bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mucosal Immunity in the Human Female Reproductive Tract: Cytotoxic T Lymphocyte Function in the Cervix and Vagina of Premenopausal and Postmenopausal Women
Authors: White Hillary D. , Yeaman Grant R. , Givan Alice L. , Wira Charles R. 
Published: September 2011

PROBLEM: To investigate the mucosal immune system in the cervix and vagina of premenopausal women in terms of immune cells present and cytolytic capacity of mucosal CD3+ T cells in the lower reproductive tract.METHODS: Fresh tissue fragments prepared by vibratome sectioning were analyzed for the presence of immune cells by confocal scanning laser microscopy (CSLM). Isolated reproductive tract cells prepared by enzymatic digestion were analyzed for CD3+ T cell phenotype by FACS analysis and for cytolytic function by an anti‐CD3 mAb mediated redirected lysis assay.RESULTS: As determined by CSLM, CD3+ cells as well as macrophages and dendritic cells are distributed throughout the lower female reproductive tract in both the epithelium and subepithelial mucosa. It was found that cervical and vaginal tissues from pre‐ and post‐menopausal women contain CD3+ T cells (CTL) that have cytolytic activity, when measured in an antigen non‐specific anti‐CD3 mAb mediated redirected lysis assay.CONCLUSIONS: These results indicate that the lower reproductive tract of women is immuno‐competent as judged by the presence of CD3, CD4, CD8, macrophage, and dendritic cells in the endocervix, ectocervix, and vagina of premenopausal and postmenopausal women. Further, these studies demonstrate that CD3+ T cells with cytolytic activity are present in the cervix and vagina during the proliferative and secretory phases of the menstrual cycle and following menopause.
Sperm Antigens and Their Use in the Development of an Immunocontraceptive
Authors: Diekman Alan B. , Herr John C. 
Published: September 2011

PROBLEM: Overpopulation is a global problem of significant magnitude, with grave implications for the future. World population is predicted to reach 10 billion people by the year 2050, an increase of more than 75% over the current population. Development of new contraceptives is necessary, since current forms of birth control are unavailable to many individuals due to sociological, financial, or educational limitations.METHODS: In an effort to identify new contraceptive alternatives, sperm‐specific antigens are under investigation as the basis for immunological regulation of fertility through contraceptive immunization. Anti‐sperm antibodies (ASA) inhibit sperm function in vitro, induce infertility in experimental models, and have been implicated in some cases of clinical infertility. Furthermore, the development of ASA in vasectomized men does not lead to physiological complications despite the persistence of these antibodies for years; thus, ASA induced by immunization of men and women may be similarly harmless. Immunization has several conceptual advantages as a method of fertility regulation: Employment of non‐pharmacologically active agents, convenience of administration, low cost, and the potential for relatively long‐lasting yet reversible effects.RESULTS: Various approaches have been taken to identify candidate sperm antigens for immunocontraceptive development. Studies that utilized monoclonal antibodies and polyclonal antisera generated against sperm preparations have identified such promising candidates as PH‐20, fertilin, SP‐17, and SP‐10. In an animal model, 100% contraceptive effects were induced following PH‐20 immunization and the effects were reversible. More recently, ASA from the sera of infertile patients were employed to identify several candidates as expressed by testis cDNA libraries. Perhaps the most extensively characterized and effective immunogen candidate identified thus far is lactate dehydrogenase‐C4 (LDH‐C4). Active immunization with LDH‐C4 suppressed fertility in a variety of mammalian species, including primates, and the reversibility of these effects was demonstrated.CONCLUSION: The successful results obtained thus far support the feasibility of an effective immunocontraceptive and indicate the importance for continued investigation of additional sperm antigens as contraceptive immunogen candidates.
The HSD‐hCG Vaccine Prevents Pregnancy in Women: Feasibility Study of a Reversible Safe Contraceptive Vaccine
Authors: Talwar G.P. , Singh Om , Gupta S.K. , Hasnain S.E. , Pal R. , Majumdar S.S. , Vrati S. , Mukhopadhay A. , Srinivasan J. , Deshmukh U. , Ganga S. , Mandokhot A. , Gupta A. 
Published: September 2011

