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CpG-B ODN Mediated Protection from Systemic Lupus Erythematosus

Award Number: F30AI186528
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 07/25/2024
PERIOD OF PERFORMANCE END DATE: 07/24/2028

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CpG-B ODN Mediated Protection from Systemic Lupus Erythematosus - 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 treatments for lupus. This work will be the focus of the applicant’s Ph.D. candidacy and training plan. The applicant also plans to attend conferences, shadow physicians, and continue to practice the skills necessary to being a successful and productive physician-scientist.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $55,114 )
2026	2026	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Allergy and Infectious Diseases Research	000	3	6/19/2026	NON-COMPETING CONTINUATION	$55,114
														Subtotal = $55,114

Issue Date FY: 2025 ( Subtotal = $45,044 )
2025	2025	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Allergy and Infectious Diseases Research	000	2	9/15/2025	NON-COMPETING CONTINUATION	$45,044
														Subtotal = $45,044

Issue Date FY: 2024 ( Subtotal = $43,943 )
2024	2024	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Allergy and Infectious Diseases Research	000	1	7/12/2024	NEW	$43,943
2024	2024	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Allergy and Infectious Diseases Research	001	1	7/12/2024	NEW	$0
														Subtotal = $43,943

Grand Total All Awards = $144,101

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CpG-B ODN Mediated Protection from Systemic Lupus Erythematosus

Award Number: F30AI186528

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 07/25/2024

PERIOD OF PERFORMANCE END DATE: 07/24/2028

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