| | Expression of indoleamine 2,3-dioxygenase in the rhesus monkey and common marmosetReceived 21 November 2007; received in revised form 5 March 2008; accepted 14 March 2008. published online 12 May 2008. Abstract Indoleamine 2,3-dioxygenase (IDO) catalyzes the initial and rate-limiting step of tryptophan degradation along the kynurenine pathway, and is hypothesized to limit tryptophan availability at embryo implantation and prevent maternal T cell activation at the maternal–fetal interface. To determine if nonhuman primates are suitable models for investigating the role of IDO during pregnancy, we defined the expression of IDO in the rhesus monkey and common marmoset with particular attention to the female reproductive tract and placenta. IDO mRNA was detected by RT-PCR in the rhesus monkey term placenta, lung, small intestine, spleen, lymph node and nonpregnant uterus, and also in the common marmoset placenta. Immunohistochemical analysis of rhesus monkey tissues localized IDO to glandular epithelium of nonpregnant endometrium and first trimester decidua, vessel endothelium of nonpregnant myometrium, first trimester decidua and term decidua, and villous vessel endothelium and syncytiotrophoblast of term placenta. Western blot analysis confirmed IDO in rhesus monkey term placenta. In the common marmoset, IDO was detected in glandular epithelium of the nonpregnant uterus and in the decidua at day 60 and day 128 of gestation. IDO activity was higher in rhesus monkey and common marmoset decidua and placentas than in other tissues. Confirmation of IDO expression in rhesus monkey and common marmoset uterine and placental tissues supports the hypothesis that this enzyme regulates immune activation at the maternal–fetal interface and demonstrates that nonhuman primates may provide models with distinct similarities to human placentation to study the role of IDO in maternal–fetal immune dialogue. 1. Introduction  The maternal immune system is aware of fetal antigens during pregnancy. Consequently, immunological mechanisms are proposed to promote tolerance of the fetal semiallograft, including regulation of decidual leukocytes by nonclassical MHC class I molecules, control of maternal immune activation by regulatory T cells, a favorable Th1/Th2 cytokine balance and the expression of indoleamine 2,3-dioxygenase (IDO) (Petroff, 2005, Szekeres-Bartho, 2002, Trowsdale and Betz, 2006, Wilczynski, 2005). IDO is the initial and rate-limiting enzyme in tryptophan catabolism along the kynurenine pathway (Thomas and Stocker, 1999) that catalyzes oxidative cleavage of the indole nucleus of indoleamine derivatives (Shimizu et al., 1978, Yoshida and Hayaishi, 1987). Cleavage of l-tryptophan results in N-formylkynurenine, which is further catabolized to kynurenine and other metabolites (Cady and Sono, 1991). The depletion of tryptophan by IDO at the maternal–fetal interface in the mouse has been shown to prevent T cells from becoming activated by fetal antigens (Munn et al., 1998). Upon administration of 1-methyl-d,l-tryptophan, a competitive inhibitor of IDO, to pregnant mice carrying allogeneic fetuses, implantation sites were lost while there was no fetal loss in mice carrying syngeneic conceptuses. Furthermore, it was concluded that a T-cell dependent, antibody-independent activation of complement deposition at the site of implantation had occurred (Mellor et al., 2001). The role of IDO in pregnancy success in species besides the mouse and human has not been explored. The purpose of this study was to define IDO expression in the rhesus monkey and common marmoset because these nonhuman primates would be useful models for testing the hypothesis that expression of IDO regulates maternal T cell activation by fetal antigens at the maternal–fetal interface due to depletion of tryptophan (Mellor and Munn, 1999) or tryptophan metabolites preventing T cell activation (Frumento et al., 2002). Our results demonstrate that the expression of IDO in the placenta and endometrium of nonhuman primates may provide a model for studying its role in maternal–fetal immune tolerance and support model development for other pathological conditions of pregnancy, including preeclampsia. 