This Article  • References  • Full text PDF  • Send to a friend  • Save in My Folder  • Save to citation manager  • Permissions  Citing Articles  • Citation map  • Citing articles on HighWire  • Citing articles on Web of Science (335)  • Contact me when this article is cited  Related Content  • Similar articles in JAMA  Social Bookmarking   What's this?

Joseph A. Hill, MD; Katalin Polgar, PhD; Deborah J. Anderson, PhD

JAMA. 1995;273(24):1933-1936.

Abstract
Objective.
—To test the hypothesis that peripheral blood mononuclear cells in women with unexplained recurrent abortion (URA) produce T-helper 1 (T_H1)—type cytokines in response to trophoblast antigens.

Design.
—Cohort study.

Setting.
—Medical center.

Participants.
—A total of 244 women with URA, 13 reproductively normal parous control women, and 10 men.

Main Outcome Measures.
—Supernatants from trophoblast-activated peripheral blood mononuclear cells from all participants were tested for toxic effects on mouse embryos and by enzyme-linked immunosorbent assay (ELISA) for interferon gamma (IFN-). Supernatants from 20 URA patients with embryotoxic activity and IFN-, 13 reproductively normal parous women, and 10 men were further tested by ELISA for other T_H1-type cytokines (interleukin-2 [IL-2], tumor necrosis factor—β [TNF-β]), T_H2-type cytokines (IL-4, IL-10), and TNF-.

Results.
—Embryotoxic activity was detected in supernatants from 160 of 244 URA patients and in none of the controls. Interferon gamma was detected in supernatants from 125 of 244 URA patients and was significantly associated with embryotoxicity (121 of 160 supernatants with embryotoxicity vs four of 84 supernatants without embryotoxicity [P<.001]). Of 20 supernatants from patients chosen for further study, all were positive for TNF-, 17 for TNF-β, two for IL-10, and one for IL-4. No cytokines were detected in supernatants from unstimulated or red blood cell membrane—activated cells of women with URA. In contrast, trophoblast-activated lymphocyte supernatants from reproductively normal women and men neither were embryotoxic nor contained T_H1-type cytokines, but most contained the T_H2-type cytokine IL-10. Three supernatants from reproductively normal women also contained IL-4.

Conclusion.
—Whereas T_H1-type immunity to trophoblast is associated with URA and may play a role in reproductive failure, T_H2-type immunity may be a natural response to trophoblast contributing to successful pregnancy.

(JAMA. 1995;273:1933-1936)

Author Affiliations
From the Fearing Research Laboratory and the Harvard Recurrent Miscarriage Center, Division of Reproductive Immunology, and the Reproductive Medicine Unit, Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass.

Footnotes
Reprint requests to Fearing Research Laboratory, 250 Longwood Ave, Room 204, Boston, MA 02115 (Dr Hill).

CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter     What's this?

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

Interleukin 10 Gene Promoter Polymorphisms in Women with Pregnancy Loss: Preferential Association with Embryonic Wastage
Cochery-Nouvellon et al.
Biol. Reprod. 2009;80:1115-1120.
ABSTRACT | FULL TEXT  

Chemokine CXCL12 promotes the cross-talk between trophoblasts and decidual stromal cells in human first-trimester pregnancy
Zhou et al.
Hum Reprod 2008;23:2669-2679.
ABSTRACT | FULL TEXT  

Cyclosporin A improves murine pregnancy outcome in abortion-prone matings: involvement of CD80/86 and CD28/CTLA-4
Zhou et al.
Reproduction 2008;135:385-395.
ABSTRACT | FULL TEXT  

Associations between tumor necrosis factor-{alpha} and lymphotoxin-{alpha} polymorphisms and idiopathic recurrent miscarriage
Zammiti et al.
Reproduction 2008;135:397-403.
ABSTRACT | FULL TEXT  

Cyclic Regulation of T-Bet and GATA-3 in Human Endometrium
Inman et al.
Reproductive Sciences 2008;15:83-90.
ABSTRACT  

