Almost 4 million infants under 6 months old die each year of infections, many of which are vaccine-preventable. The infant immune system cannot control infection, or respond to vaccination, as effectively as older children's or adults', which has been attributed to immunologic immaturity. Here, we have identified a mechanism to explain this reduced immunity in young infants: they possess innate regulatory cells, called myeloid-derived suppressor cells (MDSC), which are potent inhibitors of both NK cell and T cell activation. MDSC have never been described before in infants, and are rarely seen in healthy adults. MDSC have best been characterized in adult cancer patients where they have remarkable, albeit reversible, suppressive effects on anti-tumor T cell activity. Our overall hypothesis is that MDSC populations present in neonates and infants suppress infant NK and T cell responses resulting in inefficient responses to both infection and vaccination early in life.
The aims addressed in this application will phenotypically and functionally define MDSC in cord blood. We will perform longitudinal studies in infants during the first year of life to assess the influence of MDSC on infant immune responses to routine childhood vaccines and infections. In addition, the aims will determine if suppression of neonatal NK and T cells by MDSC is arginase-1-dependent with the use of arginase-1 inhibitors. Finally we will determine if inhibition of MDSC function will abrogate their suppressive actions and enhance neonatal NK and T cell activity. The challenge of early life vaccination lies in the limitations of the infant immune response. Thus, it is pertinent to elucidate the mechanisms behind reduced neonatal immunity to illuminate ways to enhance infant immune responses.

Public Health Relevance

The overarching goal of this study is to determine if MDSC are involved in the well-documented inability of infants to respond to infection/vaccination and to identify possible interventions that could be applied in a clinical setting.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI100018-03
Application #
8640882
Study Section
Special Emphasis Panel (ZAI1-LGR-I (J1))
Program Officer
Prabhudas, Mercy R
Project Start
2012-04-01
Project End
2017-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
3
Fiscal Year
2014
Total Cost
$394,960
Indirect Cost
$153,552
Name
Seattle Biomedical Research Institute
Department
Type
DUNS #
070967955
City
Seattle
State
WA
Country
United States
Zip Code
98109
Gervassi, Ana L; Horton, Helen (2014) Is Infant Immunity Actively Suppressed or Immature? Virology (Auckl) 2014:1-9
Gervassi, Ana; Lejarcegui, Nicholas; Dross, Sandra et al. (2014) Myeloid derived suppressor cells are present at high frequency in neonates and suppress in vitro T cell responses. PLoS One 9:e107816