Necrotizing enterocolitis (NEC) in preterm infantsjs.a complex, multi-factorial disease typically characterized by an exaggerated inflammatory response to pathogenic flora leading to bowel necrosis and often death. Dysregulated intestinal immune development may play an important role in the disease process, though this area is still poorly defined. To advance our understanding of NEC pathophysiology we propose to isolate adaptive immune cells from the lamina propria of surgically resected tissue from NEC patients and controls. We will test the hypothesis that a relative absence or reduced function of lamina propria F0XP3^ T regulatory cells (Treg) in the ileum of predisposed preterm infants is a risk factor for NEC. Treg are professional immune suppressor cells that are typically characterized as interleukin-2 receptor a (IL-2Ra = CD25)''"3'''CD4^ CD45RO* IL-7R (CD127)*"'T cells expressing high levels of the transcription factor forkhead box protein 3 (FOXPS). Depletion of Treg from the normal CD4* T cell pool or mutation ofthe FOXPS gene results in immune dysregulation involving the intestinal tract.
The Specific Aims ofthis proposal are to test the following three hypotheses: (1) Intestinal T effector cells (Teff) from preterm infants with NEC are less susceptible to Treg function. Intestinal Teff from preterm infants with NEC and controls will be compared for responsiveness to Treg by measuring inhibition of T cell proliferation. IL-2, IL-6, IL-17, TNF, and TGF-p levels in supernatants of Teff cultures will determine if NEC patients provide factors that promote or inhibit Treg generation, (2) Treg function in the ileum of preterm infants with NEC is limited. We will measure if Treg presence and/or function is reduced in NEC patients by comparing T cell suppression, cytokine production and FOXPS mRNA levels between NEC patients and controls and (3) Cord blood from preterm infants with NEC contains lower percentages of gut-homing Treg compared to controls. We will collect cord blood from infants less than 35 weeks gestational age and compare Treg presence and function between NEC patients and controls. Our findings will provide a more robust understanding of the immunological mechanisms that regulate the intestinal development of premature infants. This proposal develops novel translational approaches to identify cellular and molecular targets for reducing the pathologic host immune response in NEC and to detect infants at highest risk of this devastating disease.

Public Health Relevance

Necrotizing enterocolitis (NEC) is a common disease of the intestinal tract of premature infants that requires removal of affected intestinal tissue in one out of three cases and has a mortality rate of up to 50%. The proposed studies will test the role of specific cells (so called Treg) located in intestinal tissue in regulating the damaging immune responses associated with NEC. These studies will help identify patients at highest risk and provide the basis for the development of treatments to prevent or ameliorate this, often fatal, disease.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HD061607-04
Application #
8280358
Study Section
Pediatrics Subcommittee (CHHD)
Program Officer
Raju, Tonse N
Project Start
2009-07-10
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
4
Fiscal Year
2012
Total Cost
$125,658
Indirect Cost
$9,308
Name
Vanderbilt University Medical Center
Department
Pediatrics
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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