Neroli Sunderland

Tumor necrosis factor α induces a model of preeclampsia in pregnant baboons (Papio hamadryas).

Preeclampsia is a common disease of pregnancy characterised by maternal hypertension and proteinuria. Abnormal placentation in early pregnancy and abnormal cytokine and anti-angiogenic factor expression are thought to contribute to the clinical syndrome of endothelial dysfunction evident in the second half of gestation. The mechanisms underlying both the placental pathology and its translation to the maternal clinical syndrome are not fully understood. A model of preeclampsia manifest by clinically evident endothelial dysfunction (increased blood pressure and proteinuria) was induced by administration of low-dose TNF-α for 2weeks at mid-gestation in pregnant baboons (Papio hamadryas). Blood pressure was monitored continuously and remotely by intra-arterial radiotelemetry. Following TNF-α infusion, there was an increase in systolic and diastolic blood pressure and development of proteinuria in pregnant treated animals, but not in pregnant saline controls nor in non-pregnant TNF-α treated animals. The treated pregnant animals also developed elevated plasma soluble FMS-like tyrosine kinase-1 (sFLT-1) and increased placental mRNA expression of sFLT-1 and soluble endoglin (sEng). These results clearly demonstrate that the cytokine TNF-α can induce the clinical and biochemical features of human preeclampsia. The results identify a link between cytokines, placental dysfunction and endothelial dysfunction resulting in a loss of maternal blood pressure control.

Animal Models of Pre-eclampsia

Citation Sunderland N, Hennessy A, Makris A. Animal models of pre‐eclampsia. Am J Reprod Immunol 2010; 65: 533–541

Placental Growth Factor Reduces Blood Pressure in a Uteroplacental Ischemia Model of Preeclampsia in Nonhuman Primates

An imbalance in the angiogenesis axis during pregnancy manifests as clinical preeclampsia because of endothelial dysfunction. Circulating soluble fms-like tyrosine kinase 1 (sFLT-1) increases and placental growth factor (PlGF) reduces before and during disease. We investigated the clinical and biochemical effects of replenishing the reduced circulating PlGF with recombinant human PlGF (rhPlGF) and thus restoring the angiogenic balance. Hypertensive proteinuria was induced in a nonhuman primate (Papio hamadryas) by uterine artery ligation at 136 days gestation (of a 182-day pregnancy). Two weeks after uteroplacental ischemia, rhPlGF (rhPlGF, n=3) or normal saline (control, n=4) was administered by subcutaneous injection (100 &mgr;g/kg per day) for 5 days. Blood pressure was monitored by intra-arterial radiotelemetry and sFLT-1 and PlGF by ELISA. Uteroplacental ischemia resulted in experimental preeclampsia evidenced by increased blood pressure, proteinuria, and endotheliosis on renal biopsy and elevated sFLT-1. PlGF significantly reduced after uteroplacental ischemia. rhPlGF reduced systolic blood pressure in the treated group (−5.2±0.8 mm Hg; from 132.6±6.6 mm Hg to 124.1±7.6 mm Hg) compared with an increase in systolic blood pressure in controls (6.5±3 mm Hg; from 131.3±1.5 mm Hg to 138.6±1.5 mm Hg). Proteinuria reduced in the treated group (−72.7±55.7 mg/mmol) but increased in the control group. Circulating levels of total sFLT-1 were not affected by the administration of PlGF; however, a reduction in placental sFLT-1 mRNA expression was demonstrated. There was no significant difference between the weights or lengths of the neonates in the rhPlGF or control group; however, this study was not designed to assess fetal safety or outcomes. Increasing circulating PlGF by the administration of rhPlGF improves clinical parameters in a primate animal model of experimental preeclampsia.

Maternal parity affects neonatal survival rate in a colony of captive bred baboons (Papio hamadryas)

Background  Non‐human primates, particularly baboons, are valuable as animal models for reproductive research, because of their similarity to humans. Knowledge of colony‐specific pregnancy and neonatal outcomes is essential for interpretation of such research.

Comparison of indirect and direct blood pressure measurements in baboons during ketamine anaesthesia

The aim of this study was to assess agreement between different methods of blood pressure measurement in anaesthetised baboons.

A longitudinal analysis of angiotensin II type 1 receptor antibody and angiogenic markers in pregnancy.

