Indoleamine-dioxygenase is expressed in human decidua at the time maternal tolerance is established

Department of Anatomy and Reproductive Biology, RWTH University Aachen, Germany.
Journal of Reproductive Immunology (Impact Factor: 2.82). 07/2007; 74(1-2):34-45. DOI: 10.1016/j.jri.2006.11.001
Source: PubMed


The semi-allogeneic fetus has to be tolerated by the maternal immune system. In mice, it has been shown that inhibiting indoleamine-dioxygenase (IDO) leads to fetal rejection, suggesting a central significance for IDO in establishing maternal tolerance. Consequently, we have analyzed IDO expression in human endometrium and decidua to determine whether it may be of significance in human reproduction. Endometrial (n=60) and decidual (n=68; first and second trimester) tissue samples and isolated cells were analyzed for IDO mRNA and protein expression by real-time PCR, Western blot and immunohistochemistry. IDO expression in the decidua of proven fertile women (n=34) was compared to women presenting with their first pregnancy (n=22) and women with a history of miscarriages (n=12). Expression of IDO was localized in glandular epithelial cells and scattered stromal leukocytes. Expression started at the mid-luteal phase in the menstrual cycle and was high until the second trimester of pregnancy. However, glandular expression of IDO decreased during the second trimester, whereas expression in villous trophoblast started at this time. There were no significant differences in decidual IDO expression between proven fertile women and women presenting with their first pregnancy or women with a history of miscarriages. From the expression pattern we conclude that IDO may play a central role in human pregnancies for the establishment of maternal tolerance of fetal antigens. Thereby, IDO expression may be needed in each pregnancy independently from prior pregnancies, and a history of miscarriage may not reflect a general deficiency in IDO expression.

