# Placental extracellular vesicles as regulators of maternal adaptive immunity

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $530,341

## Abstract

RFA-AI-18-023. We submit this application in response to the recent NIAID and NICHD Funding Opportunity
Announcement RFA-AI-18-023 titled “Immune mechanisms at the maternal-fetal interface (R01)”
Pregnancy constitutes an “immunological paradox”, first described by Medawar, where despite the competent
maternal immune system, the semi-allogeneic fetus avoids maternal immune rejection. This paradox is
accentuated in the fully allograft fetus in donor oocytes or surrogate pregnancies. The regulatory mechanisms
that operate at the maternal-fetal interface that avoid the maternal immunologic attack to the fetus while
maintaining competent defense against pathogens, remain largely unknown. Our proposed research will
investigate the role of feto-placental extracellular vesicles (EVs), in communication of regulatory signals to the
maternal adaptive immune cells. Although placental EVs released in maternal blood has been proposed as a
potential mechanism, to our knowledge, such possibility has not been investigated in vivo.
 There is increasing evidence that transfer of EVs (e.g. exosomes, microvesicles), constitutes a
mechanism of cell-to-cell communication by which antigens (Ags), immuno-regulatory mediators, mRNAs, and
non-coding RNAs are transferred horizontally between donor and acceptor cells. This mechanism resembles the
EV-mediated release of donor allogeneic Ags and immuno-stimulatory mediators after transplantation. These
donor-derived EVs travel in the blood or lymph to influence immune cells in the secondary lymphoid tissues
(SLTs) of the recipient. Akin to transplantation, maternal allo-reactive T cells become aware of the (non-self)
fetal Ags in SLTs. The mechanisms by which Ags that are delivered to the mother’s lymphoid tissues can be
recognized by the allo-reactive T cells in a pro-tolerogenic fashion remain unknown. Interestingly, our preliminary
studies indicate that, analogous to transplantation, maternal leukocytes (including Ag-presenting cells) capture
conceptus-derived Ags in maternal SLTs via a cell-free mediated mechanism compatible with acquisition of EVs.
Thus, we hypothesize that placenta-derived EVs carry paternal Ags and immuno-regulatory mediators
that control the maternal adaptive immune response against the fetus. We will test our hypothesis by
analyzing the role of placental EVs in regulation of the mouse maternal immune response to feto-placental Ags
and by investigating the effect of placental EVs from normal and pathological human pregnancies on the maternal
immune response to feto-placental Ags. Long-term, we will build on knowledge and tools that were developed
in transplant immunology to mechanistically define the balance between immune competence and tolerance in
normal pregnancies and in pregnancies complicated by adverse outcomes and devise novel therapeutic
approaches to immunological imbalance in human pregnancy.

## Key facts

- **NIH application ID:** 9973145
- **Project number:** 5R01AI148690-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Adrian E. Morelli
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $530,341
- **Award type:** 5
- **Project period:** 2019-07-08 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9973145

## Citation

> US National Institutes of Health, RePORTER application 9973145, Placental extracellular vesicles as regulators of maternal adaptive immunity (5R01AI148690-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9973145. Licensed CC0.

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