Effects of Diabetes on Lymphocyte Phenotype and Function During Pregnancy
Seaward, Alexandra Victoria Catherine
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Diabetic pregnant women have an increased risk of developing pre-eclampsia, a late gestational syndrome, although the reason for this gain is unknown. Placental pathology in pre-eclampsia is linked with insufficient spiral arterial modification, a process triggered by uterine natural killer (uNK) cells, an abundant pro-angiogenic cell type found in early pregnancy decidua (endometrium of the pregnant uterus). UNK cells effect spiral arterial modification, the blood supply to the placenta, through the release of interferon gamma (Ifng), a pro-inflammatory cytokine. Peripheral blood precursors of uNK cells employ a unique pattern of homing molecules to traffic to the decidua. The goal of this thesis was to advance the understanding of how homing and functions of uNK cell precursors might be modified in diabetic pregnancy. Studies employed both murine and human models. Pregnancies were studied microscopically in normoglycemic (n-) and hyperglycemic (d-) non-obese diabetic (NOD) and NOD.Ifng-/- (NOD strain with a genetic deletion of Ifng) mice. Pre-implantation embryo development was impaired in n- and d-NOD.Ifng-/- mice. Hyperglycemia decreased both numbers of uNK cells and spiral artery remodelling within d-NOD and d-NOD.Ifng-/- decidua. This decrease in spiral artery remodelling was independent of Ifng and linked with hypertrophy of smooth muscle in implantation sites. Blood leukocytes from control and diabetic pregnant women were evaluated for adhesive function and expression of key homing molecules. Diabetic leukocytes had decreased CD56+ (uNK cell lineage) cell adhesion to decidua, increased CD56+ cell adhesion to pancreas, and comparable adhesion to lymph node compared with control leukocytes, suggesting impaired decidual homing in vivo. Of 8 lymphocyte subsets resolved by flow cytometry, type 1 cytokine CD56bright cells expressed appropriate homing molecules most abundantly. Diabetes did not alter levels of expression of these receptors. These data show that diabetes alters the potential capacity for decidual homing of pre-uNK cells but that this is not achieved through reduction in levels of key homing molecules. Diabetes also reduced spiral arterial modification in mice through hypertrophy of smooth muscle. The reproductive challenges of diabetic women who have co-morbid immunological diseases merit further study.