PROBLEM: To develop a vaccine for reversible control of fertility in women.MATERIALS AND PROTOCOLS: Purified β subunit of hCG annealed to purified alpha subunit of ovine LH linked chemically to tetanus toxoid (TT) and diphtheria (DT); vaccine employed at 300 μg gonadotropin equivalent per injection adsorbed on alhydrogel with 1 mg SPLPS added in the first injection; Phase I safety trials in 47 women with elective tubal ligation; Phase II efficacy studies in 148 proven fertile women (2 children), sexually active, desirous of family planning using IUD; IUD removed when anti‐hCG titres exceed 50 ng/ml hCG bioneutralization capacity; boosters given to maintain above threshold antibody levels; post coital tests conducted in 8 volunteers; sera of protected women analysed for immuno‐determinants recognized by competitive enzyme immunoassays employing a panel of monoclonal antibodies and by direct binding to synthetic peptides; recombinant vaccines expressing phCG as a secreted product or as a fused protein anchored on membrane.RESULTS: Immunization was well tolerated with no significant changes in endocrine, metabolic and hematological indices. Normal ovulatory cycles were maintained as indicated by menstrual regulation. The vaccine was highly effective in preventing pregnancy (1 pregnancy in 1224 cycles) at and above antibody titres of 50 ng/ml. Antibodies declined in course of time in absence of boosters, with conceptions occurring below 35 ng/ml titres indicating regain of fertility. Ability of antibodies to prevent pregnancy was confirmed by post coital tests. High avidity (1010M—1) and other characteristics of antibodies generated by the vaccine are described and compared with those induced by two other hCG vaccines having undergone Phase I trials. The antibody response of the HSD vaccine in humans is characterized predominantly to an epitope recognized by the monoclonals 206 and P3W80. The antibodies had low or no reactivity with the carboxy terminal peptide and 38–57 region peptide. Live recombinant vaccines expressing βhCG as a membrane anchored peptide generated antibody response to hCG in all animals following a single injection.CONCLUSIONS: Reversible fertility control is feasible with the HSD‐hCG vaccine without impairment of ovulation or disturbance of menstrual regularity. Suggestions have been made for further optimization of the vaccine, which include replacement of TT and DT by a panel of T non B determinants communicating with the entire MHC spectrum and development of recombinant vaccine expressing phCG along with membrane anchored carrier.
The Presence of Antithyroid Antibodies in Euthyroid Patients With Unexplained Infertility and Tubal Obstruction
Authors: Geva Eli , Lessing Joseph B. , Lerner‐Geva Liat , Azem Foad , Yovel Israel , Amit Ami 
Published: September 2011

PROBLEM: The presence of antithyroid antibodies in euthyroid patients with unexplained infertility and tubal obstruction.METHOD: The presence of antithyroid autoantibodies (microsomal and thyroglobulin) was measured in 40 patients with unexplained infertility, and 40 patients with tubal obstruction infertility, and compared to 40 healthy nulligravidae.RESULTS: Eight patients (20%) in the unexplained infertility study group, seven (17.5%) in the tubal obstruction group and two (5%) in the healthy nulligravida group, were positive for antithyroid autoantibodies: five (12.5%) were positive for antimicrosomal antibodies, two (5%) were positive for antithyroglobulin antibodies, and one patient (2.5%) was positive for both. The tubal obstruction group comprised seven (17.5%) patients positive for antithyroid autoantibodies: four (10%) for antimicrosomal antibodies, two (5%) for antithyroglobulin antibodies, and one patient (2.5%) was positive for both. In the healthy nulligravidae group only two patients (5%) were positive for antithyroid antibodies: one for antimicrosomal and one for antithyroglobulin. No significant differences were found in the presence of antithyroid antibodies between patients with unexplained infertility and those with tubal obstruction infertility. Both groups differed significantly from the healthy controls with regard to the presence of antithyroid antibodies (P < 0.05).CONCLUSION: Subclinical presence of antithyroid autoantibodies is characteristic of both unexplained and mechanical infertility, as opposed to healthy controls. Further investigation of larger groups is needed to determine the prevalence of antithyroid antibodies in the unique population of infertile women.
Effects of Serum from Pregnant Versus Nonpregnant Women on Natural Killer Cell Activity
Authors: Fujino Yuji , Nakamura Yoshihiro , Ueda Kayoko , Ozaki Kouji , Ito Fumitoshi , Sun Ting‐Ting , Umesaki Naohiko , Ogita Sachio 
Published: September 2011