2. Materials and methods 2.1. Animals and tissue collection Rhesus monkeys (Macaca mulatta) and common marmosets (Callithrix jacchus) were from the colony maintained at the Wisconsin National Primate Research Center. Common marmosets have a 28-day ovarian cycle and a gestational length of 144 days (Abbott, 1992). Rhesus monkeys have a 28-day menstrual cycle and a gestational length of approximately 165 days. Tissue samples were collected from 8 first trimester, 3 term, and 13 nonpregnant rhesus monkeys, and from 6 common marmosets ranging from day 60 to day 128 of gestation and 9 nonpregnant common marmosets. Rhesus monkey and common marmoset placental tissues were obtained by fetectomy or cesarean section, as previously described (Golos et al., 1992). Other tissues were obtained from healthy animals euthanized for other studies. All surgical procedures were performed in accordance with the NIH Guide for the Care and Use of Laboratory Animals, and under the approval of the University of Wisconsin Graduate School Animal Care and Use Committee. The collection of anonymous human placental tissue from pregnancies with uneventful spontaneous delivery was approved by the UW Human Subjects Committee. Tissues that were not used immediately after collection were stored at −80 °C. 2.2. RT-PCR and sequencing RNA was extracted with RNA STAT-60 (Tel-Test, Inc., Friendswood, TX) according to the manufacturer's protocol. RT-PCR reactions were performed as previously described (Burleigh et al., 2007). Primers for PCR were purchased from Integrated DNA Technologies (Coralville, IA). The IDO primers for the rhesus monkey were based on the sequences of human IDO mRNA: 5′-GGCCAGCTTCGAGAAAGAGTTGA-3′ (upstream) and 5′-CTGGCTTGCAGGAATCAGGATGTA-3′ (downstream). The PCR conditions were as follows: 94°C for 1min, 61°C for 1min, and 72°C for 2min for 35 cycles followed by a final extension at 72°C for 5min. Amplicons were visualized on a 1.3% agarose gel with ethidium bromide. The common marmoset IDO primer sequences were 5′-GTTTGCAGGGGGCAGTGCAG-3′ (upstream) and 5′-CATGTCCTGGAGGAACTGAG-3′ (downstream). The PCR conditions were identical to rhesus primers, except for an annealing temperature of 58.5°C. Amplicons were visualized on a 2% agarose gel with ethidium bromide. The amplified PCR products were subcloned using a TOPO TA cloning kit (Invitrogen, Carlsbad, CA). Subcloned fragments were sequenced using an ABI 3730 XL automated sequencing machine and the Prism Ready Reaction DyeDeoxy Terminator Sequencing Kit (Applied Biosystems, Foster City, CA). 2.3. Western blot Protein was isolated by homogenization of tissues in lysis buffer (10mM Tris–HCl, pH 8.0, 0.14M NaCl, 0.025% NaN3, 2% Triton X-100, and 1 protease inhibitor tablet (Roche, Indianapolis, IN) per 10ml of lysis buffer), incubation on ice for 10–20min and centrifugation at 14,000rpm for 10min at 4°C. The concentration of protein in the supernatant was determined by Bradford protein assay (Pierce, Rockford, IL) using BSA as the standard. Proteins were separated by electrophoresis on a 10% Tris–HCl SDS-polyacrylamide gel (BioRad Laboratories, Hercules, CA), transferred onto a PVDF membrane (Amersham Biosciences, Piscataway, NJ) and blocked in 5% nonfat milk. The membrane was incubated with sheep anti-human IDO polyclonal antibody (Serotec, Raleigh, NC) at a dilution of 1:1000 (final concentration 27.1μg/ml). The membrane was then incubated with secondary antibody, HRP-conjugated donkey anti-sheep IgG (Serotec), at a dilution of 1:20,000. The protein–antibody conjugates were detected by chemiluminescence (ECL, Amersham) and autoradiography with BioMax XAR film (Kodak, New Haven, CT). 