Expression of insulin-like growth factor (IGF) family members in porcine pregnancy.

Prenatal mortality is a prime concern for commercial swine industry in North America. Fetal losses occur throughout gestation but cluster in early (~day20) and mid (~day50) pregnancy. Adequate vascularization of the attachment site has emerged as a key factor contributing to fetal success.

Expression of angiogenic basic fibroblast growth factor, platelet derived growth factor, thrombospondin-1 and their receptors at the porcine maternal-fetal interface.

Background: Commercial swine breeds in North America undergo two waves of spontaneous fetal loss; one during peri-attachment and another during mid-gestation. Although an exact mechanism for this loss is not known, deficits in vasculature at the attachment sites appear to be a major cause. We hypothesized that a balance between pro-angiogenic and anti-angiogenic factors is needed at the maternal-fetal interface for successful conceptus development.

NKT cell costimulation: experimental progress and therapeutic promise.

Invariant natural killer T (iNKT) cells are innate lymphocytes with unique specificity for glycolipid antigens and remarkable immunomodulatory properties. The role of costimulatory interactions in iNKT cell responses has recently come under scrutiny. Although iNKT cells and their prototype glycolipid agonist α-galactosylceramide (α-GalCer) have shown promise in several clinical trials conducted in patients with cancer or viral diseases, current iNKT cell-based therapies are far from effective.

Expression of chemokine decoy receptors and their ligands at the porcine maternal-fetal interface.

Successful pregnancy requires coordinated maternal-fetal cross-talk to establish vascular connections that support conceptus growth. In pigs, two waves of spontaneous fetal loss occur and 30-40% of conceptuses are lost before parturition. Previous studies associated these losses with decreased angiogenic and increased inflammatory cytokines.

Angiogenic DC-SIGN(+) cells are present at the attachment sites of epitheliochorial placentae.

Spontaneous early and mid-gestation fetal losses occur in swine. At both stages, endometrial lymphocytes associated with smaller, paler conceptuses have fewer pro-angiogenic and more pro-inflammatory cytokine transcripts compared with robust conceptuses. We hypothesized that similar differences occur in conceptus-associated dendritic cells (DCs).

Cytokine array comparisons of plasma from cycling fertile women on cycle day 5 and ovulation.

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 (alpha = 0.

CD56bright cells increase expression of {alpha}4 integrin at ovulation in fertile cycles.

Leukocyte content of human endometrium changes rapidly after ovulation, particularly as a result of gains in CD56(bright) uterine NK (uNK) cells. We have proposed that uNK precursor cells are found within the blood CD56(bright) pool and are recruited to decidualizing endometrium through functional changes in their adhesion molecules and chemokine receptors. This study sought to quantify alterations in adhesion molecules, cytokines, chemokines, and receptors induced in circulating CD56(+) cells of fertile and infertile women by ovulation.

CD56+ cells are recruited to the uterus in two waves: at ovulation and during the first 2 weeks after missed menses.

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.

Decline in number of elevated blood CD3(+) CD56(+) NKT cells in response to intravenous immunoglobulin treatment correlates with successful pregnancy.

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.

Defibrinated bovine plasma inhibits retroviral transcription by blocking p52 activation of the NFkappaB element in the long terminal repeat.

Bovine leukemia virus (BLV) induces a persistent but latent infection in cattle. Viral latency is invoked by a protein known as plasma blocking factor (PBF) that is found in both bovine and human plasma. We report here on pathways that mediate latency in the presence of PBF.

Uterine natural killer cells: a specialized differentiation regulated by ovarian hormones.

In adult females of many species, a transient population of natural killer (NK) cells appears in cycles within the uterine endometrium (lining). Appearance of these lymphocytes coincides with specific phases of the ovarian hormone cycle and/or early pregnancy. Studies in rodents, women, and pigs dominate the literature and suggest the uterine (u)NK cells are an activated subset sharing many but not all features with circulating or lymphoid organ-residing NK cells.

A review of trafficking and activation of uterine natural killer cells.