PROBLEM: To test the effect of serum obtained from in vitro fertilization‐embryo transfer (IVF‐ET) patients on the healthy volunteers natural killer (NK) cell activity.METHOD OF STUDY: Retrospective non‐randomized clinical study. Suppressive effect on NK cell activity was measured with serum obtained from 25 pregnant and 24 non‐pregnant women during IVF‐ET procedure.RESULTS: Suppressive serum effect of volunteers' NK cell activity was significantly higher in pregnant than in non‐pregnant women (P < 0.01).CONCLUSIONS: The suppressive activity of serum from pregnant women on NK cell suppression activity was useful in predicting the establishment of a successful pregnancy.
Lactation Stage‐Dependent Changes of Lymphocyte Subpopulations in Mammary Secretions: Inversion of CD4+/CD8+ T Cell Ratios at Parturition
Authors: Yang T.J. , Ayoub Ihsan A. , Rewinski Michael J. 
Published: September 2011

PROBLEM: Determination of lactation stage‐dependent changes in levels of lymphocyte subpopulations in milk.METHOD: Flow cytometric assay was used to identify and assay lymphocyte subpopulations in bovine milk at different stages of lactation.RESULTS: Lymphocyte subpopulations in mammary secretions of dairy cows change during the lactation cycle. In involuting glands (dry gland), ∼ 80–90% of lymphocytes were CD2+ T cells. The proportion of CD2+ T cells, however, decreased to ∼ 50% at the colostral stage and fluctuated between 50 to 60% in normal (mature) milk. Throughout the lactation stages, less than 5% were B cells as identified by the monoclonal antibodies against CD21 and MHC class II antigens. Subset analysis showed, however, that the proportion of CD5+ T cells decreased from 90% in involuting gland secretions to 75% in colostrum (peripartum stage), and to ∼ 40–50% in the normal (mature) milk. CD4+ T cells constituted between 45 to 55% of lymphocytes in the dry gland secretion but decreased drastically at parturition and maintained at the level below 20% throughout normal lactation. In contrast, the proportion of CD8+ T cells in the dry gland secretion was low, between 30 to 40%, but increased steadily, in an inversely‐related manner with that of CD4+ T cells, to ∼ 40–50% at parturition and maintained at ∼ 30–40% during the normal lactation stage thereafter. Two‐color immunofluorescence study revealed further that practically all of the CD8+ cells in dry gland secretions were CD2+, and approximately 40% of them were CD5—. Throughout the lactation cycle, WC1+γδ T cells comprised only 2 to 5% of lymphocytes in mammary secretions.CONCLUSIONS: T lymphocyte subpopulations change dynamically during stages of the lactation cycle. The selective migration of T lymphocyte subpopulations to and from the mammary gland, and their functional roles in the immune competence and regulation of the dam and sucklings remain to be elucidated.
Estrogen Inhibits Fetal Thymocyte Development In Vitro
Authors: Rijhsinghani Asha , Bhatia Sudershan K. , Kantamneni Lakshmi , Schlueter Annette , Waldschmidt Thomas J. 
Published: September 2011

PROBLEM: Transient involution of the maternal thymus in mice is known to occur during pregnancy. We have previously reported that the hormone responsible for this involution is estrogen. Interestingly, although estrogen crosses the placenta, fetal thymus gland enlarges with advancing gestational age. It is not known if fetal thymocytes are resistant to estrogen or if there are other factors that prevent estrogen from exerting an effect on the development of fetal thymocytes. Therefore we studied the effect of estrogen on isolated fetal thymic glands in vitro.METHOD OF STUDY: Pregnant Balb/c mice were sacrificed at 15 days gestation and fetal thymic lobes were obtained from all fetuses. The glands were cultured in vitro using either control medium or medium to which estrogen was added in two concentrations of 0.5 mg/ 100 ml and 1.0 mg/100 ml. After 12 days of organ culture, total thymocyte counts and phenotypic analysis by three color flow cytometry were performed by using monoclonal antibodies to surface markers of T cell subsets.RESULTS: Estrogen treatment caused a marked suppression of the total number of fetal thymocytes. All CD4 and CD8 defined T cell subsets were reduced with a disproportionate loss of CD4+ single positive (SP), CD8+ SP; CD4+CD8+ double positive (DP) cells. The early thymocyte developmental stages, based on CD44 and CD25 expression, revealed the CD4‐CD8‐CD3‐ triple negative compartment (TN) to be composed of almost entirely the earliest population (CD44+CD25‐) with the remaining maturational stages depleted.CONCLUSIONS: This study demonstrates that fetal thymus removed from the intact fetus is susceptible to the inhibitory effects of estrogen. Since the fetal thymus enlarges with advanced gestational age, it is clear that the intact fetus invokes a regulatory mechanism which neutralizes the anti‐lymphopoietic action of estrogen observed in the adult female.
Interferon Tau: A Novel Pregnancy Recognition Signal
Authors: Bazer Fuller W. , Spencer Thomas E. , Ott Troy L. 
Published: September 2011