Toll-like receptor 4 polymorphisms and idiopathic chromosomally normal miscarriage
Hirschfeld et al.
Hum Reprod 2007;22:440-443.
ABSTRACT | FULL TEXT  

Kinetics of murine decidual dendritic cells
Zarnani et al.
Reproduction 2007;133:275-283.
ABSTRACT | FULL TEXT  

Cycling and early pregnant endometrium as a site of regulated expression of the vitamin D system.
Vigano et al.
J Mol Endocrinol 2006;36:415-424.
ABSTRACT | FULL TEXT  

Primary unexplained infertility is associated with reduced expression of the T-regulatory cell transcription factor Foxp3 in endometrial tissue
Jasper et al.
Mol Hum Reprod 2006;12:301-308.
ABSTRACT | FULL TEXT  

Gestation stage-dependent mechanisms of invariant natural killer T cell-mediated pregnancy loss
Boyson et al.
Proc. Natl. Acad. Sci. USA 2006;103:4580-4585.
ABSTRACT | FULL TEXT  

Maternal CD46H*2 and IL1B-511*1 homozygosity in T helper 1-type immunity to trophoblast antigens in recurrent pregnancy loss
Wang et al.
Hum Reprod 2006;21:818-822.
ABSTRACT | FULL TEXT  

Inflammatory Cytokine and Thrombin Regulation of Interleukin-8 and Intercellular Adhesion Molecule-1 Expression in First Trimester Human Decidua
Lockwood et al.
J. Clin. Endocrinol. Metab. 2005;90:4710-4715.
ABSTRACT | FULL TEXT  

Natural Killer Cells in Pregnancy and Recurrent Pregnancy Loss: Endocrine and Immunologic Perspectives
Dosiou and Giudice
Endocr. Rev. 2005;26:44-62.
ABSTRACT | FULL TEXT  

TNF-{alpha} Is a Critical Effector and a Target for Therapy in Antiphospholipid Antibody-Induced Pregnancy Loss
Berman et al.
J. Immunol. 2005;174:485-490.
ABSTRACT | FULL TEXT  

Exogenous interferon-{gamma} alters murine inner cell mass and trophoblast development. Effect on the expression of ErbB1, ErbB4 and heparan sulfate proteoglycan (perlecan)
Fontana et al.
Reproduction 2004;128:717-725.
ABSTRACT | FULL TEXT  

Convergence of Interferon-{gamma} and Progesterone Signaling Pathways in Human Endometrium: Role of PIASy (Protein Inhibitor of Activated Signal Transducer and Activator of Transcription-y)
Zoumpoulidou et al.
Mol. Endocrinol. 2004;18:1988-1999.
ABSTRACT | FULL TEXT  

Maternal serum levels of interferon-{gamma} and interleukin-2 soluble receptor-{alpha} predict the outcome of early IVF pregnancies
Fasouliotis et al.
Hum Reprod 2004;19:1357-1363.
ABSTRACT | FULL TEXT  

Boar seminal immunosuppressive fraction attenuates the leptin concentration and restores the thymus mass during pregnancy in mice
Veselsky et al.
Reproduction 2004;127:581-585.
ABSTRACT | FULL TEXT  

Aberrant gene expression associated with recurrent pregnancy loss
Baek
Mol Hum Reprod 2004;10:291-297.
ABSTRACT | FULL TEXT  

No difference in natural killer or natural killer T-cell population, but aberrant T-helper cell population in the endometrium of women with repeated miscarriage
Shimada et al.
Hum Reprod 2004;19:1018-1024.
ABSTRACT | FULL TEXT  

Immune Modulation in Multiple Sclerosis Patients Treated with the Pregnancy Hormone Estriol
Soldan et al.
J. Immunol. 2003;171:6267-6274.
ABSTRACT | FULL TEXT  