Problem: Enrichment of uterine natural killer (uNK) cells occurs during pregnancy in many species. However, functions of uNK cells and regulation of their uterine homing are not fully defined. In mice and women, uNK cells contribute to angiogenesis, a role reviewed here and now addressed in a mammal with an alternative placental type.

Purified bovine plasma blocking factor decreases Bovine leukemia virus p24 expression while increasing protein synthesis and transcriptional activity of peripheral blood mononuclear cells in short-term culture.

Bovine leukemia virus (BLV) induces a persistent infection in the B-cells causing polyclonal expansion of B-cells in one-third of infected cattle and lymphosarcoma in less than 5% of infected cattle. While BLV is difficult to detect in vivo, it is readily produced by cultured lymphocytes and is diminished when supplemented by bovine plasma. This phenomenon is attributed to a poorly characterized plasma blocking factor (PBF).

Trafficking of peripheral blood CD56(bright) cells to the decidualizing uterus--new tricks for old dogmas?

CD56(bright) lymphocytes become abundant in the human uterus during every menstrual cycle, following the surge in pituitary-derived luteinizing hormone (LH), which initiates final oocyte maturation. While the uterus is host to some CD56(bright) cells prior to ovulation, the rapid increase is thought to be due to proliferation of the resident population, accompanied by recruitment of CD56(bright) lymphocytes from the circulation. The rapid increase in CD56(bright) cells is concurrent with the onset of decidualization, the transformation of uterine stromal cells into secretory decidual cells.

Isolation of a bovine plasma fibronectin-containing complex which inhibits the expression of bovine leukemia virus p24.

Bovine leukemia virus (BLV) is a deltaretrovirus that infects cattle worldwide. In agriculturally intensive regions, approximately 30% of dairy cows are BLV infected. Like the human T-cell leukemia virus (HTLV), there is a lengthy period of viral quiescence after initial infection with BLV.

Periovulatory increases in tissue homing potential of circulating CD56(bright) cells are associated with fertile menstrual cycles.

CD56(bright) lymphocytes appear in the uterus 3-5 d after ovulation coincident with the onset of stromal cell decidualization. Although the source of these uterine immune cells is not defined, a subset of blood CD56(bright) cells exhibits enhanced capacity to adhere to decidual vascular endothelium during the periovulatory period of menstrual cycles. In this study, the effects of early pregnancy on the adhesive capacity of CD56(bright) cells to bind uterine substrates were examined in a time-course study of 18 infertile women undergoing natural cycles before transfer of frozen/thawed embryos and 18 infertile women undergoing controlled ovarian stimulation.

Menstrual cycle hormones induce changes in functional interactions between lymphocytes and decidual vascular endothelial cells.

During the secretory phase of the menstrual cycle, a natural killer (NK) cell subset expressing cluster of differentiation (CD)56bright appears in the decidualizing uterus and remains until onset of menses. If pregnancy occurs, decidual NK cells increase to become the predominant uterine lymphocytes of early pregnancy. To elucidate mechanisms of CD56bright cell recruitment to the uterus, an in vitro adhesion assay was used to assess the effect of the menstrual cycle, as well as cycle-associated hormones on adhesive properties of human lymphocytes.

Coordinate regulation of lymphocyte-endothelial interactions by pregnancy-associated hormones.

Precursors of uterine NK cells home to the uterus during early pregnancy from multiple lymphohemopoietic sources. In mouse uterine tissue, pregnancy markedly up-regulates both L-selectin- and alpha(4) integrin-dependent adhesion pathways for circulating human CD56(bright) cells, the phenotype of human uterine NK cells. Based on roles for these adhesion molecules in lymphocyte homing, we examined effects of pregnancy or the steroid hormones 17beta-estradiol or progesterone on lymphocyte-endothelial interactions in secondary lymphoid tissues and in uterus.

Uterine natural killer cells: insights into their cellular and molecular biology from mouse modelling.

In primates, including women, and in rodents, natural killer lymphocytes (NK cells) have a unique relationship with the decidualizing uterus. Implantation sites from genetically modified and transplanted mice have proven useful models for understanding potential mechanisms involved in the recruitment, activation and functions of human CD56(bright) uterine (u)NK cells. Key findings are reviewed in this article.