Effects of biological factors on the expression of arginine vasopressin receptors

Arginine vasopressin (AVP) is a hormone that functions to regulate blood pressure and bodily fluid homeostasis. Vasopressin has three main receptors AVPR1a, AVPR1b, and AVPR2 which were investigated in this project along with OXTR, LNPEP, and CUL5. AVPR1a functions in the smooth muscle and causes vasoconstriction, AVPR1b functions in the pituitary helping to regulate adrenocorticotropic hormone release, and AVPR2 is expressed highly in the kidneys and works to concentrate urine. This project investigates how these various receptors are expressed with different factors related to pregnancy such as, sex of the baby, chronically hypertensive mothers, and gestational age at deliver

The relationship between obesity, pregnancy, and levels of indoleamine 2,3-dioxygenase

For a successful pregnancy to occur, foreign genetic material such as the allogeneic fetus must be tolerated within the maternal host. Indoleamine 2,3-dioxygenase (IDO) is an enzyme induced by pro-inflammatory cytokines that has been shown to be key to this process. Obesity as a pro-inflammatory state is associated with poor obstetric outcomes. The primary objective of this study is to investigate the relationship between obesity and IDO activity

Impact of vasopressin receptors on regulation of immune response in preeclampsia

Preeclampsia is a common disorder of pregnancy resulting in increased blood pressure and end organ effects. The pathogenesis of preeclampsia is multi-factorial. Arginine vasopressin (AVP) is increased in preeclampsia, and the chronic infusion of AVP throughout gestation has previously been shown to be sufficient to produce a phenotype of preeclampsia in C57BL/6J mice representative of some of the cardiovascular and renal events seen in humans. Alterations in T-helper cell populations and their effector cytokines are also known to occur in preeclampsia. Therefore, we proposed that the increased secretion of AVP may be responsible for the immune changes that occur in preeclampsia. We also hypothesized that known pharmacological AVP antagonist, vaptans, may be able to reverse the effects of AVP infusion

Regulatory dendritic cell treatment prevents the development of vasopressin-induced preeclampsia

The concept that persistent feto-placental intolerance is important in the pathogenesis of preeclampsia (PE) has been demonstrated by our lab and others. Arginine vasopressin (AVP) infusion during pregnancy induces cardiovascular, renal, and immune alterations in mice consistent with human PE. These findings identify AVP as a potential contributor to poor fetal tolerance and the development of PE. In addition to their conventional immuno-stimulatory role, dendritic cells (DCs) also play a vital role in immune tolerance. In contrast to conventional DCs, regulatory DCs (DCregs) express low levels of co-stimulatory markers, produce anti-inflammatory cytokines, induce T regulatory cells, and promote tolerance. In mice, DCregs are able to prevent pro-inflammatory responses and induce antigen-specific tolerance. Given these known functions of DCregs, we hypothesize that DCregs will prevent the development of AVP-induced PE

Betamethasone: a novel therapeutic intervention for preeclampsia

The early pathogenesis of preeclampsia (PE) involves a systemic inflammatory immune response. Recent data demonstrate that increased circulating arginine vasopressin (AVP) in humans is predictive of PE and that infusion of AVP in mouse dams phenocopies the pregnancy-specific cardiovascular and immune alterations observed in human PE. Specifically, AVP suppresses anti-inflammatory cytokines and cells. Betamethasone (BMTZ), commonly given to women at risk for preterm birth, is both an AVP and immune response modulator. We hypothesize that early treatment with BMTZ will prevent the development of AVP-induced PE

Static urine osmolality with elevated first trimester urine copeptin in human preeclampsia

We have previously shown that maternal plasma copeptin (CPP), as a marker of vasopressin, is highly predictive of preeclampsia (PE) in the first trimester and remains elevated throughout pregnancy. Furthermore, in maternal urine samples we demonstrated that CPP was also significantly elevated in the first trimester in women who later developed PE. Because a urine dipstick test could be easily used in the clinic, we sought to validate this finding in a new and expanded cohort of samples and to determine whether these changes persist throughout pregnancy. In addition, to begin to address the mechanism for this difference, we also assessed urine osmolality to further probe renal function

