# CpG-B ODN Mediated Protection from Systemic Lupus Erythematosus

> **NIH NIH F30** · VIRGINIA POLYTECHNIC INST AND ST UNIV · 2024 · $43,943

## Abstract

PROJECT SUMMARY
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with no known cure. Current therapies
focus on symptom relief with corticosteroids or immunosuppressants but have significant side effects. The gut
microbiome plays an important role in immune regulation, and modulation of the gut microflora could provide a
novel avenue for SLE therapy. The Luo Lab has demonstrated that bacterial DNA (bDNA) can stimulate IL-10
production and regulatory B cell (Breg) proliferation, which are both associated with improved lupus symptoms.
Toll-like receptor 9 (TLR9) is an endosomal sensor that recognizes bDNA and is associated with less severe
lupus symptoms. CpG-B oligonucleotides (ODNs) are short nucleotide sequences that mimic bDNA and agonize
TLR9. We have shown that CpG-B ODNs can robustly induce IL-10 production and Breg proliferation in vitro
through two distinct, TLR9-dependent mechanisms: a B cell intrinsic mechanism, where TLR9 is agonized in
B cells themselves, and a B cell extrinsic mechanism, where TLR9 is agonized in a secondary cell type, creating
IL-6 that subsequently expands Bregs. IL-6 can expand Bregs but is also capable of expanding inflammatory
cell subsets. We have in vivo data to show that increased IL-6 is associated with increased Bregs but is also
associated with increased renal damage in lupus prone (MRL/lpr) mice. Therefore, we aim to enhance the IL-6
independent, B cell intrinsic mechanism, while limiting the IL-6 dependent, B cell extrinsic mechanism. This
proposal aims to determine the therapeutic potential of CpG-B ODNs in the management of SLE. We propose
to study these TLR9 agonists with MRL/lpr and humanized models, both in vitro and in vivo, to demonstrate the
translatability of my work. We hypothesize that CpG-B ODNs can increase the number of Bregs and protect
the host against SLE by acting through B cell intrinsic, TLR9 agonization. This application is broken down
into two aims: Aim 1 is to delineate the cellular and molecular mechanisms by which CpG-B ODNs stimulate
Breg differentiation in vitro. The first objective is to elucidate the mechanism of the B cell extrinsic pathway by
using cell-specific Tlr9-/- co-culture experiments. By elucidating its mechanism, we can more effectively limit the
B cell extrinsic pathway in the future. We will then analyze the pro- vs. anti-inflammatory profiles of the intrinsic
and extrinsic mechanisms. Lastly, we propose to validate these findings in human PBMCs. Aim 2 is to determine
the efficacy of using CpG-B ODNs in vivo. We aim to enhance the B cell intrinsic mechanism, while limiting the
B cell extrinsic mechanism using Tlr9 conditional knockout mice. After determining that we can confer protection
in MRL/lpr mice, we will demonstrate that we can protect mice with a human immune system. These experiments
will demonstrate the potential efficacy of CpG-B ODNs in future human trials. We believe that CpG-B ODNs have
the potential to be passive, yet effective t...

## Key facts

- **NIH application ID:** 10998519
- **Project number:** 1F30AI186528-01
- **Recipient organization:** VIRGINIA POLYTECHNIC INST AND ST UNIV
- **Principal Investigator:** DAVID NOAH OAKLAND
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $43,943
- **Award type:** 1
- **Project period:** 2024-07-25 → 2028-07-24

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10998519

## Citation

> US National Institutes of Health, RePORTER application 10998519, CpG-B ODN Mediated Protection from Systemic Lupus Erythematosus (1F30AI186528-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10998519. Licensed CC0.

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