Immune system profile of newborns born to mothers treated with TNF inhibitors through pregnancy

Abstract

[eng] This thesis is framed in the concept that tumor necrosis factor (TNF) is a fundamental cytokine for: 1) the immune responses against mycobacterial challenge being a key component for the IL-12/IFN-γ axis integrity, and 2) for lymphoid organogenesis, a process that begins in the human fetus and undergoes a postnatal maturation process. We hypothesize that exposure to TNF inhibitors (TNFi) during whole pregnancy interferes with the normal development of the immune system of children born to mothers with rheumatic diseases and inflammatory bowel disease, resulting in secondary immunodeficiency, including dysfunction of the IL-12/IFN-γ axis with increased risk of intramacrophagic infections, and disturbance of fetal/neonatal lymphoid organogenesis.

The general objective of this project is to characterize the immune profile of children born to mothers with chronic inflammatory diseases, concretely rheumatic diseases (RMD) and inflammatory bowel disease (IBD), exposed or not to TNFi during pregnancy compared with a healthy control cohort. Secondarily, to characterize the normal immune maturation process during childhood. The specific objectives are: Objective 1. To determine the concentration of TNFi in umbilical cord blood and peripheral blood of the Exposed newborns. • • Objective 1.1. To determine the correlation of TNFi concentration in maternal peripheral blood and umbilical cord blood. • • Objective 1.2. To determine the TNFi clearance in the Exposed newborns’ bloodstream after birth.

Objective 2. To characterize if cellular and humoral immunity development are affected in newborns born to mothers with RMD and IBD exposed or not to TNFi from birth to 12 months of age compared to healthy control. • • Objective 2.1. To characterize the general leukocyte populations and lymphocyte populations, including T cells, B cells, natural killer cells, and regulatory cells. • • Objective 2.2. To characterize the T cell proliferation capacity. • • Objective 2.3. To characterize the humoral immunity and vaccine responses in the Exposed newborns. • • Objective 2.4. To determine if the changes in lymphoid organogenesis are correlated with the TNFi drug concentration in umbilical cord blood and peripheral blood of the Exposed newborns.

Objective 3. To study if the IL-12/IFN-γ axis is affected in newborns born to mothers with RMD and IBD exposed or not to TNFi from birth to 12 months of age compared to a healthy control. • • Objective 3.1. To study the function of the IL-12/IFN-γ axis. • • Objective 2.3. To determine if the changes in IL-12/IFN-γ axis are correlated with the TNFi drug concentration in umbilical cord blood and peripheral blood of the Exposed newborns.

Objective 4. To analyze the clinical manifestations of the newborns exposed to TNFi during pregnancy, including the infection history and general pondostatural development. Objective 5. To establish and communicate a protocol for the follow-up of children exposed to TFNi during pregnancy, including specific recommendations for routine immunization schedules. Objective 6. To define the maturation profile of lymphocyte populations including the regulatory populations in healthy pediatric population, from 1- 18 years of age. Objective 7. To define the IL-12/IFN-γ axis maturation profile in healthy pediatric population from 1 – 18 years of age.