann U, Lehmann M, Southard D, Iyer S, Schmidbauer G, Sawitzki B, Reinke P, Neuhaus P, Volk HD (2002) Inhibition of ischemia/reperfusion injury and chronic graft deterioration by a single-donor treatment with cobalt-protoporphyrin for the induction of heme oxygenase-1. Transplantation 74(5):591–598

    Article  PubMed  CAS  Google Scholar 

  123. Braudeau C, Bouchet D, Tesson L, Iyer S, Rémy S, Buelow R, Anegon I, Chauveau C (2004) Induction of long-term cardiac allograft survival by heme oxygenase-1 gene transfer. Gene Ther 11(8):701–710

    Article  PubMed  CAS  Google Scholar 

  124. Juan SH, Lee TS, Tseng KW, Liou JY, Shyue SK, Wu KK, Chau LY (2001) Adenovirus-mediated heme oxygenase-1 gene transfer inhibits the development of atherosclerosis in apolipoprotein E-deficient mice. Circulation 104(13):519–525

    Article  Google Scholar 

  125. Fujii H, Takahashi T, Nakahira K, Uehara K, Shimizu H, Matsumi M, Morita K, Hirakawa M, Akaqi R, Sassa S (2003) Protective role of heme oxygenase-1 in the intestinal tissue injury in an experimental model of sepsis. Crit Care Med 31(3):893–902

    Article  PubMed  CAS  Google Scholar 

  126. Chora AA, Fontoura P, Cunha A, Pais TF, Cardoso S, Ho PP, Lee LY, Sobel RA, Steinman L, Soares MP (2007) Heme oxygenase-1 and carbon monoxide suppress autoimmune neuroinflammation. J Clin Invest 117(2):438–447

    Article  PubMed  CAS  Google Scholar 

  127. Pamplona A, Ferreira A, Balla J, Jeney V, Balla G, Epiphano S, Chora A, Rodrigues CD, Gregoire IP, Cunha-Rodrigues M, Portugal S, Soares MP, Mota MM (2007) Heme oxygenase-1 and carbon monoxide suppress the pathogenesis of experimental cerebral malaria. Nat Med 13(6):703–710

    Article  PubMed  CAS  Google Scholar 

  128. Christiansen OB, Nielsen HS, Kolte AM (2006) Inflammation and miscarriage. Semin Fetal Neonatal Med 11:302–308

    Article  PubMed  Google Scholar 

  129. Ryter SW, Alam J, Choi AM (2006) Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications. Physiol Rev 86(2):583–650

    Article  PubMed  CAS  Google Scholar 

  130. Zenclussen ML, Anegon I, Bertoja AZ, Chauveau C, Vogt K, Gerlof K, Sollwedel A, Volk HD, Ritter T, Zenclussen AC (2006) Over-expression of heme oxygenase-1 by adenoviral gene transfer improves pregnancy outcome in a murine model of abortion. J Reprod Immunol 69(1):35–52

    Article  PubMed  CAS  Google Scholar 

  131. Sollwedel A, Bertoja AZ, Zenclussen ML, Gerlof K, Lisewski U, Wafula P, Sawitzki B, Woiciechowsky C, Volk HD, Zenclussen AC (2005) Protection from abortion by heme oxygenase-1 up-regulation is associated with increased levels of bag-1 and neuropilin-1 at the fetal-maternal interface. J Immunol 175(8):4875–4885

    PubMed  CAS  Google Scholar 

  132. Ihara N, Akagi R, Ejiri K, Kudo T, Furuyama K, Fujita H (1998) Developmental changes of gene expression in heme metabolic enzymes in rat placenta. FEBS Lett 439:163–167

    Article  PubMed  CAS  Google Scholar 

  133. Barber A, Robson SC, Myatt L, Bulmer J, Lyall F (2001) Heme oxygenase expression in human placenta and placental bed: reduced expression of placenta endothelial HO-2 in pre-eclampsia and fetal growth restriction. FASEB J 15:1158–1168

    Article  PubMed  CAS  Google Scholar 

  134. Zenclussen AC, Lim E, Knoeller S, Knackstedt M, Hertwig K, Hagen E, Klapp BF, Arck PC (2003) Heme oxygenases in pregnancy II: HO-2 is downregulated in human pathologic pregnancies. Am J Reprod Immunol. 50:66–76

    Article  PubMed  CAS  Google Scholar 

  135. Zenclussen AC, Sollwedel A, Zambon Bertoja A, Gerlof K, Zenclussen ML, Woiciechowsky C, Volk HD (2005) Heme oxygenase as a therapeutic target in immunological pregnancy complications. Int Immunopharmacol 5(1):41–51

