Date of Award

January 2015

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Vikki Abrahams

Subject Area(s)

Obstetrics and gynecology

Abstract

HYDROXYCHLOROQUINE PREVENTS ANTIPHOSPHOLIPID ANTIBODY- INDUCED INHIBITION OF TROPHOBLAST MIGRATION

Women with antiphospholipid syndrome (APS) are at high risk of recurrent pregnancy complications. Antiphospholipid antibodies (aPL) target the trophoblast by binding beta2-glycoprotein I (b2GPI) and alter human first trimester trophoblast function by: triggering a pro-inflammatory cytokine response; modulating angiogenic factor secretion; and inhibiting cell migration. While patients with APS are often treated with hydroxychloroquine (HCQ), and it is safe to use during pregnancy, little is known about the effects of HCQ on aPL-associated adverse pregnancy outcomes. Therefore, the objective of this study was to test the hypothesis that HCQ prevents the effects of aPL on human first trimester trophoblast function. A human first trimester trophoblast cell line was treated with or without anti-human b2GPI monoclonal antibodies in the presence or absence of HCQ. Using ELISA, culture supernatants were analyzed for: pro- inflammatory cytokines IL-8 and IL-1b; pro-angiogenic factors VEGF and PlGF; anti- angiogenic factors sFlt-1 and soluble Endoglin; pro-migratory cytokine IL-6; and tissue inhibitors of metalloproteinase 1 and 2 (TIMP1 and TIMP2). Cell migration was measured using a colormetric two-chamber assay. The aPL-induced upregulation of trophoblast IL-8, IL-1b, PlGF, and sEndoglin secretion was not significantly altered by the presence of HCQ. The presence of HCQ partially, yet significantly, reversed the aPL- induced inhibition of trophoblast cell migration and secretion of pro-migratory cytokine IL-6. aPL-induced upregulation of trophoblast TIMP secretion appears to inhibit cell migration. HCQ was unable to completely prevent aPL-induced TIMP secretion, and this may explain why migration was only partially restored. HCQ reversed the aPL-induced inhibition of IL-6 secretion and partially limited the ability of aPL to reduce trophoblast cell migration. Our data indicate the possibility that some form of combination therapy that includes HCQ may be beneficial to pregnant APS patients and warrants further investigation.

Comments

This is an Open Access Thesis.

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