# Depletion, Repopulation and Tolerance in Sensitized Recipients

> **NIH NIH U19** · DUKE UNIVERSITY · 2020 · $1,251,943

## Abstract

ABSTRACT – Project 2 (Knechtle, Project Lead)
While perioperative immune cell depletion with either polyclonal antibody or alemtuzumab is used in the
majority of renal transplants in the U.S., our lab has shown in both humans and non-human primates (NHP)
that homeostatic repopulation following depletion is associated with B cell activation, elevated BAFF levels,
and de novo donor-specific alloantibody (DSA). We have also shown that Belatacept is capable of
suppressing such DSA in NHP following depletion. Recently, we have shown in a presensitized NHP model
that blockade of CD28 and CD154 in combination with proteasome inhibition substantially lowers alloantibody
levels pre-transplant, disrupting germinal centers and lowering plasma cell numbers. However, depletion of
plasma cells by proteasome inhibition alone is also associated with germinal center and Tfh cell activation.
Thus, depletion of immune cells leads to both beneficial and deleterious consequences with respect to
tolerance. This project seeks to define the elements of immune cell depletion in sensitized hosts that foster
tolerance. We believe that lymphocyte and plasma cell depletion and subsequent homeostatic repopulation
present both an opportunity to shape the alloreactive immune repertoire to favor tolerance, and a risk to disrupt
regulation, ignite viral infection and induce activation of alloreactive clones. We hypothesize that the
consequences of immune cell depletion in sensitized hosts create compensatory responses by the immune
system that are predictable and need to be therapeutically controlled to promote tolerance. To explore this
hypothesis, we propose 3 specific aims: 1) To develop safer and more effective means to lower the amount
and number of allospecific antibodies, plasma cells, and memory B cells that prevent allotransplantation using
proteasome inhibition together with complementary adjuvant therapies prior to renal transplantation; 2) To
reshape the immune repertoire using depletion, donor-specific transfusion, and rapamycin to promote
regulation, AICD, and pro-tolerant homeostatic repopulation in the sensitized recipient; and 3) To evaluate the
safety and efficacy of Belatacept with and without Rapamycin as components of post-transplant
immunosuppressive regimens promoting long-term survival of renal allografts following desensitization therapy
as described in SA1 and 2 above.

## Key facts

- **NIH application ID:** 9980792
- **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:** $1,251,943
- **Award type:** 5
- **Project period:** 2017-08-15 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9980792

## Citation

> US National Institutes of Health, RePORTER application 9980792, Depletion, Repopulation and Tolerance in Sensitized Recipients (5U19AI131471-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9980792. Licensed CC0.

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