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Problem Understanding of uterine natural killer (u NK) cell functions during normal pregnancy remains incomplete. Method of study Cloud tag analysis of literature was used to document themes addressed experimentally for u NK cells. Immunohistochemistry, including whole-mount staining of early implantation sites, separation of u NK cells into molecularly distinct subsets, and physiologic measurements in normal and mutant mice, are further advancing understanding of u NK cell biology. Results Literature analyses revealed three key, current u NK cell research themes: angiogenesis, spiral arterial remodeling/pre-eclampsia/hypertension and infertility. UNK cells are being defined as cells potentially regulated by Wnt signaling that are heterogeneous in progenitor source and function and make unique contributions to implantation site development prior to spiral arterial remodeling. Conclusion Future studies are poised to define uNK cell progenitor cells, identify the signaling pathways supporting established u NK cell functions and move current understanding of mouse u NK cells to clinical research questions. [ABSTRACT FROM AUTHOR]

Problem To identify plasma immuno-regulatory molecules up or down regulated between the follicular phase and ovulation of the human menstrual cycle. Method of study RayBio® cytokine arrays were used to screen 174 immuno-regulatory molecules in plasma collected during the follicular phase at menstrual cycle day 5 and at ovulation from five healthy, non-smoking, fertile women of reproductive age not using hormonal contraception. Results A total of 23 differentially expressed molecules were found: 10 molecules were differentially up-regulated and 13 down-regulated at ovulation compared with that at the follicular phase (α = 0.05, false discovery rate of 0.45). Conclusion Circulating immuno-regulatory molecules fluctuate over the menstrual cycle in healthy women. The combination of differentially expressed molecules suggests roles in cyclical regulation of angiogenesis and immune cell trafficking. [ABSTRACT FROM AUTHOR]

Problem Uterine natural killer (uNK) cells are enriched in the post-ovulatory uterus and during pregnancy. Whether these cells arise from blood pre-cursors or from stem cells in the uterus is undefined. To support a hypothesis that precursors of uNK cells are recruited from blood, adhesive function of blood CD56+ subsets were assessed during one cycle and during pregnancy. Method of study Fifteen women of proven fertility provided serial blood samples during one menstrual cycle and thirty women with a history of implantation failure or recurrent spontaneous abortion provided serial samples during infertility treatment. Results CD56bright cells, but not CD56dim cells or NKT cells, increased in ligand-binding capacity during ovulation in fertile cycles only and during the first 2 weeks from date of missed menses. Conclusion Enhanced adhesive function at ovulation in CD56bright cells in fertile cycles and during early gestation supports a hypothesis of recruitment of pre-uNK cells from the blood CD56bright subset. [ABSTRACT FROM AUTHOR]

Problem Patients with elevated blood natural killer (NK) cells may be offered intravenous immunoglobulin (IVIG) treatment, but there is controversy about the utility of blood NK cell testing. Human CD56+ NK cells include several subpopulations that include the putatively cytotoxic CD56+ CD16+ subset. In mouse models of pregnant failure, NKT cells appear to be important. However, a mouse model may only be pertinent to a subset of patients, as recurrent pregnancy failure is a heterogenous group. Method of study An ethics-approved observational study was done to observe the effect of treatment on total blood lymphoid cells, and subsets of CD56+ blood lymphocytes including CD56+ CD3+ NKT cells determined by flow cytometry, and to correlate with pregnancy outcome. Fifteen fertile women with a history of successful pregnancy and thirty-one women suffering from repeated implantation failure or recurrent spontaneous abortion provided serial blood samples during one menstrual cycle or prior to and during treatment. IVIG was administered to the latter group with or without heparin/aspirin. Results Eight of thirty infertile women presented with high numbers of CD56+ CD3+ NKT cells, which declined after treatment with IVIG. The elevated NKT cell group with or without concomitant autoimmunity achieved a significantly higher successful pregnancy rate over the course of the study, as compared to women with average numbers of NKT cells and no evidence of autoimmunity ( P = 0.018). Elevated NKT levels alone was an independent predictor of success on treatment ( P = 0.003). Conclusion Elevated NKT cells in recurrent pregnancy loss or implantation failure can be ameliorated with IVIG treatment, and result in successful pregnancy. Assay of NKT cell numbers may idengif"y patients who are more likely to benefit from IVIG therapy and merits further examination in randomized phase II studies. [ABSTRACT FROM AUTHOR]

Citation Burke SD, Barrette VF, Gravel J, Carter ALI, Hatta K, Zhang J, Chen Z, Leno-Durán E, Bianco J, Leonard S, Murrant C, Adams MA, Anne Croy B. Uterine NK cells, spiral artery modification and the regulation of blood pressure during mouse pregnancy. Am J Reprod Immunol 2010 Reproductive success in mammals involves coordinated changes in the immune and cardiovascular as well as in the neuroendocrine and reproductive systems. This review addresses studies that identify potential links for NK cells and T cells with the local and systemic cardiovascular adaptations of pregnancy. The studies reviewed have utilized immunohistochemisty and in vivo analyses of vascular parameters by ultrasound, chronic monitoring of hemodynamics via radiotelemetric recording and intravital microscopy. At the uterine level, functional subsets of uterine natural killer cells were identified. These included subsets expressing molecules important for vasoregulation, in addition to those previously identified for angiogenesis. Spiral arteries showed conducted responses that could account for conceptus control of vasoactivity and mouse gestational blood pressure 5-phase pattern. Vascular immunology is an emerging transdisciplinary field, critical for both reproductive immunology and cardiovascular disease. [ABSTRACT FROM AUTHOR]