Pregnancy: Tolerance and Suppression of Immune Responses

Methods in Molecular Biology

Volumn 677, Issue , 2011, Pages 397-417

  Leber, Anne ^c   Zenclussen, Maria Laura ^a   Teles, Ana ^b   Brachwitz, Nadja ^b   Casalis, Pablo ^a   El Mousleh, Tarek ^b   Jensen, Federico ^b   Woidacki, Katja ^b   Zenclussen, Ana Claudia ^b  

^a CHARITÉ UNIVERSITÄTSMEDIZIN BERLIN   (Germany)

^b OTTO VON GUERICKE UNIVERSITY   (Germany)

^c NONE

Author keywords

Dendritic cells; Heme oxygenase 1; Pregnancy; Regulatory T cells; Tolerance

Indexed keywords

ALLOANTIGEN; HEME OXYGENASE 1; HLA ANTIGEN CLASS 1;

ARTICLE; CELL CULTURE; DENDRITIC CELL; FEMALE; FETUS; HUMAN; IMMUNOLOGICAL TOLERANCE; IMMUNOLOGY; MAST CELL; NATURAL KILLER CELL; PLACENTA; PREGNANCY; REGULATORY T LYMPHOCYTE; UTERUS;

CELLS, CULTURED; DENDRITIC CELLS; FEMALE; FETUS; HEME OXYGENASE-1; HISTOCOMPATIBILITY ANTIGENS CLASS I; HUMANS; IMMUNE TOLERANCE; ISOANTIGENS; KILLER CELLS, NATURAL; MAST CELLS; PLACENTA; PREGNANCY; T-LYMPHOCYTES, REGULATORY; UTERUS;

EID: 79952196723     PISSN: 10643745     EISSN: 19406029     Source Type: Book Series    
DOI: 10.1007/978-1-60761-869-0_25     Document Type: Chapter

References (150)