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    • "The second series of studies that support our hypothesis is based on the analyses of IDO expression during pregnancy. Elevated IDO expression has been found in the epithelium of cervical glands, Fallopian tubes and endometrial stromal cells during decidualization in both animal and human studies [37,38,40,41]. Interestingly, CD8 T cells comprise the largest fraction of T cells at the fetal-maternal interface [42]. "
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    ABSTRACT: Background The local tissue microenvironment plays an important role in the induction, homing, maintenance and development of effector functions of T cells. Thus, site-specific differences in phenotypes of mucosal and systemic T cell populations have been observed. Chlamydia trachomatis most commonly infects the endocervix in women, yet little is known about Chlamydia-specific effector T cell immunity at this unique mucosal site. Our previous flow-cytometry-based study of cervical-cytobrush retrieved cells indicated that CD8 T cells are significantly increased in the C. trachomatis-infected human endocervix. The cytolytic function of CD8 T cells is important in the protective immunity against many intracellular pathogens, and requires the cytolytic granule perforin to facilitate the entry of other molecules that mediate the lysis of target cells. Determination of perforin expression of the CD8 T cell population in the endocervix would therefore provide insights on the granule-mediated cytolytic potential of these cells at this site. Results Our histological data revealed that C. trachomatis-infected tissues have significantly higher numbers of CD3 and CD8 T cells compared to non-infected tissues (p<0.01), and that the majority of CD8+ cells do not express perforin in situ. A subsequent flow cytometric analysis of paired blood and endocervix-derived cells (n=16) revealed that while all the CD8 T cell subsets: naïve, effector memory (TEM), central memory (TCM) and terminally differentiated effector memory (TEMRA) can be found in the blood, the endocervix is populated mainly by the TEM CD8 T cell subset. Our data also showed that perforin expression in the TEM population is significantly lower in the endocervix than in the blood of C. trachomatis positive women (n=15; p<0.0001), as well as in C. trachomatis-negative individuals (n=6; p<0.05). Interestingly, our in vitro co-culture study suggests that the exposure of HeLa 229 cervical epithelial cells to IFN gamma could potentially induce a decrease in perforin content in CD8 TEM cells in the same microenvironment. Conclusions The low perforin content of CD8 TEM cells in the endocervix, the local site of C. trachomatis infection in women, may reflect the unique immunological environment that balances immune protection against sexually transmitted infections and immune- tolerance to support conception.
    BMC Immunology 12/2012; 13(1):66. DOI:10.1186/1471-2172-13-66 · 2.48 Impact Factor
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    • "Indoleamine -2,3 dioxygenase (IDO) and tryptophanyl-tRNA synthetase (TTS/WARS) were up-regulated 5.7 fold and 2.4 fold respectively in endometrium of pregnant cows' in the current study. Upregulation of IDO has been reported in other species [56-58] and is likely to have an immunosuppressive function in the cow. Munn et al (1998) described a novel mechanism by which the maternal system prevents fetal rejection through increased IDO expression, specifically through the suppression of T-cell activity. "
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    ABSTRACT: A large proportion of pregnancy losses occur during the pre-implantation period, when the developing embryo is elongating rapidly and signalling its presence to the maternal system. The molecular mechanisms that prevent luteolysis and support embryo survival within the maternal environment are not well understood. To gain a more complete picture of these molecular events, genome-wide transcriptional profiles of reproductive day 17 endometrial tissue were determined in pregnant and cyclic Holstein-Friesian dairy cattle. Microarray analyses revealed 1,839 and 1,189 differentially expressed transcripts between pregnant and cyclic animals (with > or = 1.5 fold change in expression; P-value < 0.05, MTC Benjamini-Hochberg) in caruncular and intercaruncular endometrium respectively. Gene ontology and biological pathway analysis of differentially expressed genes revealed enrichment for genes involved in interferon signalling and modulation of the immune response in pregnant animals. The maternal immune system actively surveys the uterine environment during early pregnancy. The embryo modulates this response inducing the expression of endometrial molecules that suppress the immune response and promote maternal tolerance to the embryo. During this period of local immune suppression, genes of the innate immune response (in particular, antimicrobial genes) may function to protect the uterus against infection.
    BMC Genomics 08/2010; 11(1):474. DOI:10.1186/1471-2164-11-474 · 3.99 Impact Factor
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    • "Suzuki et al. showed that IDO protein and its mRNA were not expressed during early murine gestation, but they appeared 2-3 days afterwards, lasting for about three days and declining rapidly thereafter (26). According to von Rango's study (27), IDO expression starts at the mid-luteal phase in the menstrual cycle and remains high until the second trimester of pregnancy. However, glandular expression of IDO decreases during the second trimester, whereas its expression in villous tropho-blasts starts in the meantime. "
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    ABSTRACT: The cells expressing Indoleamine 2, 3-dioxygenase (IDO) in feto-maternal interface mediate tryptophan catabolism, hence protect allogeneic fetus from lethal rejection by maternal immune responses. In this study, we report immuno-localization of IDO(+) cells in murine reproductive tract and placenta throughout mouse pregnancy by immunohistochemistry. Syngeneic pregnant mice were examined for vaginal plug to discover about their state of pregnancy. A total of three pregnant mice were examined at each stage.The examination was further confirmed by the detection of sperm in vaginal smear. On the gestational days of 2(nd), 12(th) and 18(th), the uterus and oviduct were removed and expression of IDO was investigated in the endometrium, placenta and oviduct by immunohistochemistry. Our results showed that IDO is expressed consistently in feto-maternal interface throughout pregnancy. In endometrium, expression of IDO was predominantly confined to luminal and glandular epithelial cells. Cells at junctional and labyrinth zones of placenta showed strong IDO immunoreactivity as well. Expression of IDO at the protein level in reproductive tract of pregnant mice during entire periods of gestation points to its potential protective role in maintenance of pregnancy. In our knowledge this is the first report of expression of IDO in feto-maternal phase during murine pregnancy.
    Journal of Reproduction and Infertility 10/2009; 10(3):177-83.
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