# Determinants of donor-specific B cell tolerance in kidney transplantation in sensitized recipients

> **NIH NIH U19** · DUKE UNIVERSITY · 2024 · $1,096,539

## Abstract

ABSTRACT – Project 2
Kidney transplantation is the preferred treatment for end-stage renal failure due to improved patient survival,
quality of life, and healthcare costs compared to dialysis. However, sensitized patients with preformed human
leukocyte antigen (HLA) antibodies due to prior exposure to allogeneic HLA via transfusion, pregnancy, and
previous transplantation face lower rates of transplantation that result in higher waitlist mortality. Furthermore,
even if these patients are transplanted after desensitization, they frequently have worse short- and long-term
graft survival compared to non-sensitized patients due to increased risk of rejection. We have shown that a
combination of plasma cell targeting with proteasome inhibitor (carfilzomib) and co-stimulation blockade with
belatacept reduces preformed antibody prior to kidney transplantation in sensitized nonhuman primates (NHP).
Together with cytolytic induction, this pharmacological desensitization prevented early antibody-mediated
rejection (AMR) and significantly prolonged graft survival in sensitized recipients. However, the peri-transplant
desensitization was not able to control late AMR. Interestingly, post-transplant belatacept was able to suppress
donor-specific antibody (DSA), disrupt germinal centers, and prevent plasma cell increase in NHP following
depletion. This approachachievedprolonged graft survival with less AMR but promoted significant complications
including viral reactivation and post-transplant lymphoproliferative disorders (PTLD). We hypothesize that the
more specific (and even donor-specific) targeting of humoral responses including B cells, plasma cells, and
complement may better control post-transplant AMR in sensitized hosts and create a therapeutic window to
induce donor-specific tolerance. We will evaluate guided homeostatic repopulation with apoptotic donor cells for
re-establishing an immune repertoire that favors transplantation tolerance. To explore this hypothesis, we
propose 3 specific aims: 1) To evaluate adjuvant therapies targeting down-stream post-transplant humoral
responses following desensitization. 2) To determine efficacy of antigen-specific pro-tolerant approaches in
highly sensitized NHPs recipients. 3) To identify the functional phenotype of allo-specific T and B cell repertoires
required to establish tolerance in sensitized recipients.

## Key facts

- **NIH application ID:** 10821468
- **Project number:** 5U19AI131471-08
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Jean Kwun
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,096,539
- **Award type:** 5
- **Project period:** 2017-08-15 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10821468

## Citation

> US National Institutes of Health, RePORTER application 10821468, Determinants of donor-specific B cell tolerance in kidney transplantation in sensitized recipients (5U19AI131471-08). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10821468. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*