2.4. Immunohistochemistry Tissues were fixed in 2% paraformaldehyde and then either immersed in 9% sucrose for 4h, 20% sucrose overnight and embedded in OCT mounting medium (Sakura Finetek USA, Torrance, CA) for cryosectioning or embedding in paraffin. Both paraffin and frozen sections were cut at 7μm thickness. Paraffin sections were deparaffinized and then subjected to microwave heat for 7min at full power followed by 6min at power level 6 (Samsung, Model MW 5536, 800W) in 10mM sodium citrate, pH 6.0. Some sections were treated with hydrogen peroxide/methanol, blocked in 20% horse serum (Sigma, St. Louis, MO) and then incubated in mouse anti-human IDO monoclonal antibody (Chemicon, Temecula, CA) at a dilution of 1:100 (final concentration 10μg/ml). Mouse IgG3 (Sigma) at the same concentration was the negative control. The secondary antibody was biotinylated horse anti-mouse IgG (Vector Laboratories, Burlingame, CA). Alternatively, sections were blocked in 20% donkey serum (Jackson ImmunoResearch Laboratories, Inc., West Grove, PA) followed by incubation with a sheep anti-human IDO polyclonal antibody (Serotec) at a dilution of 1:100 (final concentration 271μg/ml). Normal sheep serum (Sigma) at the same concentration was the negative control. The secondary antibody was biotinylated donkey anti-sheep IgG (Jackson). Vectastain ABC peroxidase complex (Vector Laboratories) and NovaRed substrate (Vector Laboratories) were used for positive immunostaining visualization of either primary antibody. Effective blocking of Fc receptors in monkey tissues by normal sera was demonstrated by lack of staining with nonspecific primary antibodies. The sections were then counterstained with hemotoxylin, dehydrated and mounted. Images were captured on a Leica DMIRB microscope using MagnaFire software. Immunohistochemical staining was generally more satisfactory with paraffin sections with the polyclonal IDO antibody and on cryosections with the monoclonal IDO antibody, with rhesus monkey samples. Both antibodies worked equally on common marmoset tissue sections. 3. Results 3.1. Messenger RNA and protein expression of indoleamine 2,3-dioxygenase To confirm the expression of IDO in the rhesus monkey, RNA was isolated and reverse transcribed for PCR amplification of IDO mRNA. IDO mRNA was detected in the rhesus monkey term placenta, nonpregnant uterus, lung, small intestine, spleen and lymph node (Fig. 1A). The primers designed for detecting rhesus monkey IDO mRNA based on human IDO sequences did not amplify amplicons from common marmoset RNA. Therefore, a consensus sequence was compiled that aligned the complete coding sequence from human, rat and mouse, and the partial coding sequence from rhesus monkey and woodchuck (Fig. 1B). Using new primers based on this consensus, IDO mRNA was detected in common marmoset placentas, although some samples had multiple bands (Fig. 1C) which may indicate mRNA splice variants. The rhesus monkey and common marmoset RT-PCR amplicons were cloned, sequenced and shown to represent IDO mRNA rather than IDOL1 mRNA (Ball et al., 2007) (not shown). Protein expression of IDO in first trimester and term rhesus monkey placentas was analyzed by Western blot (Fig. 1D). The antibody detected IDO in term rhesus monkey placenta as indicated by a ∼42kDa band, which corresponded to the location of the band for the human term placenta. However, IDO was not detectable by Western blot in day 36 rhesus monkey placenta. 3.2. Immunohistochemistry of indoleamine 2,3-dioxygenase Using anti-human IDO antibodies, IDO was localized in the common marmoset to the glandular epithelium of nonpregnant endometrium (Fig. 2A), of day 60 decidua (Fig. 2C) and day 128 decidua (Fig. 2D). IDO was not detectable in the placental villi or trophoblasts at day 60 or day 128 (data not shown). IDO was localized in the nonpregnant rhesus monkey to the glandular epithelium of the endometrium during the proliferative (Fig. 3A) and secretory phase (Fig. 3C). IDO was detected also in the vascular endothelium of the myometrium during the proliferative phase (Fig. 3E) and secretory phase (Fig. 3F). During pregnancy, IDO was detected in day 24 decidua in glandular epithelium (Fig. 4A) and vascular endothelium (Fig. 4B). At day 36 of gestation in the rhesus monkey, IDO was not detected in the villi (Fig. 4C). In rhesus monkey term placenta, IDO was localized to villous vascular endothelium and syncytiotrophoblast (Fig. 4D). In addition, IDO was detected in the vascular endothelium of rhesus monkey term decidua (Fig. 