# The Risks and Opportunities of Homeostatic Repopulation

> **NIH NIH U19** · DUKE UNIVERSITY · 2020 · $2,802,151

## Abstract

ABSTRACT – Overall
Thousands of patients benefit each year from the lifesaving impacts of organ transplantation, but this benefit is
hampered by the requirement of preventing rejection of the donor graft. Establishing immunologic tolerance in
organ transplant recipients using life-long immunosuppressive therapy, in particular, the lymphocyte depletion
immunosuppression strategy has been a critical component of all successful approaches. Following
lymphocyte depletion, immune cells proliferate to fill the newly created gap in the immune repertoire, a process
referred to as homeostatic repopulation. During this process the immune microenvironment critically influences
the ensuing immunologic repertoire and can detour the response to allogeneic donor tissue either toward
rejection or tolerance. We propose that the post-depletional fate of lymphocytes depends on its differentiation
state, its exposure to antigen, and the effect of exogenous factors driving or inhibiting its growth. Within this
context, we advance a generalizable framework for repopulation: recollective homeostasis, positing that the
lymphocyte repertoire at any given time is determined by an ongoing process of memory acquisition and
deletion. Importantly, depletion accelerates turnover, creating an intense period of opportunity during which we
propose this process can be manipulated, exploiting relative differences in cell susceptibility to create, over
time, a state of sustained allospecific hypo-responsiveness. This proposal seeks to capitalize on this window of
opportunity to reshape the immune repertoire towards tolerance through the work of two interrelated projects
investigating specific repopulation events supported by an administrative core and a scientific core for immune
profiling. Project 1 will focus on depletional T lymphocyte repopulation, while Project 2 will focus on B
lymphocyte/plasma cell/antibody modulation. These projects are scientifically distinct but are interactive in
methodologies and mechanisms. Specifically, both projects will employ our major histocompatibility complex
(MHC)-defined, nonhuman primate (NHP) renal transplantation model that provides rigorous translational
evaluation of potential novel tolerance induction strategies. Homeostatic repopulation is a central theme in our
work that serves to generalize our approach beyond tolerance protocols, to broader immunosuppressant- and
viral-induced lymphopenic states. This proposal will also improve upon our understanding of the role of
costimulation blockade and the drug belatacept in tolerance induction; their ability to enhance the specificity
and tolerability of anti-rejection therapy and to downregulate alloantibody has been a longstanding focus of our
research. Our proposed studies will build on two decades of collaborative experience investigating both
depletion and costimulation blockade in NHPs. The knowledge gained from these studies will further our
understanding of tolerance mechanisms in NHPs...

## Key facts

- **NIH application ID:** 9980776
- **Project number:** 5U19AI131471-04
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Stuart Johnston Knechtle
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $2,802,151
- **Award type:** 5
- **Project period:** 2017-08-15 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9980776

## Citation

> US National Institutes of Health, RePORTER application 9980776, The Risks and Opportunities of Homeostatic Repopulation (5U19AI131471-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9980776. Licensed CC0.

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