# Mechanistic studies on pregnancy-induced humoral sensitization in organ transplantation

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2024 · $837,620

## Abstract

Project Abstract
Long-term success of transplantation and achieving transplant tolerance in the clinic is hindered by recipient
sensitization and immunological memory, which predominantly arise as a result of graft rejection, pregnancy and
blood transfusions. Paradoxically, semi-allogeneic pregnancy provides a unique example of allogeneic tolerance
spontaneously induced in adults. Using preclinical mouse models, we showed that semi-allogeneic pregnancy
simultaneously induces T cell tolerance to the semi-allogeneic fetus and to subsequent offspring-matched heart
grafts. However, pregnancy also induces humoral sensitization to fetal antigens, and this sensitization overrides
pregnancy-induced as well as co-stimulation-induced allograft acceptance. Our research aims to define the
mechanisms underlying humoral sensitization by semi-allogeneic pregnancy, and how this sensitization over-
rides pregnancy-induced and co-stimulation blockade-induced T cell tolerance of offspring-matched heart grafts.
In Aim 1, we will test the hypothesis that at a cellular level, pregnancy enables the differentiation of CD4+ T cells
into T follicular helper (Tfh) cells providing help to fetus-specific B cells and facilitating their differentiation into
post-partum B cells and antibody-secreting cells. Simultaneously, pregnancy induceds a persistent state of cell-
intrinsic hypofunction in fetus-specific non-Tfh cells. In Aim 2, we will test the hypothesis that pregnancy-
sensitized Tfh, B cell and antibody responses synergize to constitute a barrier to the induction of transplantation
tolerance by co-stimulation blockade. Completion of this project will provide an in-depth mechanistic
understanding for the basis and consequence of humoral sensitization by semi-allogeneic pregnancy, and
identify treatments capable of preventing and reversing this sensitization. The long-term goal of this project is to
improve access to transplantation in historically-disadvantaged multiparous women and to optimize their post-
transplant outcomes through the induction of transplant tolerance.

## Key facts

- **NIH application ID:** 10855755
- **Project number:** 1R01AI182097-01
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Anita S Chong
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $837,620
- **Award type:** 1
- **Project period:** 2024-06-03 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10855755

## Citation

> US National Institutes of Health, RePORTER application 10855755, Mechanistic studies on pregnancy-induced humoral sensitization in organ transplantation (1R01AI182097-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10855755. Licensed CC0.

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