BACKGROUND: Preeclampsia can be caused by shallow trophoblast invasion and results in endothelial dysfunction. Angiotensin II type 1 receptor antibodies may have a role in both processes. Other angiogenic markers (placental growth factor, soluble fms‐like tyrosine kinase‐1, and soluble endoglin) have been shown to alter before clinically evident preeclampsia. OBJECTIVE: The aim of this study is to assess the longitudinal changes and utility of biomarker angiotensin II type 1 receptor antibodies and angiogenic markers in hypertensive disorders of pregnancy, gestational hypertension, and preeclampsia. STUDY DESIGN: A longitudinal prospective cohort observational study of angiogenic markers and a secondary retrospective case‐control study of angiotensin II type 1 receptor antibody changes were conducted. The studies were conducted in a large tertiary metropolitan teaching hospital (Sydney, Australia). Sequential recruitment of women with a singleton pregnancy (N = 351) was undertaken. Plasma concentrations of angiotensin II type 1 receptor antibodies, placental growth factor, soluble fms‐like tyrosine kinase‐1, and soluble endoglin were measured using validated enzyme‐linked immunosorbent assays at 12, 18, 28, 36, and 40 weeks’ gestation and 6 weeks’ postpartum. Clinical, demographic, and pregnancy data were prospectively collected. Pregnancy outcomes were classified as normotensive, gestational hypertension, or preeclampsia. Analyses were carried out using software and significance set at P < .05. RESULTS: In all, 351 women were recruited, 17 developed gestational hypertension, and 18 developed preeclampsia. Women with preeclampsia at baseline were heavier (P = .015), were taller (P = .046), and had higher systolic (P = .029) and diastolic (P = .006) blood pressure. The preeclampsia group had higher soluble fms‐like tyrosine kinase‐1 from ≥28 weeks (P = .003) and lower placental growth factor from 18 weeks (P = .004). Soluble endoglin and angiotensin II type 1 receptor antibodies did not vary over time or between groups. Angiotensin II type 1 receptor antibody (12 weeks) was positively correlated with serum pregnancy associated plasma protein A (P = .008) and human chorionic gonadotrophin (P = .04). CONCLUSION: Angiogenic markers vary longitudinally during pregnancy and placental growth factor and soluble fms‐like tyrosine kinase‐1 have a role for predicting and diagnosing preeclampsia later in disease. Our data show that angiotensin II type 1 receptor antibodies are not sensitive for disease and hence not useful as a biomarker. Larger studies are required to describe the role and functionality of angiotensin II type 1 receptor antibodies in preeclampsia.

Incidence of lymphoma in a captive-bred colony of hamadryas baboons (Papio hamadryas).

OBJECTIVE To assess the incidence of lymphoma and wasting-related deaths in the National Baboon Colony of Australia and relate it to the presence of simian T-cell lymphotrophic virus 1 (STLV-1) infection. DESIGN AND PROCEDURE The records of all animals that had died since establishment of the National Baboon Colony in Australia were reviewed retrospectively. The clinical signs and histopathological findings were recorded and assessed to determine the involvement of lymphoma in the deaths. The presence of STLV-1 was recorded if known and correlated with the STLV-1 status of the colony. RESULTS Of the deaths from disease or illness, 53% were diagnosed as or suspected to be lymphoma, occurring in mature animals with no sex predisposition. The most common presentation was rapidly occurring generalised lymphadenomegaly. CONCLUSIONS This study has described a relatively high prevalence of lymphoma in a colony of captive-bred baboons, and it is evident that STLV-1 may play a role in the disease. Management practices in baboon colonies need to take into account the possible presence of STLV-1 and aim to reduce the transmission of the virus by preventing sexual contact between positive and negative animals. Lymphoma needs to be considered as one of the more common causes of wasting and death.