Prospective, serial investigations of in-vitro lymphocyte cytokine production, CD62L expression and proliferative response to microbial antigens in women with recurrent miscarriage
Kruse et al.
Hum Reprod 2003;18:2465-2472.
ABSTRACT | FULL TEXT  

Predominance of Th2-promoting dendritic cells in early human pregnancy decidua
Miyazaki et al.
J. Leukoc. Biol. 2003;74:514-522.
ABSTRACT | FULL TEXT  

Decrease of T-helper 2 and T-cytotoxic 2 cells at implantation sites occurs in unexplained recurrent spontaneous abortion with normal chromosomal content
Michimata et al.
Hum Reprod 2003;18:1523-1528.
ABSTRACT | FULL TEXT  

Concentrations of Soluble Fas in Maternal Serum and Amniotic Fluid During Uncomplicated Pregnancies
Malamitsi-Puchner et al.
Reproductive Sciences 2003;10:158-160.
ABSTRACT  

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
Kwak-Kim et al.
Hum Reprod 2003;18:767-773.
ABSTRACT | FULL TEXT  

Decreased serum levels of macrophage migration inhibition factor in miscarriages with normal chromosome karyotype
Yamada et al.
Hum Reprod 2003;18:616-620.
ABSTRACT | FULL TEXT  

A polymorphism of the interleukin-6 gene promoter and idiopathic recurrent miscarriage
Unfried et al.
Hum Reprod 2003;18:267-270.
ABSTRACT | FULL TEXT  

Expression of Interleukin-10 and Its Receptor Is Up-Regulated in Early Pregnant Versus Cycling Human Endometrium
Vigano et al.
J. Clin. Endocrinol. Metab. 2002;87:5730-5736.
ABSTRACT | FULL TEXT  

Aberrant cytokine production by peripheral blood mononuclear cells in recurrent pregnancy loss?
Bates et al.
Hum Reprod 2002;17:2439-2444.
ABSTRACT | FULL TEXT  

Cytokine imbalance in pregnancies with fetal chromosomal abnormalities
Vesce et al.
Hum Reprod 2002;17:803-808.
ABSTRACT | FULL TEXT  

Accumulation of CRTH2-positive T-helper 2 and T-cytotoxic 2 cells at implantation sites of human decidua in a prostaglandin D2-mediated manner
Michimata et al.
Mol Hum Reprod 2002;8:181-187.
ABSTRACT | FULL TEXT  

Polymorphisms of the angiotensinogen gene, the endothelial nitric oxide synthase gene, and the interleukin-1{beta} gene promoter in women with idiopathic recurrent miscarriage
Hefler et al.
Mol Hum Reprod 2002;8:95-100.
ABSTRACT | FULL TEXT  

Expression of Epstein-Barr Virus-Induced Gene 3, an Interleukin-12 p40-Related Molecule, throughout Human Pregnancy : Involvement of Syncytiotrophoblasts and Extravillous Trophoblasts
Devergne et al.
Am. J. Pathol. 2001;159:1763-1776.
ABSTRACT | FULL TEXT  

Interleukin-10 is produced by human uterine natural killer cells but does not affect their production of interferon-{gamma}
Vigano et al.
Mol Hum Reprod 2001;7:971-977.
ABSTRACT | FULL TEXT  

Th1 and Th2 cytokine profiles in recurrent aborters with successful pregnancy and with subsequent abortions
Makhseed et al.
Hum Reprod 2001;16:2219-2226.
ABSTRACT | FULL TEXT  

The PROGINS Progesterone Receptor Gene Polymorphism and Idiopathic Recurrent Miscarriage
Kurz et al.
Reproductive Sciences 2001;8:295-298.
ABSTRACT  

Sex Hormones in Experimental Autoimmune Encephalomyelitis: Implications for Multiple Sclerosis
Voskuhl and Palaszynski
Neuroscientist 2001;7:258-270.
ABSTRACT  

High anti-paternal cytotoxic T-lymphocyte precursor frequencies in women with unexplained recurrent spontaneous abortions
Kotlan et al.
Hum Reprod 2001;16:1278-1285.
ABSTRACT | FULL TEXT  

