Intrauterine growth restriction (IUGR) commonly results in neurological deficits ranging from cognitive and behavioral disabilities to cerebral palsy. White matter injuries are a leading part of the pathogenesis of these disabilities, including diffuse lack of myelin and lack of the mature oligodendrocytes that synthesize the myelin sheath. The causes of the white matter pathology are thought to be oxidative stress, inflammation and excitotoxicity. Oligodendrocyte progenitors, the predominant form of the oligodendrocyte lineage present in the developing CNS during the period of injury, are exquisitely sensitive to these factors which arrest them in a pre-myelinating state. The ability to identify exactly how oligodendrocyte differentiation is blocked during IUGR would allow us to devise therapies to enable the oligodendrocytes to complete their maturation and protect the progenitors from further harm. We have used an animal model of IUGR, created by bilateral ligation of the intrauterine artery during the pre-natal period, to study the etiology of the white matter deficits. We find that the affected animals lack more than 50% of the normal complement of oligodendrocytes and myelinating axons during the peak of myelination. Our recent studies have examined the immune phenotype in the IUGR brain and have identified an increase in activated microglia and an altered cytokine protocol in which Th2 cytokines are specifically elevated over controls. The normal fetus and newborn exhibit a Th2 bias to allow for maternal-fetal immune tolerance however, the IUGR pups appear to have an exaggerated response. We identified the cytokine IL-4 as particularly elevated during the period of rapid myelination. By treating newborn IUGR pups with an IL-4 function blocking antibody, we were able to rescue oligodendrocyte differentiation and myelin protein expression, suggesting that the excess IL-4 was responsible for the myelin deficit. This is a highly novel role for the IL-4 cytokine, which is thought to be anti-inflammatory and protective in adult demyelinating diseases such as multiple sclerosis. Experiments designed in this proposal will determine the immune phenotype in the neonatal IUGR brain, which cell synthesizes the excess IL-4 in IUGR, and which cell responds to it. Although our preliminary data suggests that IL-4 can decrease oligodendrocyte differentiation in purified primary culture, we will determine if oligodendrocytes are the direct or indirect targets in the IUGR brain and which processes of differentiation are inhibited. These experiments in combination will facilitate further studies on neuroimmune regulation and how it modulates myelination in the newborn.

Public Health Relevance

Intrauterine growth retardation (IUGR) often results in cognitive and behavioral deficits and is characterized, in part, by white matter injury including a lack of oligodendrocytes and myelin. We have identified a novel Th2 immune phenotype in an animal model of IUGR and find that blocking the effect of one elevated cytokine, IL4, can rescue significant myelin and oligodendrocyte deficits in these animals. We will begin to study this highly novel result by identifying the altered immune cell types in the brain, which of them synthesize the IL-4 and whether the excess IL-4 directly effects oligodendrocyte maturation and myelination.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS103075-02
Application #
9685950
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Koenig, James I
Project Start
2018-04-15
Project End
2021-03-31
Budget Start
2019-04-01
Budget End
2021-03-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19146