Intrauterine infection/inflammation (IUI) is a major contributor to preterm labor and fetal inflammation leading to injury responses in fetal organs such as the brain, lung and the GI tract. However, the mechanisms and precise therapeutic approaches remain elusive largely because of lack of relevant animal models. We have developed a powerful new model of intrauterine infection in preterm Rhesus macaques: Intraamniotic (IA) injection of live E. coli followed 24h later with antibiotics. This model results in persistent IUI. Importantly, the maternal and fetal inflammation persists despite clearance of E. coli bacteremia, resulting in preterm labor (PTL), fetal immune aberrations and fetal neuroinflammation. We now propose validating IL1 as a drug target for IUI induced prematurity and fetal inflammation. This grant is based on our data that Anakinra (IL1 receptor antagonist used clinically for rheumatoid arthritis) significantly decreased neutrophilic infiltration at the maternal-fetal interface and amniotic fluid IL6, PGE2 in a different but widely used model of IA LPS. Furthermore, Anakinra reversed the LPS-induced ?inflammatory Treg? in the fetal spleen. We propose to test the hypothesis that Anakinra will reduce the residual maternal and fetal inflammation in infectious models that closely simulate IUI in pregnant women with two Aims.
In Aim 1, we will ask if anti IL1 directed anti- inflammatory therapy will decrease intrauterine infection induced inflammation and preterm labor. We will use state-of-the-art single-cell transcriptomic approach to unravel cellular and molecular mechanisms of inflammation at the maternal-fetal interface, define labor associated pathways of IUI that are responsive to IL1 inhibition. Using multi-parameter flow cytometry, we will identify mechanisms of neutrophil recruitment and activation in the chorio-decidua.
In Aim 2, We will identify mucosal and systemic fetal immune perturbations resulting from transient bacteremia and sterile fetal inflammation. We will determine if Anakinra can reduce fetal systemic inflammation and neuroinflammation resulting from IUI. These studies will develop the critical knowledge base for future studies aimed at repurposing of Anakinra as a novel anti-inflammatory therapy for human IUI. A collaborative multi-disciplinary team will use high-resolution immunology, genomics/proteomics, neuro-science, and translational approaches in modeling IUI and fetal inflammation in an animal model that closely mimics the human pathology.
Intrauterine inflammation is an important cause of preterm labor and injury to the brain, lung and GI tract of the unborn fetus and thus constitutes a major public health problem in this population. This grant will study the efficacy of Anakinra (IL-1 inhibitor) as a novel therapy in preventing preterm labor and intrauterine inflammation in Rhesus macaques. This knowledge will be important to develop treatment approaches aimed at improving maternal and child health.