CD83 is a new potential biomarker and therapeutic target for Hodgkin lymphoma

Chemotherapy and hematopoietic stem cell transplantation are effective treatments for most Hodgkin lymphoma patients, however there remains a need for better tumor-specific target therapy in Hodgkin lymphoma patients with refractory or relapsed disease. Herein, we demonstrate that membrane CD83 is a diagnostic and therapeutic target, highly expressed in Hodgkin lymphoma cell lines and Hodgkin and Reed-Sternberg cells in 29/35 (82.9%) Hodgkin lymphoma patient lymph node biopsies. CD83 from Hodgkin lymphoma tumor cells was able to trogocytose to surrounding T cells and, interestingly, the trogocytosing CD83+T cells expressed significantly more programmed death-1 compared to CD83−T cells. Hodgkin lymphoma tumor cells secreted soluble CD83 that inhibited T-cell proliferation, and anti-CD83 antibody partially reversed the inhibitory effect. High levels of soluble CD83 were detected in Hodgkin lymphoma patient sera, which returned to normal in patients who had good clinical responses to chemotherapy confirmed by positron emission tomography scans. We generated a human anti-human CD83 antibody, 3C12C, and its toxin monomethyl auristatin E conjugate, that killed CD83 positive Hodgkin lymphoma cells but not CD83 negative cells. The 3C12C antibody was tested in dose escalation studies in non-human primates. No toxicity was observed, but there was evidence of CD83 positive target cell depletion. These data establish CD83 as a potential biomarker and therapeutic target in Hodgkin lymphoma.

Characterization of the New Immune Suppressive Anti Human CD83 Monoclonal Antibody 3C12C in Non-Human Primates

Introduction CD83 is a member of the Ig superfamily. It is membrane bound on activated dendritic cells (DC) and B cells. We developed a potential therapeutic human anti-human CD83 monoclonal antibody (3C12C) and showed it prevents graft versus host disease in a human PBMC mouse xenograft model. After establishing that 3C12C binds to non-human primate (NHP, baboon Papio Hamadryas) cells, we tested 3C12C in vivo in NHPs before a first in man, first in class, Phase I clinical trial. Methods Five baboons received 3C12C (1, 5, 10mg/kg, iv) or human IgG 10mg/kg on d0, 7, 14 and d21. Peripheral blood and serum were collected weekly (x4) then every 4 weeks (x2). Bone marrow and lymph node (LN) biopsies were taken at d28. Blood counts and biochemistry were monitored. Flow cytometry analysis followed the PBMC DC subsets, B cells and T cells and bone marrow haematopoietic stem cells. Immune histological studies were performed on LNs. Results All 5 animals remained well following anti-CD83 antibody injection. 3C12C did not change blood counts or liver function. CD4+T, CD8+T and B cells remained normal to d84. 3C12C injection increased peripheral Treg transiently at d21. 3C12C reduced blood CD1c+DC in a dose dependent manner. CD1c+DC were reduced in LN. 3C12C had no influence on bone marrow hematopoietic stem cell numbers. Conclusion Our results demonstrate that 3C12C is safe in NHPs and that it reduced activated DC numbers. This data will facilitate our planned Phase I trial of 3C12C in allogenic hematopoietic stem cell transplantation.

Increased salt sensitivity in offspring of pregnancies complicated by experimental preeclampsia

Preeclampsia is a hypertensive disorder of pregnancy known to increase the risk of cardiovascular disease in mothers and offspring. Offspring exposed to a suboptimal intrauterine environment may experience altered fetal programming and subsequent long‐term cardiovascular changes. This study investigated changes in the vascular response in offspring from experimental preeclampsia (EPE) induced by uterine artery ligation, in the absence of fetal growth restriction, compared to normal baboon pregnancies (controls), following a high salt diet challenge. After 1 week of standard diet (containing <1% salt), animals were fed a high salt diet (6%) for 2 weeks. Systolic and diastolic blood pressure (SBP, DBP), aldosterone, renin and creatinine clearance were evaluated in EPE (n = 6, 50% male) and control (n = 6, 50% male) offspring. A repeated measures analysis was performed, and P < 0.05 was considered significant. At baseline, there were no differences between the groups in any parameter (EPE, mean age and weight 3.2 ± 1.2 years, 6.8 ± 1.0 kg, respectively; Control, 2.9 ± 0.8 years, 7.1 ± 1.5 kg). After salt loading the EPE group had significantly higher SBP (92 ± 5 mm Hg) compared to the control group (83 ± 4 mm Hg, P = 0.03). Aldosterone concentration was higher in the EPE group despite the same salt excretion and no difference in renal function. Salt sensitivity may differ in offspring from hypertensive pregnancies due to fetal programming. This could have long‐term consequences for cardiovascular health of EPE offspring and further research is required to determine the exact pathological mechanisms.