Search for Immunomodulatory Effects of Blood Transfusion in Gastric Cancer Patients: Flow Cytometry of Th1/Th2 Cells in Peripheral Blood
Sun et al.
Annals of Clinical & Laboratory Science 2001;31:171-178.
ABSTRACT | FULL TEXT  

Cutting Edge: Regulation of Uterine NKT Cells by a Fetal Class I Molecule Other Than CD1
Dang and Heyborne
J. Immunol. 2001;166:3641-3644.
ABSTRACT | FULL TEXT  

Delayed Hypersensitivity to Tuberculin, Total Immunoglobulin E, Specific Sensitization, and Atopic Manifestation in Longitudinally Followed Early Bacille Calmette-Guerin-Vaccinated and Nonvaccinated Children
Grüber et al.
Pediatrics 2001;107:36e-36.
ABSTRACT | FULL TEXT  

Pregnancy and Murine Thyroiditis: Thyroglobulin Immunization Leads to Fetal Loss in Specific Allogeneic Pregnancies
Imaizumi et al.
Endocrinology 2001;142:823-829.
ABSTRACT | FULL TEXT  

The functionally important IL-10 promoter polymorphism (-1082G{->}A) is not a major genetic regulator in recurrent spontaneous abortions
Karhukorpi et al.
Mol Hum Reprod 2001;7:201-203.
ABSTRACT | FULL TEXT  

The effect of intercourse on pregnancy rates during assisted human reproduction
Tremellen et al.
Hum Reprod 2000;15:2653-2658.
ABSTRACT | FULL TEXT  

Circulating cytokines and CD30 in normal human pregnancy and recurrent spontaneous abortions
Makhseed et al.
Hum Reprod 2000;15:2011-2017.
ABSTRACT | FULL TEXT  

Role of Estrogen Receptor {alpha} in Hematopoietic Stem Cell Development and B Lymphocyte Maturation in the Male Mouse
Thurmond et al.
Endocrinology 2000;141:2309-2318.
ABSTRACT | FULL TEXT  

Cytokine production by maternal lymphocytes during normal human pregnancy and in unexplained recurrent spontaneous abortion
Raghupathy et al.
Hum Reprod 2000;15:713-718.
ABSTRACT | FULL TEXT  

Interleukin-10 receptors are expressed by basement membrane anchored, {alpha}6 integrin+ cytotrophoblast cells in early human placenta
Szony et al.
Mol Hum Reprod 1999;5:1059-1065.
ABSTRACT | FULL TEXT  

A Deficiency of Placental IL-10 in Preeclampsia
Hennessy et al.
J. Immunol. 1999;163:3491-3495.
ABSTRACT | FULL TEXT  

IL-10 selectively induces HLA-G expression in human trophoblasts and monocytes
Moreau et al.
Int Immunol 1999;11:803-811.
ABSTRACT | FULL TEXT  

Estriol ameliorates autoimmune demyelinating disease: Implications for multiple sclerosis
Kim et al.
Neurology 1999;52:1230-1230.
ABSTRACT | FULL TEXT  

Cutting Edge: Cytokine-Dependent Abortion in CBA DBA/2 Mice Is Mediated by the Procoagulant fgl2 Prothombinase
Clark et al.
J. Immunol. 1998;160:545-549.
ABSTRACT | FULL TEXT  

Immunotherapy for Recurrent Pregnancy Loss: "Standard of Care of Buyer Beware"
Hill
Reproductive Sciences 1997;4:267-273.
 

Correlation of Serum Cytokine and Adhesion Molecule Determinations With Pregnancy Outcome
Schust and Hill
Reproductive Sciences 1996;3:259-261.
ABSTRACT  

Recurrent Pregnancy Loss and Cytokines: Not as Simple as It Seems
Dudley
JAMA 1995;273:1958-1959.
ABSTRACT