4E). Since IDO mRNA (Fig. 1) and enzymatic activity (Table 1) were detected in other tissues outside the reproductive tract, we evaluated several of these for IDO protein expression by IHC. In addition to detecting IDO in the rhesus monkey nonpregnant and pregnant uterus and placenta, IDO was also detectable in the rhesus monkey lymph node (Fig. 5A), spleen (Fig. 5B) and small intestine (Fig. 5C). In lymphoid tissues, immunopositive cells included cells with the morphological appearance of both macrophages and endothelial cells (Fig. 5A and B). In the small intestine, goblet cells had well-defined clusters of positive staining in the cytoplasm (Fig. 5C). | | |  | Tissue | Rhesus monkey | Common marmoset | |
|---|
| First trimester placenta | 0.15±0.12b | – | | | Term placenta | 0.44a | – | | | Day 60–72 placenta | – | 0.16±0.022c | | | Day 100–128 placenta | – | 0.22±0.065b | | | Nonpregnant uterus | 0.14±0.042b | 0.038±0.025 | | | Spleen | 0.26±0.024 | 0.16±0.073 | | | Lymph node | 0.055±0.029 | 0.073±0.029 | | | Small intestine | 0.17±0.10 | 0.03±0.00047 | | | Lung | 0.35±0.24 | 0.21±0.062 | | | | |
3.3. Assay of indoleamine 2,3-dioxygenase IDO enzymatic activity was measured in various rhesus monkey and common marmoset tissues (Table 1). IDO activity in the rhesus monkey term placenta and the control human term placenta (0.46nmol/mg/min) was in agreement with previous reports of human term placenta (Kudo et al., 2003). Similarly, a previous report of the activity of first trimester human placenta (Kudo et al., 2001) was comparable to rhesus monkey first trimester placentas in our study. We also defined IDO activity in common marmoset tissues, and common marmoset placental tissues were within the range observed for rhesus monkey placentas. IDO activity was generally detectable in lymphoid tissues of both rhesus and common marmoset monkeys. However, in common marmoset small intestine and uterine tissues, IDO activity was relatively low compared with rhesus monkey tissue, which was somewhat unexpected since expression was readily detectable by immunohistochemistry in the common marmoset endometrium (Fig. 2). 4. Discussion Expression of IDO in the uterus and placenta, as well as in other selected tissues, was defined in the rhesus monkey and common marmoset. IDO activity in the placenta was higher than in other tissues, which indicates that the placenta is likely a site of increased tryptophan depletion and metabolite production. The presence of this enzyme at the maternal–fetal interface supports the hypothesis that IDO is performing a critical function in maternal–fetal immune tolerance either by directly catabolizing tryptophan or indirectly via its metabolites. IDO in the rhesus monkey and common marmoset female reproductive tracts was found to be expressed in similar locations as in the human when analyzed by immunohistochemistry. Strong detection of IDO in human first trimester syncytiotrophoblast was observed by Kudo et al. (2004b) and Ligam et al. (2005). However, IDO was not detected in first trimester syncytiotrophoblasts by Hönig et al. (2004) and, in agreement with those results, we did not also detect IDO in first trimester syncytiotrophoblast of rhesus monkey and common marmoset. In human term syncytiotrophoblast, observations of IDO expression have ranged from absent (Ligam et al., 2005) to sporadic (Hönig et al., 2004, Sedlmayr et al., 2002) to strong (Kamimura et al., 1991, Kudo et al., 2004b). Our results from the rhesus monkey term placenta indicated that expression of IDO in syncytiotrophoblast was strong. Positive staining in fetal vascular endothelial cells has been detected by multiple investigators in the human term placenta (Hönig et al., 2004, Kudo et al., 2004b, Ligam et al., 2005, Santoso et al., 2002, Sedlmayr et al., 2002). The rhesus monkey term placenta had positive staining also in the endothelium of villous fetal blood vessels. In nonpregnant endometrium, expression of IDO in glandular epithelium of humans has been observed to increase from the proliferative to the secretory phase (Kudo et al., 2004a, Sedlmayr et al., 2002). In the rhesus monkey, expression