PROBLEM: Trophectoderm of ruminant conceptuses (embryo and associated membranes) secretes tau interferons (IFNẗ) as the pregnancy recognition signal. How does it act?METHOD: Review of current data.RESULTS: IFNt acts on uterine epithelium to suppress transcription of the genes for estrogen receptor and oxytocin receptor. This blocks development of the uterine luteolytic mechanism and, therefore, release of luteolytic pulses of prostaglandin F2α, but it has no effect on expression of the progesterone receptor. Maintenance of progesterone secretion by the corpus luteum ensures establishment and maintenance of pregnancy. Secretion of IFNẗ on days 12–15 for sheep and days 14–17 for cows and goats is essential for pregnancy recognition.CONCLUSION: We propose that IFNẗ affects endometrial gene expression by activating the Jak/Stat pathway, which results in formation of the ISGF3α transcription factor complex. ISGF3α binds to interferon‐stimulated response elements and activates transcription of interferon‐responsive genes such as interferon regulatory factor‐1 (IRF‐1) which, in turn, activates expression of the negative‐acting transcription factor IRF‐2. Pregnancy (or intrauterine injection of roIFNẗ) results in a transient increase in endometrial IRF‐1 expression followed 36–48 hr later by a sustained increase in IRF‐2. We propose that IRF‐2, or an IFNẗ‐induced negative regulatory factor like IRF‐2, suppresses expression of the estrogen receptor gene and directly or indirectly blocks expression of the gene for oxytocin receptor to abrogate the uterine luteolytic mechanism and ensure the establishment of pregnancy.
Immune Suppression and Th1/Th2 Balance in Pregnancy Revisited: A (Very) Personal Tribute to Tom Wegmann
Authors: Chaouat Gérard , Diallo Juliette Tranchot , Volumenie Jean Luc , Menu Elisabeth , Gras Gabriel , Delage Geneviéve , Mognetti Barbara 
Published: September 2011

PROBLEM: The paradigm of local suppression necessary to understand the survival of the fetal allograft is often compared with the host‐tumor relationship.METHODS: We investigated two components of local immune suppression: placenta‐induced immunosuppression, which is mediated at least in part by a soluble factor of low molecular weight that can induce anergy in lymphocytes, and interleukin‐10 (IL‐10).RESULTS: We show that enhancement of IL‐10 production in the decidua and placenta after alloimmunization requires the presence of Asialo GM1+ cells. Placenta‐induced immunosuppression is linked with defects in phosphorylation of some components of the T cell receptor.CONCLUSION: NK cells could be in fact regulatory cells pushing maternal immune response toward a Th2 profile, beneficial for fetal survival, or toward a Th1 type of immune response, which acts in synergy. Modulation of TcR may represent a new mechanism for maternal‐fetal tolerance.
Uterine NK Cells and Trophoblast HLA Class I Molecules
Authors: King A. , Hiby S.E. , Verma S. , Burrows T. , Gardner L. , Loke Y. W. 
Published: September 2011

PROBLEM: To investigate the proposal that NK cells in decidua may control trophoblast migration during implantation of the human placenta.METHOD: Use Mab specific for HLA‐G and for HLA‐C in association with flow cytometry and immunoprecipitation to determine the expression of these HLA molecules by trophoblast. Expression of Killer inhibitory/activatory receptors (KIR/KAR) and the CD94 receptor by decidual NK cells was also studied.RESULTS: Extravillous trophoblast expressed HLA‐G and HLA‐C in both β2m‐associated form and as free heavy chains. KIR and KAR are expressed by decidual NK cells. The repertoire of receptors varied between different women and also between blood and decidual NK cells from the same women. The expression of CD94 was also different between blood and decidual NK cells.CONCLUSION: The recognition of HLA‐G/HLA‐C by KIR/KAR and CD94 could provide a mechansm by which decidual NK cells control trophoblast migration.
Uterine Natural Killer Cells Do Not Require Interleukin‐2 for Their Differentiation or Maturation
Authors: Croy B. Anne , Guimond Marie‐Josee , Luross Jeffrey , Hahnel Ann , Wang Baoping , van den Heuvel Marianne 
Published: September 2011

