# Immunological identity redefined by genetically foreign microchimeric cells

> **NIH NIH DP1** · CINCINNATI CHILDRENS HOSP MED CTR · 2020 · $1,092,000

## Abstract

Abstract. Engrained in the conceptual fabric of how interrelated immunological disciplines including
autoimmunity, transplantation, tumor immunology and vaccinology are currently viewed is the classical tenet of
binary “self” versus “non-self” antigen distinction. However, reliance on genetically homogenous inbred animals
in establishing these immunological principles precludes their applicability to individuals in natural outbred
populations that ubiquitously encounter genetically foreign antigens during development and reproduction. For
example in humans, exposure to genetically foreign maternal tissue beginning in utero consistently primes in
offspring tolerance to immunologically discordant non-inherited maternal antigens. Reciprocally, long-lasting
tolerance to genetically foreign fetal chimeric cells that express discordant paternal antigens is retained in
mothers after pregnancy. These human observations highlight potent immune regulatory pathways engrained
within mammalian reproduction that are efficiently masked when developmental and hereditary genetic
diversity is artificially eliminated. Therefore, restoring genetic and antigen heterogeneity amongst homologous
chromosomes within individuals, and between individuals for mating has exciting potential to unveil
fundamental new insights on the pathogenesis of autoimmunity, and new strategies for therapeutically fine-
tuning the balance between immune stimulation and suppression. The long-term goal of my research is
improved health for infants and children that suffer unduly from communicable infection. Considering infants
born prematurely are especially vulnerable to death or long-term morbidity, my laboratory has uniquely re-
focused many leading edge tools to investigate maternal-fetal immunological tolerance and the immune-
pathogenesis of pregnancy complications triggered by prenatal infection. Central to our approach has been
development of innovative reproductive models that recapitulate genetic heterogeneity between individuals,
and heterogeneity amongst homologous chromosomes within individuals, naturally encountered in humans
and other outbred populations. By probing depots of genetically foreign antigen encountered within the
maternal-fetal gestational dyad needed for persistent bi-directional immunological tolerance, we recently
identified the remarkable necessity for genetically foreign microchimeric cells in maintaining tolerance in each
developmental context. These newly established reproductive benefits demonstrating nature's intent in
preserving bi-directional transfer of cells between mother and fetus during pregnancy, and long-term retention
of these genetically foreign microchimeric cells in both mother and offspring, pivotally transforms chimeric cells
from a curious scientific phenomena to invaluable tools for illuminating how immunological tolerance naturally
works. Accordingly, support from the NIH Pioneer Award would be used to launch my laboratory in the new
scien...

## Key facts

- **NIH application ID:** 9988351
- **Project number:** 5DP1AI131080-05
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Sing Sing Way
- **Activity code:** DP1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,092,000
- **Award type:** 5
- **Project period:** 2016-09-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9988351

## Citation

> US National Institutes of Health, RePORTER application 9988351, Immunological identity redefined by genetically foreign microchimeric cells (5DP1AI131080-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9988351. Licensed CC0.

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