of IDO in glandular epithelium was detected in both the proliferative and secretory phases. IDO was detected in common marmoset glandular epithelium in nonpregnant endometrium and decidua at days 60 and 128. IDO has also been detected also in glandular epithelium of humans during the first trimester (Hönig et al., 2004, Kudo et al., 2004a, Kudo et al., 2004b, Ligam et al., 2005, Sedlmayr et al., 2002). Similarly, IDO was detected in first trimester glandular epithelium in the rhesus monkey. The endothelium of spiral arteries and capillaries was positive for IDO expression in human first trimester decidua (Sedlmayr et al., 2002), and IDO was detected also in rhesus monkey first trimester and term decidua. Several investigators have focused on the role of IDO in T cell immunosuppression in the setting of the maternal–fetal interface. In a previous study using the rhesus monkey, endometrial CD3+ T cells increased significantly from the proliferative phase to day 19 of pregnancy and significantly then decreased by day 36 of pregnancy compared with the proliferative phase (Slukvin et al., 2004). CD3+ T cells were located in aggregates surrounding endometrial vessels and, to a lesser extent, were associated with endometrial glands. In addition, the number of CD68+ macrophages was significantly higher at implantation and early pregnancy decidua compared with proliferative endometrium. Tissue macrophages are known to express IDO (Munn et al., 1999), and IDO has been detected in human decidual macrophages (Ligam et al., 2005). While it is tempting to speculate that this relationship between the increasing population of macrophages and decreasing population of T cells may be occurring because of the effects of IDO, it is difficult to reconcile this view with our failure to identify IDO expression in decidual macrophages. Expression of IDO by human first trimester decidual macrophages was not observed by Cupurdija et al. (2004). We observed substantial expression of IDO in vascular endothelium of the rhesus monkey endometrium and decidua. One possible role of IDO in the endothelium may be as a free radical scavenger due to its use of superoxide anion (Ligam et al., 2005, Thomas and Stocker, 1999). During pregnancy, the placenta is a site of oxidative stress associated with the presence of polyunsaturated fatty acids and lipid peroxides (Ligam et al., 2005, Santoso et al., 2002). In preeclampsia, levels of IDO in placental endothelial cells are decreased compared with normal pregnancy (Kudo et al., 2003, Santoso et al., 2002, Walsh, 1998). Therefore, maternal endothelium can be damaged by oxygen free radical-initiated lipid peroxidation (Santoso et al., 2002). Thus, IDO may be responsible for maintaining healthy maternal and fetal endothelium. While there may be beneficial effects of IDO expression in endometrium for pregnancy success, no precise role of IDO during pregnancy has been experimentally established in human gestation. The role of IDO may be one of immunotolerance at initiation of pregnancy when its expression at the maternal–fetal interface may limit the amount of tryptophan necessary for T cell proliferation (Moffett and Namboodiri, 2003, Munn et al., 1999), or catabolism of tryptophan may generate metabolites that cause apoptosis of potentially anti-fetal cytotoxic T cells (Fallarino et al., 2002). In later gestation, as placental and endothelial expression is maintained, IDO may serve an important antioxidant role ensuring that fetal and maternal blood vessels remain healthy and dilated as pregnancy progresses (Ligam et al., 2005). Understanding, in particular, this latter role may lead to treatments for preeclampsia and recurrent spontaneous abortion (Kudo et al., 2003, Santoso et al., 2002, Wilczynski, 2006). For further investigation of the in vivo role(s) of IDO, experimental animal models such as the rhesus monkey and common marmoset should be valuable approaches for exploring its basic biological function and its feasibility as a therapeutic as well as experimental target. Acknowledgements We thank the Pathology Unit at the W.N.P.R.C. for embedding tissues in paraffin and tissue collection at necropsy, W.N.P.R.C. Veterinary Services for animal surgeries, Heather Simmons DVM for immunohistochemical analysis assistance, Fritz Wegner of W.N.P.R.C. Assay Services for assistance in activity assay standard curve preparation and Jeremy Sullivan for advice in Western blot analysis. This research was supported by NIH grants R01 HD34215 to T.G.G., P51 RR000167 to the W.N.P.R.C. and T32 HD041921 Training Grant in Endocrinology Reproductive Physiology to J.G.D. References Abbott, 1992. 