    Article  PubMed  CAS  Google Scholar 

  136. Cross JC (2005) How to make a placenta: mechanisms of trophoblast cell differentiation in mice- a review. Placenta 26(Suppl A, Trophoblast Research 19):S3–S9

    Article  PubMed  CAS  Google Scholar 

  137. Faria TN, Soares MJ (1991) Trophoblast cell differentiation: establishment, characterization, and modulation of rat trophoblast cell line expressing members of the placental prolactin family. Endocrinology 129(6):2895–2906

    Article  PubMed  CAS  Google Scholar 

  138. Sahgal N, Canham LN, Konno T, Wolfe MW, Soares MJ (2005) Modulation of trophoblast stem cell and giant cell phenotypes: analyses using the Rcho-1 cell model. Differentiation 73:452–462

    Article  PubMed  CAS  Google Scholar 

  139. Poss K, Tonegawa S (1997) Reduced stress defense in heme oxygenase-1 deficient cells. Proc Natl Acad Sci USA 94:10925–10930

    Article  PubMed  CAS  Google Scholar 

  140. Yet SF, Perrella MA, Layne MD, Hsieh CM, Maemura K, Kobzik L, Wiesel P, Christou H, Kourembanas S, Lee ME (1999) Hypoxia induces severe right ventricular dilatation and infarction in heme oxygenase-1 null mice. J Clin Invest 103(8):R23–R29

    Article  PubMed  CAS  Google Scholar 

  141. Espey LL, Bellinger AS, Healy JA (2004) Ovulation: An inflammatory cascade of gene expression, In: The ovary, PCK Leung and EY Adashi, Eds. Academic Press, New York, pp. 145–165

    Google Scholar 

  142. Jablonka-Shariff A, Olson LM (1998) The role of nitric oxide in oocyte meiotic maturation and ovulation: meiotic abnormalities of endothelial nitric oxide synthase knock-out mouse oocytes. Endocrinology 139:2944–2954

    Article  PubMed  CAS  Google Scholar 

  143. Drazen DL, Klein SL, Burnett AL, Wallach EE, Crone JK, Huang PL, Nelson RJ (1999) Reproductive function in female mice lacking the gene for endothelial nitric oxide synthase. Nitric Oxide 3:366–374

    Article  PubMed  CAS  Google Scholar 

  144. Hefler LA, Gregg AR (2002) Inducible and endothelial nitric oxide synthase: genetic background affects ovulation in mice. Fertil Steril 77:147–151

    Article  PubMed  Google Scholar 

  145. Yang J, Ajonuma LC, Rowlands DK, Tsang LL, Ho LS, Lam SY, Chen WY, Zhou CX, Chung YW, Cho CY, Tse JY, James AE, Chan HC (2005) The role of inducible nitric oxide synthase in gamete interaction and fertilization: a comparative study on knockout mice of three NOS isoforms. Cell Biol Int 29:785–791

    Article  PubMed  CAS  Google Scholar 

  146. McGarry HF, Plant LD, Taylor MJ (2005) Diethylcarbamazine activity against Brugia malayi microfilariae is dependent on inducible nitric-oxide synthase and the cyclooxygenase pathway. Filaria J 4:4

    Article  PubMed  CAS  Google Scholar 

  147. Ejima K, Perrella MA (2004) Alteration in heme oxygenase-1 and nitric oxide synthase-2 gene expression during endotoxemia in cyclooxygenase-2 deficient mice. Antioxid Redox Signal 6(5):850–857

    PubMed  CAS  Google Scholar 

  148. Venturini CM, Isakson P, Needleman P (1998) Non-steroidal anti-inflammatory drug-induced renal failure: a brief review of the role of cyclo-oxygenase isoforms. Curr Opin Nephrol Hypertens 7(1):79–82

    Article  PubMed  CAS  Google Scholar 

  149. Matsumoto H, Ma W, Smalley W, Trzaskos J, Breyer RM, Dey SK (2001) Diversification of cyclooxygense-2-derived prostaglandins in ovulation and implantation. Biol Reprod 64:1557–1565

    Article  PubMed  CAS  Google Scholar 

  150. Poss KD, Thomas MJ, Ebralidze AK, O’Dell TJ, Tonegawa S (1995) Hippocampal long-term potentiation is normal in heme oxygenase-2 mutant mice. Neuron 15:867–873

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Humana Press

About this protocol

Cite this protocol

Leber, A. et al. (2010). Pregnancy: Tolerance and Suppression of Immune Responses. In: Cuturi, M., Anegon, I. (eds) Suppression and Regulation of Immune Responses. Methods in Molecular Biology, vol 677. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60761-869-0_25

Download citation

  • DOI: https://doi.org/10.1007/978-1-60761-869-0_25

  • Published:

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-60761-868-3

  • Online ISBN: 978-1-60761-869-0

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics