This resubmission is in response to PAR-18-333 ?Understanding the Early Development of the Immune System?. Increasing evidence suggests that commensal bacteria play an important role in health and disease, including in pregnancy. Using advanced methodology, recent studies have indicated that the fetus may not live in a sterile environment. Our preliminary data using antibiotics suggest that commensal bacteria play an important role, during pregnancy, in shaping the early development of fetal immune tolerance to islet autoimmunity that may manifest later in life of the offspring. This has led us to hypothesize that removing the low number of commensal bacteria in the uterus may regulate the early development of fetal immune system and fetal immune programming to be tolerant or not, to islet autoimmunity. The overall goal of our proposal is to address an important gap in our knowledge and understanding of the role of maternal microbiota in influencing fetal immune system development and immune tolerance. We propose three specific aims to test our different but inter-connected hypotheses:
Aim 1 : To test the hypothesis that the mode of birth delivery contributes to the development/programming of the immune system of the neonates, which later affects development of immune tolerance later in life in non obese diabetic (NOD) mice;
Aim 2 : To test the hypothesis that fetal immune system development is associated with the presence of maternal commensal bacteria, using germ free (GF) NOD mice;
Aim 3 : To determine whether an oral commensal, which expresses an islet autoantigen mimic peptide, will influence immune tolerance to self antigen and autoimmunity, by maternal-fetal transfer and subsequent fetal immune system development in GF mice.

Public Health Relevance

We have found that prenatal exposure to antibiotics during pregnancy influences immune tolerance in the offspring later in life and that different antibiotics have different effects. Introducing commensal gut bacteria to pregnant germ-free (GF) dams also affect the development of fetal immune system. We hypothesize that maternal commensal bacteria during pregnancy have significant impact in regulating fetal immune programming and we will test our hypothesis step-wise in this project.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD097808-02
Application #
9998994
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Russo, Denise
Project Start
2019-08-20
Project End
2022-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520