Background/Purpose: Macrophages and T cells are central to the pathophysiology of autoimmune diseases. Synovial macrophages, synovial fibroblasts and infiltrating T lymphocytes are the most abundant cell populations found in the synovium of patients diagnosed with rheumatoid arthritis (RA). Activation of these cells leads to the production of proinflammatory cytokines and mediators. Triggering Receptor Expressed on Myeloid Cells 1 (TREM-1) and T cell receptor (TCR), expressed on macrophages and T cells, respectively, play a critical role in the signal transduction pathways leading to the onset and development of RA. In this study, novel ligand-independent peptide inhibitors of TREM-1 and TCR were rationally designed by employing a new model of immune signaling, the Signaling Chain HOmoOLigomerization (SCHOOL) model, and these inhibitors, for the first time, were evaluated in a mouse collagen-induced arthritis (CIA) model.

Methods: CIA was induced by immunizing male DBA/1J mice on days 0 and 21 by bovine type II collagen in Freund’s complete adjuvant. On day 24, animals were weighed, randomized across study groups and given daily intraperitoneal (IP) doses of SCHOOL TREM-1 inhibitory peptide GF-9 or TCR inhibitory peptide MG-11 in free and targeted nanoparticle-bound forms, at doses of 25 mg/kg and 2.5 mg/kg, respectively. The mice were weighed every second day and all paws were scored daily for clinical signs of arthritis.

Results: Mice treated with GF-9 or MG-11 showed a significant delay in arthritis onset as well as a striking reduction in disease severity. This effect is specific as administration of the control peptide did not affect disease onset or severity. Targeted delivery of SCHOOL peptides utilizing self-assembling lipid-peptide nanoparticles significantly increased peptide dosage efficacy.

Conclusion: This study provides clear data demonstrating that inhibition of TREM-1 and TCR signal transduction pathways using short synthetic peptides that employ a novel ligand-independent mechanism of action (SCHOOL peptides) may represent a new, targeted, and non-toxic treatment for RA. Importantly, this ligand-independent mode of TREM-1 inhibition may significantly decrease the risk of failure in clinical development because of the unknown nature of the TREM-1 ligand(s).

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/novel-ligand-independent-peptide-inhibitors-of-triggering-receptor-expressed-on-myeloid-cells-1-trem-1-and-t-cell-receptor-tcr-efficacy-in-a-collagen-induced-arthritis-model-suggests-new-targeted/