PROJECT SUMMARY
TITLE: Maternal B cells enforce fetal tolerance
GOALS/OBJECTIVES: The overall goal of this five-year proposal for a Mentored Clinical Scientist Research
Career Development Award (K08) is for me to develop into a productive, independent academic investigator in
the field of reproductive immunology. My prior training has provided me expertise regarding T cell and antibody
mediated host defense. Through this proposal I will gain additional experience in B cell biology,
glycoimmunology and fetal tolerance. The long-term goal of this research is to improve pregnancy outcomes,
which will lead to healthier pregnancies and neonates. I graduated from the American Board of Pediatrics
Accelerated Research Pathway for Residency in General, and I completed my Fellowship in Neonatal-
Perinatal Medicine at Cincinnati Children’s Hospital (CCHMC). I joined the faculty of CCHMC and the
University of Cincinnati as an Attending Physician and Research Assistant Professor in the Division of
Neonatology. My mentor for this award, Dr. Sing Sing Way, is a physician-scientist with a longstanding track
record of scientific innovation and providing exceptional training to mentees at all levels. As an internationally
recognized expert in the immunology of pregnancy, microchimerism, commensalism and neonatal sepsis, Dr.
Way’s work highly complements my own. My mentorship committee brings needed expertise to the areas of
antigen-specific B cell responses (Dr. Justin Taylor), B cell interactions with N-linked glycans (Dr. Shiv Pillai),
placental immunology (Dr. Tamara Tilburgs), transgenic lymphocytes (Dr. Koichi Araki) and maternal-fetal
immunology (Dr. Hitesh Deshmukh). I am also extremely fortunate to have the unfettered support of CCHMC
and the Perinatal Institute, whose combined resources are unmatched.
Scientifically, this proposal focuses on deepening our understanding of mechanisms of fetal tolerance. The
field currently focuses on immune suppressive CD4+ Foxp3+ regulatory T cells (Treg) as the key mediators of
tolerance. This is based on observations that maternal Treg expand throughout pregnancy and are blunted in
pregnancy complications associated with fetal intolerance (e.g., preeclampsia, stillbirth). However, there is
growing appreciation that Treg do not work in isolation, and often require support from other cell types, including
regulatory B cells (Breg). Activation of B cells is tightly regulated by the inhibitory receptor CD22, which binds to
sialic acid present at the terminal position of certain glycoproteins. There remain numerous gaps in knowledge
regarding the role of maternal B cells in mediating fetal tolerance, factors affecting their activation, and
modification of fetal antigens. Additionally, whether these maternal B cells work independently or
synergistically with maternal Treg remains to be determined. My central hypothesis is that CD22 impairs
maternal B cell immune regulatory functions, preventing B cells from upholding fetal tolerance. This is based on
very interesting preliminary data showing that CD22 blockade reverses pregnancy complications and fetal loss
when maternal Treg are depleted or functionally impaired by infection. The aims of this proposal will establish:
1) how maternal B cell immune suppression is counter-regulated though antigen recognition and CD22, as well
as 2) how maternal B cells enforce fetal tolerance through IL10-mediated inhibition of maternal T cells with
fetal-specificity.
The scientific rigor of this proposal is supported by numerous career development objectives that will help
enable a transition to a successful independent research program. I will work closely with my mentor, Sing
Sing Way, and mentoring committee to gain expertise in reproductive immunology, fetal tolerance, spectral
flow cytometry, characterization of rare antigen-specific B cells, placental immunology, glycobiology and
genetic manipulation of antigen-specific B cells. Coursework, seminars, scientific conferences and hand-on
training in laboratories of collaborators/mentors will add additional layers of expertise. Overall, this mentored
career development award will broaden my scientific acumen to include reproductive immunology with a focus
on B cell biology and glycobiology. As pregnancy complications remain the leading cause of infant and
childhood mortality, results of these studies will potentially lead to novel B cell-directed therapies aimed at
improving outcomes for pregnant mothers and their children.