1.Abbott DH. Reproduction in female marmoset monkeys, Callithrix jacchus. In: Hamlett WC editors. Reproductive Biology of South American Vertebrates. New York: Springer-Verlag; 1992;p. 245–261. Ball et al., 2007. 2.Ball HJ, Sanchez-Perez A, Weiser S, Austin CJD, Astelbauer F, Miu J, et al. Characterization of an indoleamine 2,3-dioxygenase-like protein found in humans and mice. Gene. 2007;396:203–213. MEDLINE |
CrossRef
Burleigh et al., 2007. 3.Burleigh DW, Kendziorski CM, Choi YJ, Grindle KM, Grendell RL, Magness RR, et al. Microarray analysis of BeWo and JEG3 trophoblast cell lines: identification of differentially expressed transcripts. Placenta. 2007;28:383–389. Cady and Sono, 1991. 4.Cady SG, Sono M. 1-Methyl-dl-tryptophan, beta-(3-benzofuranyl)-dl-alanine (the oxygen analog of tryptophan), and beta-[3-benzo(b)thienyl]-dl-alanine (the sulfur analog of tryptophan) are competitive inhibitors for indoleamine 2,3-dioxygenase. Arch. Biochem. Biophys. 1991;291:326–338. MEDLINE |
CrossRef
Cupurdija et al., 2004. 5.Cupurdija K, Azzola D, Hainz U, Gratchev A, Heitger A, Takikawa O, et al. Macrophages of human first trimester decidua express markers associated to alternative activation. Am. J. Reprod. Immunol. 2004;51:117–122. Fallarino et al., 2002. 6.Fallarino F, Grohmann U, Vacca C, Bianchi R, Orabona C, Spreca A, et al. T cell apoptosis by tryptophan catabolism. Cell Death Differ. 2002;9:1069–1077. MEDLINE |
CrossRef
Frumento et al., 2002. 7.Frumento G, Rotondo R, Tonetti M, Damonte G, Benatti U, Ferrara GB. Tryptophan-derived catabolites are responsible for inhibition of T and natural killer cell proliferation induced by indoleamine 2,3-dioxygenase. J. Exp. Med. 2002;196:459–468. MEDLINE |
CrossRef
Golos et al., 1992. 8.Golos TG, Handrow RR, Durning M, Fisher JM, Rilling JK. Regulation of chorionic gonadotropin-alpha and chorionic somatomammotropin messenger ribonucleic acid expression by 8-bromo-adenosine 3′,5′-monophosphate and dexamethasone in cultured rhesus monkey syncytiotrophoblasts. Endocrinology. 1992;131:89–100. MEDLINE |
CrossRef
Hönig et al., 2004. 9.Hönig A, Rieger L, Kapp M, Sütterlin M, Dietl J, Kämmerer U. Indoleamine 2,3-dioxygenase (IDO) expression in invasive extravillous trophoblast supports role of the enzyme for materno–fetal tolerance. J. Reprod. Immunol. 2004;61:79–86. Abstract | Full Text |
Full-Text PDF (385 KB)
|
CrossRef
Kamimura et al., 1991. 10.Kamimura S, Eguchi K, Yonezawa M, Sekiba K. Localization and developmental change of indoleamine 2,3-dioxygenase activity in the human placenta. Acta Med. Okayama. 1991;45:135–139. Kudo et al., 2001. 11.Kudo Y, Boyd CA, Sargent IL, Redman CW. Tryptophan degradation by human placental indoleamine 2,3-dioxygenase regulates lymphocyte proliferation. J. Physiol. 2001;535:207–215. MEDLINE |
CrossRef
Kudo et al., 2003. 12.Kudo Y, Boyd CA, Sargent IL, Redman CW. Decreased tryptophan catabolism by placental indoleamine 2,3-dioxygenase in preeclampsia. Am. J. Obstet. Gynecol. 2003;188:719–726. Abstract | Full Text |
Full-Text PDF (281 KB)
|
CrossRef
Kudo et al., 2004a. 13.Kudo Y, Hara T, Katsuki T, Toyofuku A, Katsura Y, Takikawa O, et al. Mechanisms regulating the expression of indoleamine 2,3-dioxygenase during decidualization of human endometrium. Hum. Reprod. 2004;19:1222–1230. MEDLINE |
CrossRef
Kudo et al., 2004b. 14.Kudo Y, Boyd CA, Spyropoulou I, Redman CW, Takikawa O, Katsuki T, et al. Indoleamine 2,3-dioxygenase: distribution and function in the developing human placenta. J. Reprod. Immunol. 2004;61:87–98. Abstract | Full Text |
Full-Text PDF (319 KB)
|
CrossRef