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
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
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
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
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
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
7. Jiang SP, Vacchio MS (1998) Multiple mechanisms of peripheral T cell tolerance to the fetal “allograft”. J Immunol 160(7):3086– 3090
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
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
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
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
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
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
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
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
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
17. Peel S (1989) Granulated metrial gland cells. Adv Anat Embryol Cell Biol 115:1–112
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
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
20. Sharma R, Bulmer D, Peel S (1986) Effects of exogenous progesterone following ova-riectomy on the metrial glands of pregnant mice. J Anat 144:189–199
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
22. Metzger H (1992) The receptor with high affinity for IgE. Immunol Rev 125:37–48
23. Gilfillan AM, Tkaczyk C (2006) Integrated signalling pathways for mast-cell activation. Nat Rev Immunol 6:218–230
24. Galli SJ, Nakae S, Tsai M (2005) Mast cells in the development of adaptive immune responses. Nat Immunol 6:135–142
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
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
27. Theoharides TC, Kalogeromitros D (2006) The critical role of mast cells in allergy and inflammation. Ann N Y Acad Sci 1088:78–99
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 Fce receptor I expression. J Exp Med 188:1135–1145
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 reg- ulation by TNF-alpha. J Immunol 167(7): 4008–4016
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
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
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
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
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
35. Harvey EB (1964) Mast cell distribution in the uterus of cycling and pregnant hamsters. Anat Rec 148:507–516
36. Tabb NT (1994) Immune control of myo-metrial contractility: Role of mast cells. In: Control of uterine contractility, RE Garfield, NT Tabb, Eds. CRC Press, Boca de Raton, FL, pp. 355–373
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
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
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
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
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
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
43. Schmith A, Goepfert C, Feitsma K, Buddecke E (2002) Lovastatin-stimulated superinduc-tion of E-selectin, ICAM-1 and VCAM in TNF alpha-activated human vascular endothelial cells. Atherosclerosis 164(1):57–64
44. Worobec AS, Akin C, Scott LM, Metcalfe DD (2000) Mastocytosis complicating pregnancy. Obstet Gynecol 95(3):391–395
45. Waldmann H (2006) Immunology: protection and privilege. Nature 442(7106):987–988
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
47. Mowbray JF, Underwood JL (1985) Immunology of abortion. Clin Exp Immunol 60:1–7
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
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
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
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
52. Margni RA, Malan Borel I (1998) Paradoxical behavior of asymmetric IgG antibodies. Immunol Rev 163:77–87
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
54. Zenclussen AC, Gentile T, Kortebani G, Mazzolli A, Margni R (2001) Asymmetric antibodies and pregnancy. Am J Reprod Immunol 45(5):289–294
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
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
57. Margni RA, Malan Borel I (1999) Role of asymmetric antibodies in fetal maintenance. Curr Trends Immunol 2:53–163
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
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
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
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
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
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
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
65. Saito S (2001) Cytokine network at the feto– maternal interface. J Reprod Immunol 47:87–103
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
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
68. Dealtry GB, O’Farrell MK, Fernandez N (2000) The Th2 cytokine environment of the placenta. Int Arch Allergy Immunol 123(2):107–119
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
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
71. −/− double knockout mice display severe midline fusion defects and early embryonic lethality. Anat Embryol (Berl) 206(1–2):73–83
72. Kruse A, Merchant MJ, Hallmann R, Butcher EC (1999) Evidence of specialized leuko-cyte-vascular homing interactions at the maternal/fetal interface. Eur J Immunol 29(4):1116–1126
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
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
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
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
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
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
79. Moller G (1988) Do suppressor T cells exist? Scand J Immunol 27:247–250
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
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
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
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
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
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 pro-liferation and cytokine production. J Immunol 150:353–360
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
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 allo-responses. J Immunol 168:1080–1086
88. Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299:1057–1061
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
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
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
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
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
94. Aluvihare V, Kallikourdis M, Betz A (2004) Regulatory T cells mediate maternal tolerance to the fetus. Nat Immunol 3:266–271
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
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
97. Athanassakis I, Iconomidou B (1996) Cytokine production in the serum and spleen of mice from day 6 to 14 of gestation: cytok-ines/placenta/spleen/serum. Dev Immunol 4:247–255
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
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
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
101. Weiner HL (2001) Induction and mechanism of action of transforming growth fac-tor-beta-secreting Th3 regulatory cells. Immunol Rev 182:207–214
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
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
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
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
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
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
108. Hu W, Feng Z, Teresky AK, Levine AJ (2007) p53 regulates maternal reproduction through LIF. Nature 450(7170):721–724
109. Robertson SA (2005) Seminal plasma and male factor signaling in the female reproductive tract. Cell Tissue Res 322(1):43–52
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
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
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
113. Tenhunen R, Marver HS, Schmid R (1969) Microsomal heme oxygenase – characterization of the enzyme. J Biol Chem 244(23): 6388–6394
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
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
116. Montellano PR (2000) The mechanism of heme oxygenase. Curr Opin Chem Biol 4(2):221–227
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
118. Morse D, Choi AM (2002) Heme oxygenase-1: the “Emerging Molecule” has arrived. Am J Respir Cell Mol Biol 27(1):8–16
119. Maines MD (1997) The heme oxygenase system: a regulator of second messenger gases. Annu Rev Pharmacol Toxico 37:517–554
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
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
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
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
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
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
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
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
128. Christiansen OB, Nielsen HS, Kolte AM (2006) Inflammation and miscarriage. Semin Fetal Neonatal Med 11:302–308
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
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
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
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
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
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
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
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
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
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
139. Poss K, Tonegawa S (1997) Reduced stress defense in heme oxygenase-1 deficient cells. Proc Natl Acad Sci USA 94:10925–10930
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
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
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 knockout mouse oocytes. Endocrinology 139: 2944–2954
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
144. Hefler LA, Gregg AR (2002) Inducible and endothelial nitric oxide synthase: genetic background affects ovulation in mice. Fertil Steril 77:147–151
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
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
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
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
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
150. Poss KD, Thomas MJ, Ebralidze AK, O’Dell TJ, Tonegawa S (1995) Hippocampal long-term potentiation is normal in heme oxyge-nase-2 mutant mice. Neuron 15:867–873