First trimester elevation in circulating endothelin-1 and arterial stiffness are predictive of late pregnancy preeclampsia

Preeclampsia (PE) is characterized by late pregnancy hypertension and proteinuria. PE causes significant morbidity for the maternal-fetal unit. Circulating endothelin-1 (ET-1), a potent vasoconstrictor, is elevated at the time of diagnosis of human PE. In addition, women with PE demonstrate arterial stiffness as early as the end of the first trimester. However, it is unknown if arterial stiffness is associated with a first trimester elevation in ET-1 and post-delivery placental ET-1. We hypothesized that 1) first trimester plasma ET-1 is elevated and is associated with arterial stiffness in women who develop PE; 2) first trimester ET-1 is predictive of PE; and 3) placental ET-1 is increased in PE. To address these questions, we performed a nested case-control study in women at risk for P

Characterization of Regulatory Dendritic Cells That Mitigate Acute Graft-versus-Host Disease in Older Mice Following Allogeneic Bone Marrow Transplantation

<div><p>Despite improvements in human leukocyte antigen matching and pharmacologic prophylaxis, acute graft-versus-host disease (GVHD) is often a fatal complication following hematopoietic stem cell transplant (HSCT). Older HSCT recipients experience significantly increased morbidity and mortality compared to young recipients. Prophylaxis with syngeneic regulatory dendritic cells (DCreg) in young bone marrow transplanted (BMT) mice has been shown to decrease GVHD-associated mortality. To evaluate this approach in older BMT recipients, young (3–4 months) and older (14–18 months) DCreg were generated using GM-CSF, IL-10, and TGFβ. Analysis of young versus older DCreg following culture revealed no differences in phenotype. The efficacy of DCreg treatment in older BMT mice was evaluated in a BALB/c→C57Bl/6 model of GVHD; on day 2 post-BMT (d +2), mice received syngeneic, age-matched DCreg. Although older DCreg-treated BMT mice showed decreased morbidity and mortality compared to untreated BMT mice (all of which died), there was a small but significant decrease in the survival of older DCreg-treated BMT mice (75% survival) compared to young DCreg-treated BMT mice (90% survival). To investigate differences between dendritic cells (DC) in young and older DCreg-treated BMT mice that may play a role in DCreg function <i>in vivo</i>, DC phenotypes were assessed following DCreg adoptive transfer. Transferred DCreg identified in older DCreg-treated BMT mice at d +3 showed significantly lower expression of PD-L1 and PIR B compared to DCreg from young DCreg-treated BMT mice. In addition, donor DC identified in d +21 DCreg-treated BMT mice displayed increased inhibitory molecule and decreased co-stimulatory molecule expression compared to d +3, suggesting induction of a regulatory phenotype on the donor DC. In conclusion, these data indicate DCreg treatment is effective in the modulation of GVHD in older BMT recipients and provide evidence for inhibitory pathways that DCreg and donor DC may utilize to induce and maintain tolerance to GVHD.</p> </div

DCreg treatment attenuates GVHD in young and older BMT mice.

<p>(A) Young and older survival and morbidity following BMT in B6 mice. Data are ± SEM. N = 3-5 mice/group. (B) Survival and morbidity of young and older BMT mice following DCreg treatment. Data are mean ± SEM. N ≥ 16 mice/group. * = p<0.05, ** = p<0.01, *** = p<0.001.</p

Regulatory dendritic cells express low levels of co-stimulatory molecules, but high levels of anti-inflammatory cytokines.

<p>Young BALB/c and B6 cDC and DCreg were stained for co-stimulatory (A) and inhibitory (B) cell surface molecules directly following culture. Live cells were gated and DC identified by gating on CD11c⁺ cells. (These cells were primarily CL II low.) rIg = rat IgG isotype control. Histograms are representative of N ≥ 4 independent experiments per group. (C) Cytokine concentrations in culture supernatants were measured by ELISA. ND, not detected. Data are mean ± SEM and represent 3 independent experiments.</p