# Mixed chimerism induced tolerance in heart recipients requires donor kidney cotransplantation

> **NIH NIH U01** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $608,912

## Abstract

The Project Summary / Abstract is unchanged from original U01AI131470 application:
Tolerance of kidney allografts has been achieved in non-human primates (NHPs) and in humans using a
combination of nonmyeloablative conditioning and donor bone marrow transplantation (DMBT) that results
in transient donor chimerism. However, similar conditioning failed to induce tolerance in heart recipients
despite comparable levels of chimerism. The reasons for this organ-specific difference are not clear.
However, it is clear that all transplanted organs are not created equally. Not only does the strength of the
immune response to a particular organ vary with the organ transplanted but the nature of response itself,
rejection versus tolerance, varies from organ to organ. It is well known that some organs, such as kidney
and liver, are tolerance-prone while others, such as heart and lung, are tolerance-resistant. In earlier
studies using miniature swine, we took advantage of the tolerogenicity of kidney allografts and by
cotransplanting donor kidneys with heart allografts, achieved long-term stable tolerance of heart allografts
which, if transplanted alone, would have rejected acutely. We have now extended those findings to NHPs
by combining donor kidney cotransplantation with a mixed chimerism protocol that induces transient donor
chimerism. This protocol is the first to achieve long-term tolerance of MHC mismatched heart allografts in
NHPs. Importantly, every recipient that successfully completed its protocol achieved indefinite allograft
survival and did so without evidence of cardiac allograft vasculopathy (CAV). Kidney-induced cardiac
allograft tolerance (KICAT) is made even more compelling by its consistency across 1) different species
(mouse, swine, NHP), 2) different histocompatibility barriers, and 3) different tolerance protocols. These
findings suggest that immune mechanisms exist which are capable of inducing tolerance to any organ.
Elucidating those mechanisms would lead to strategies that extend tolerance to all allograft recipients. To
achieve that goal we propose to 1) investigate novel mechanisms that may explain the tolerogenicity of
kidney allografts, 2) evaluate unique regulatory mechanisms the may facilitate KICAT, and 3) test
alternative strategies that obviate the need for donor kidney cotransplantation in achieving heart allograft
tolerance. Our specific aims are 1) to determine if MHC crossdressing via donor microvesicles (exosomes)
or Treg-rich organized lymphoid structures (TOLs) underlie the fundamental differences observed in host
alloresponses to kidney allografts, 2) to evaluate the contribution of Tr1 cells and a novel CD8+CD20+ B
cell to kidney-induced cardiac allograft tolerance, and 3) to determine if combined low dose IL-2/anti-IL-6R
therapy or donor thymus cotransplantation will successfully substitute for donor kidney transplantation and
achieve tolerance in recipients of isolated heart allografts.
RELEVANCE (See instructions...

## Key facts

- **NIH application ID:** 10518435
- **Project number:** 4U01AI131470-06
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Joren C Madsen
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $608,912
- **Award type:** 4C
- **Project period:** 2017-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10518435

## Citation

> US National Institutes of Health, RePORTER application 10518435, Mixed chimerism induced tolerance in heart recipients requires donor kidney cotransplantation (4U01AI131470-06). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10518435. Licensed CC0.

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