# Project 2: Mechanisms of Induction of Tolerance to Murine Heart Allografts by Kidney Allografts

> **NIH NIH P01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $412,236

## Abstract

PROJECT SUMMARY / ABSTRACT
Kidney allografts are naturally tolerogenic in mice. Mice develop tolerance of kidney allografts across full MHC
incompatibilities without immunosuppression. This tolerance is initially dependent Foxp3+ cells which are
concentrated in the graft in distinctive Treg-rich organized lymphoid structures (TOLS). Recipients of allograft
kidneys develop systemic tolerance to skin and heart allografts. This project will identify the immunobiologic
features for induction of heart allograft tolerance by kidney allografts in a sequential series of experiments that
will determine the timing of systemic tolerance, the dependence on the continued presence of the allograft
kidney and thymus, whether the kidney promotes regulatory and/or deletional tolerance and the hypothesized
role of kidney dendritic cells, tubular cells and kidney related mediators. We will test for dependence on
Foxp3+ cells using B6.Foxp3DTR recipients. We will test whether generation of Foxp3+ cells is related to donor
DCs in the kidney and whether adoptively transferred plasmacytoid DCs (pDCs) from the kidney are sufficient
to induce acceptance of heart allografts. Renal tubular epithelial cells (RTEC) will be tested in vitro and in vivo
for their ability to promote differentiation into Treg and whether selective RTEC injury affects tolerance
induction. Infiltrates in cardiac allografts with or without co-transplanted kidneys will be compared for presence
of TOLS, pDCs and activated Treg. Finally the mechanisms responsible for the resistance of kidney allografts
to sensitized T cells will sought, whether the kidney promotes conversion of T cells to Treg or inactivates or
deletes T cells, or is resistant to their action. The kinetics and distribution of Treg and sensitized T cells in the
grafts, lymphoid organs and blood will be assessed using in vivo bioluminescence imaging. The fate of the
transferred cells in the kidney allograft and their interactions with DCs will be assessed. These studies are
expected to reveal mechanisms by which the kidney promotes tolerance of heart grafts, thereby helping to
clarify and interpret the observations made in Projects 1 and the EPO experiments in Project 3 and guide the
development of clinically applicable treatment protocols.

## Key facts

- **NIH application ID:** 9987474
- **Project number:** 5P01AI123086-05
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Robert B Colvin
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $412,236
- **Award type:** 5
- **Project period:** 2016-08-05 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9987474

## Citation

> US National Institutes of Health, RePORTER application 9987474, Project 2: Mechanisms of Induction of Tolerance to Murine Heart Allografts by Kidney Allografts (5P01AI123086-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9987474. Licensed CC0.

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