Ligam et al., 2005. 15.Ligam P, Manuelpillai U, Wallace EM, Walker D. Localisation of indoleamine 2,3-dioxygenase and kynurenine hydroxylase in the human placenta and decidua: implications for role of the kynurenine pathway in pregnancy. Placenta. 2005;26:498–504. Mellor and Munn, 1999. 16.Mellor AL, Munn DH. Tryptophan catabolism and T-cell tolerance: immunosuppression by starvation?. Immunol. Today. 1999;20:469–473. MEDLINE |
CrossRef
Mellor et al., 2001. 17.Mellor AL, Sivakumar J, Chandler P, Smith K, Molina H, Mao D, et al. Prevention of T cell-driven complement activation and inflammation by tryptophan catabolism during pregnancy. Nat. Immunol. 2001;2:64–68. MEDLINE |
CrossRef
Moffett and Namboodiri, 2003. 18.Moffett JR, Namboodiri MA. Tryptophan and the immune response. Immunol. Cell Biol. 2003;81:247–265. MEDLINE |
CrossRef
Munn et al., 1999. 19.Munn DH, Shafizadeh E, Attwood JT, Bondarev I, Pashine A, Mellor AL. Inhibition of T cell proliferation by macrophage tryptophan catabolism. J. Exp. Med. 1999;189:1363–1372. MEDLINE |
CrossRef
Munn et al., 1998. 20.Munn DH, Zhou M, Attwood JT, Bondarev I, Conway SJ, Marshall B, et al. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science. 1998;281:1191–1193. MEDLINE |
CrossRef
Petroff, 2005. 21.Petroff MG. Immune interactions at the maternal–fetal interface. J. Reprod. Immunol. 2005;68:1–13. Abstract | Full Text |
Full-Text PDF (136 KB)
|
CrossRef
Santoso et al., 2002. 22.Santoso DI, Rogers P, Wallace EM, Manuelpillai U, Walker D, Subakir SB. Localization of indoleamine 2,3-dioxygenase and 4-hydroxynonenal in normal and pre-eclamptic placentae. Placenta. 2002;23:373–379. Sedlmayr et al., 2002. 23.Sedlmayr P, Blaschitz A, Wintersteiger R, Semlitsch M, Hammer A, MacKenzie CR, et al. Localization of indoleamine 2,3-dioxygenase in human female reproductive organs and the placenta. Mol. Hum. Reprod. 2002;8:385–391. MEDLINE |
CrossRef
Shimizu et al., 1978. 24.Shimizu T, Nomiyama S, Hirata F, Hayaishi O. Indoleamine 2,3-dioxygenase. Purification and some properties. J. Biol. Chem. 1978;253:4700–4706. MEDLINE Slukvin et al., 2004. 25.Slukvin II, Breburda EE, Golos TG. Dynamic changes in primate endometrial leukocyte populations: differential distribution of macrophages and natural killer cells at the rhesus monkey implantation site and in early pregnancy. Placenta. 2004;25:297–307. Szekeres-Bartho, 2002. 26.Szekeres-Bartho J. Immunological relationship between the mother and the fetus. Int. Rev. Immunol. 2002;21:471–495. MEDLINE |
CrossRef
Thomas and Stocker, 1999. 27.Thomas SR, Stocker R. Redox reactions related to indoleamine 2,3-dioxygenase and tryptophan metabolism along the kynurenine pathway. Redox Rep. 1999;4:199–220. MEDLINE |
CrossRef
Trowsdale and Betz, 2006. 28.Trowsdale J, Betz AG. Mother's little helpers: mechanisms of maternal–fetal tolerance. Nat. Immunol. 2006;7:241–246. MEDLINE |
CrossRef
Walsh, 1998. 29.Walsh SW. Maternal–placental interactions of oxidative stress and antioxidants in preeclampsia. Semin. Reprod. Endocrinol. 1998;16:93–104. MEDLINE Wilczynski, 2005. 30.Wilczynski JR. Th1/Th2 cytokines balance—yin and yang of reproductive immunology. Eur. J. Obstet. Gynecol. Reprod. Biol. 2005;122:136–143. Abstract | Full Text |
Full-Text PDF (178 KB)
|
CrossRef
Wilczynski, 2006. 31.Wilczynski JR. Immunological analogy between allograft rejection, recurrent abortion and pre-eclampsia—the same basic mechanism?. Hum. Immunol. 2006;67:492–511. MEDLINE |
CrossRef
Yoshida and Hayaishi, 1987. 32.Yoshida R, Hayaishi O. Indoleamine 2,3-dioxygenase. Methods Enzymol. 1987;142:188–195. MEDLINE |
CrossRef
a Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, WI, USA b Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA c Department of Obstetrics and Gynecology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA  Corresponding author at: Wisconsin National Primate Research Center, University of Wisconsin, 1223 Capitol Court, Madison, WI 53715-1299, USA. Tel.: +1 608 263 3567; fax: +1 608 263 3524.
PII: S0165-0378(08)00029-6 doi:10.1016/j.jri.2008.03.005 © 2008 Elsevier Ireland Ltd. All rights reserved. | |
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