# Project 1: Evolution and Durability of allo(auto)immune B cell responses in organ transplant recipients

> **NIH NIH U19** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2024 · $364,253

## Abstract

Project Summary
Project 1: Evolution and Durability of allo(auto)immune B cell responses in organ transplant recipients
Antibodies (Abs), which are produced by B lineage-derived Ab secreting cells (ASCs) following pathogen
exposure and vaccination, play critical roles in protection from infection. However, ASCs and Abs can be
pathogenic if directed against the wrong target, as is the case for autoimmune disease and organ transplantation.
In the setting of kidney transplant (KT), Abs made by the recipient directed against the donor's Major
Histocompatibility Complex or Human Leukocyte Antigen (HLA) proteins (donor-specific Ab, DSA) contribute to
Ab-mediated rejection (AMR). Pre-formed DSA at the time of transplant can cause acute AMR and de novo DSA,
which is elicited months to years after transplantation, can cause chronic AMR. Both conditions are difficult to
treat and associated with organ failure. Thus, while overall transplant success rates have improved, there is still
a need to better understand the fundamental mechanisms that control the development, evolution and
durability of the B cell and B cell-derived DSA responses against donor (allo) HLA Class-I and Class-II. In fact,
we know remarkably little about B cell responses to alloHLA proteins, which unlike pathogen-derived antigens,
are very similar to the HLA proteins expressed by the patient (selfHLA). Studies using Rituximab to deplete
circulating B cells in DSA+ transplant patients reveal that DSA levels remain high in many patients. These data
support the idea that the DSA response is largely driven by Rituximab-resistant long-lived bone marrow ASCs
(LL-ASC). However, memory B cells (Bmem), particularly those that reside in tissues, are also more resistant to
Rituximab and both Bmem and LL-ASCs are formed by germinal center (GC) B cell responses that can take
place in lymphoid and inflamed tissues. Bmem, which can rapidly differentiate into new cohorts of ASCs, could
potentially serve as a reservoir to sustain systemic Ab responses. We found that HLA-reactive Bmem were
present in the blood and kidney of a DSA+ KT patient diagnosed with AMR. These HLA-specific B cells were
present in expanded B cell lineages and the BCRs expressed by these B cells were high affinity, class-switched
and extensively somatically mutated, suggesting that they were generated via a TFH-dependent GC response.
Moreover, we observed extensive clonal relationships between the Bmem and ASCs in both tissues and we
identified Bmem and ASCs lineages that contributed to the serum DSA response. Intriguingly, many of the
recombinant monoclonal Abs derived from multiple HLA-reactive B cell lineages bound both donor alloHLA and
selfHLA. Therefore, we hypothesize that ongoing evolution of the alloHLA B cell response occurs in the face of
a durable low affinity selfHLA response, which is not censored. The immediate goals of Project 1 are to: (i) define
the B cell populations in blood and kidney that contribute to HLA reac...

## Key facts

- **NIH application ID:** 10824857
- **Project number:** 1U19AI181105-01
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Frances E. Lund
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $364,253
- **Award type:** 1
- **Project period:** 2024-04-16 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10824857

## Citation

> US National Institutes of Health, RePORTER application 10824857, Project 1: Evolution and Durability of allo(auto)immune B cell responses in organ transplant recipients (1U19AI181105-01). Retrieved via AI Analytics 2026-05-31 from https://api.ai-analytics.org/grant/nih/10824857. Licensed CC0.

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