# The Risks and Opportunities of Homeostatic Repopulation

> **NIH NIH U19** · DUKE UNIVERSITY · 2024 · $3,208,377

## Abstract

ABSTRACT – Overall
The NHP kidney transplant model offers unique and important pathways to the improved understanding and
implementation of novel therapies for human transplant patients. Being an outbred, large animal model with
close genetic similarities to humans allows more accurate modeling of mechanisms and drugs/drug
combinations, and virtually all recently approvedimmunosuppressive agents and strategies have beenevaluated
in a NHP model. Our group has contributed to these advances substantially for approximately three decades,
resulting in over five clinical trials arising from our NHP research. Now we propose to focus on novel strategies
to promote donor-specific tolerance, to further develop our understanding of the interrelationship between CMV
infection and alloimmunity, and to advance our strategies for addressing the T and B cell response to
alloantigens. We have developed a collaboration that allows us to interrogate the T cell and B cell receptor
repertoire of macaques and their changes in response to immune interventions. This novel tool will greatly
enhance our ability to measure the impact of therapies at the cellular level in rhesus monkeys. In addition, we
have pioneered methodologies to assess the immune response within lymph nodes of rhesus monkeys and
measure germinal center changes and changes of T follicular helper cells as a means of better understanding
the B cell response to allotransplantation. We plan to use our collective experience in rhesus monkey kidney
transplantation and biology to evaluate therapies that are translatable to human kidney transplantation and will
also use mechanistic assays that can be performed in humans. In addition to the translational benefits of the
proposed work such as donor-specific regulatory T cell augmentation, we expect to gain fundamental new
insights into B cell memory durability and the breadth of T and B cell repertoires to alloantigens and how these
change with therapy and during rejection or infection. Our proposal involves many academic and industry
collaborations that are ongoing as attested by letters of support. We will continue to train individuals who plan
careers in transplant medicine, surgery, and immunology such that they will be prepared to lead the future of our
field. The impact of this proposal has broad implications that may benefit U.S. citizens affected by end stage
renal failure or by immune-mediated illnesses or infections.

## Key facts

- **NIH application ID:** 10821464
- **Project number:** 5U19AI131471-08
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Stuart Johnston Knechtle
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $3,208,377
- **Award type:** 5
- **Project period:** 2017-08-15 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10821464

## Citation

> US National Institutes of Health, RePORTER application 10821464, The Risks and Opportunities of Homeostatic Repopulation (5U19AI131471-08). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10821464. Licensed CC0.

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