PROBLEM: Natural Killer lymphocytes (NK cells) from the pregnant uterus and from other tissues in pregnant and nonpregnant mammals can be stimulated by interleukin‐2 (IL‐2) during culture to become Lymphokine Activated Killer (LAK) cells. The susceptibility of cultured trophoblast cells to lysis by LAK cells raises the enigma of why uterine (u) NK cells that are characterized by morphology and by surface phenotyping as “activated,” and thus potentially damaging to the placenta, become localized to implantation sites during normal rodent gestation.METHOD: uNK cells migrating from explant cultures of the metrial gland were assessed for expression (mRNA and protein) of each chain of the IL‐2 receptor (IL‐2R). Implantation sites from transgenic mice lacking a functional IL‐2 gene were examined histologically for the differentiation of mature, granulated uNK cells.RESULTS AND CONCLUSION: Early post‐implantation, mRNA from migrating uNK cells contains transcripts for all three chains of the IL‐2R. Only IL‐2Rγ was expressed at day 12 of gestation; expression of this gene was also lost by day 16. Loss of IL‐2R transcription did not result in loss of protein expression; however, it did coincide with loss of uNK cell viability in vivo. Apparently normal differentiation of uNK cells occurred in IL‐2—/‐ mice and in doubly mutant IL‐2—/‐.β2m—/‐mice. Thus, despite uNK cell expression of the full 1L‐2R at day 8 of gestation, IL‐2 is not required for the maturation of uNK cells to their fully granulated form or for normal placental development.
Decidual Infiltration and Activation of Macrophages Leads to Early Embryo Loss
Authors: Baines M.G. , Duclos A.J. , Antecka E. , Haddad E.K. 
Published: September 2011

PROBLEM: There is considerable controversy concerning the root cause and mechanisms of early embryo loss. It has been suggested that most pregnancy losses occur due to morphogenetic anomalies of the embryo. It has also been suggested that the maternal specific immune system rejects the embryo.METHODS: Existing data on the cell and molecular biology of early embryo loss in murine experimental models is reviewed.RESULTS: Using the CBA ♀ × DBA/2 ♂ model of early embryo loss, it has been established that maternal inflammatory cells infiltrate the decidua basalis of all implantation sites within 48 hr after implantation. For most embryos, the relatively low numbers of macrophages (MΦ) and natural killer‐like (NK‐like) cells of maternal origin remain relatively constant after day 8, whereas 20–30% of the embryos show a significant increase in inflammatory cells in the maternal decidua, corresponding to the incidence of early embryo resorption visible at day 12. Evidence will be reviewed to suggest that decidual NK‐like cells are not cytolytic but may be producing the MΦ‐activating cytokine interferon gamma (IFN‐γ), which activates decidual MΦ and other cells. Furthermore, embryo loss is ameliorated by in vivo treatment with anti‐IFNγ or anti‐NK antisera, indicating that NK‐like cells and/or IFNγ are required for embryo loss, but not for embryo survival. In resorbing embryos, the inflammatory MΦ show evidence of having been primed during early pregnancy, in that in vitro incubation with lipopolysaccharide induced the production of tumor necrosis factor alpha and nitric oxide.CONCLUSION: These findings support the concept that early embryo loss is a nonspecific event mediated by the triggering of cytotoxin production by primed decidual macrophages.
Maternal Anti‐Placental Cell‐Mediated Reactivity and Spontaneous Abortions
Authors: Raghupathy Raj 
Published: September 2011

PROBLEM: Does Th1/Th2 balance determine pregnancy outcome, and if so, what determines Th1/Th2 balance in pregnancy?METHOD: Review and synthesis of existing data.RESULTS: A bias toward Th1 is strongly correlated with pregnancy failure in mice and humans. Pregnancy usually shifts the balance toward Th2 and placental factors/progesterone and progesterone‐stimulated CD8+ T cell production of suppressor factor; TGFβ2 and IL4/ 10 may be responsible. The bias toward a Th1 response may result from intracellular parasitic infection and other as yet undefined factors.CONCLUSION: The Th1/Th2 balance thesis appears to be valid.