# Discovering a novel therapy for RA patients

> **NIH VA I01** · JESSE BROWN VA MEDICAL CENTER · 2023 · —

## Abstract

Rheumatoid arthritis (RA) is the most common autoimmune disease which affects 2.5 million people in
US, many of which are VA military personnel. One in four veterans has arthritis (25.6%), compared to one in
five civilians. RA is a chronic, disabling autoimmune disease in which the body attacks its own tissues. As RA
progresses, performing simple daily activities can become increasingly difficult for patients suffering from the
disease. There is no cure for RA and up to 50% of patients do not respond to anti-TNF therapies as circulating
Th17/IL-17 levels are highly elevated subsequent to TNF blockade. For this subset of RA patients, disruption of
a novel pathway that impairs the synergy between TNF and IL-17 cascades may provide an alternative
treatment. Effective therapies can benefit all active and retired military and VA members with RA, as well as
their families and friends who may suffer from RA. Findings that lead to new therapy will benefit the VA
personnel by reducing the cost for medical and surgical care; in addition to the secondary RA complications
including depression, cardiovascular disease and psychosocial stress. Consequently, effective RA therapy will
improve the pain & the life quality of the retired veterans.
 We discovered that toll like receptor (TLR)5 is highly elevated in RA compared to normal macrophages,
and its expression closely correlates with RA disease activity score (DAS28). We also demonstrated that TLR5
natural ligands are present in RA synovial fluid. Ligation of TLR5 to its natural ligands, transforms RA
peripheral blood (PB) naïve cells into classical M1 macrophages (Mφs) which produce high levels of TNF, IL-6
and IL-1β. In addition, IL-6 and IL-1β produced from TLR5 driven M1 Mφs can differentiate the naïve T cells
into inflammatory RA Th17 cells that secrete IL-17. In mice, systemic and local injection of a TLR5 agonist
exacerbates joint swelling.
 The objective of this proposal is to understand the cellular and molecular mechanisms of TLR5 function
and to evaluate whether TLR5 antibody (Ab) can be utilized as a promising strategy for RA therapy. We
hypothesize that ligation of joint TLR5 triggers differentiation of proinflammatory Mφs and T cells which can
ultimately expand the RA inflammatory process to the erosive phase. We further postulate that a novel TLR5
Ab generated by our lab may be an alternative treatment strategy for non-responders as it negates the
interaction of effector myeloid and lymphoid cells in RA.
 To test our hypothesis, we will examine the contribution of RA Mϕ and T cell cross talk with endothelial
cells on bone neovascularization. Subsequently, to establish the preclinical stage efficacy, TLR5 Ab therapy
will be compared to the currently available treatments in RA cells and preclinical models. Successful
completion of this project will identify a novel mechanism that links the function of effector myeloid cells to
lymphoid cells as well as establishing a novel treatment strategy for ...

## Key facts

- **NIH application ID:** 10620205
- **Project number:** 5I01BX002286-08
- **Recipient organization:** JESSE BROWN VA MEDICAL CENTER
- **Principal Investigator:** SHIVA SHAHRARA
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2023
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2015-07-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10620205

## Citation

> US National Institutes of Health, RePORTER application 10620205, Discovering a novel therapy for RA patients (5I01BX002286-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10620205. Licensed CC0.

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