# Project 1: Induction of Tolerance to Heart Allograft in Nonhuman Primates by Donor Kidney Co-Transplantation

> **NIH NIH P01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $901,353

## Abstract

PROJECT SUMMARY / ABSTRACT
Protocols that achieve tolerance of kidney allografts in nonhuman primates (and in humans) fail to induce
tolerance of heart allografts. We have taken advantage of the intrinsic tolerogenicity of kidney allografts and,
through donor kidney cotransplantation, have achieved stable tolerance of heart allografts in nonhuman
primates (NHP) which, if transplanted alone, are rejected acutely. The consistency with which kidney allografts
confer tolerance upon recipients of cotransplanted heart allografts across different species (mouse, swine,
NHP), across different histocompatibility barriers, and across different tolerance protocols is compelling.
Registry studies furthermore confirm that human recipients of kidney and heart allografts from the same donor
experience less acute rejection and less cardiac allograft vasculopathy (CAV) compared to those receiving
heart transplants alone. Understanding the mechanisms underlying these unique observations has broad
implications for the transplant community, well beyond the relatively small numbers of patients likely to receive
kidney/heart cotransplants. Once these mechanisms are better understood, they could be exploited to guide
novel therapeutic approaches that induce tolerance to heart allografts (and other tolerance-resistant organs) in
the absence of a kidney, or improve outcomes without inducing tolerance. The mechanisms driving kidney-
induced cardiac allograft tolerance (KICAT) and its implications for human heart transplant recipients is the
focus of this Project. Our preliminary results in murine, swine, and NHP models implicate regulatory T cells
(Treg) as the end effectors of KICAT with kidney-specific cells (e.g. plasmacytoid dendritic cells (pDC)) and/or
cell products (i.e. erythropoietin (EPO)) amplifying those regulatory mechanisms. Indeed, emerging data from
Heeger's group suggest that the unique ability of the kidney to induce tolerance is mediated in part by
erythropoietin (EPO), a hormone traditionally thought to only be responsible for erythropoiesis but newly
shown to function as a Treg-enhancing immunosuppressant. Together, our joint data support the following
working model: high local concentrations of EPO in the donor kidney graft directly inhibit pathogenic effector T
cells and promote the ability of kidney pDC to facilitate the generation and stability of donor-reactive Tregs via
TGFβ production. The enhanced activity of host Tregs induced by donor kidney elements leads to a robust
state of heart allograft tolerance. Our goals are to test this model by determining the specific roles of Tregs,
pDC, EPO and TGFβ in achieving KICAT in NHPs and to characterize the robustness of the tolerance induced
by KICAT in anticipation of clinical application. The newly acquired knowledge will be used to develop novel
strategies to improve heart transplant outcomes and to induce tolerance of other highly resistant allografts.

## Key facts

- **NIH application ID:** 9987472
- **Project number:** 5P01AI123086-05
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Joren C Madsen
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $901,353
- **Award type:** 5
- **Project period:** 2016-08-05 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9987472

## Citation

> US National Institutes of Health, RePORTER application 9987472, Project 1: Induction of Tolerance to Heart Allograft in Nonhuman Primates by Donor Kidney Co-Transplantation (5P01AI123086-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9987472. Licensed CC0.

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