OP0113 Homeostatic Regulation of T-Cell Trafficking by a B-Cell Derived Peptide is Lost in Early Rheumatoid Arthritis
Authors: H.M. McGettrick, M. Chimen, A. Martin, F. Barone, L. Walker, A. Filer, K. Raza, C.D. Buckley, P. Narendran, G.E. Rainger
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> A significant component of the pathogenesis of rheumatoid arthritis is driven through inappropriate recruitment of T-cells into the joint. Indeed, targeting T-cell recruitment may moderate the onset, severity and persistence of RA. However, very little is known about the mechanisms by which T-cell migration is regulated during inflammation. <h3>Objectives</h3> Here, we examined the ability of adiponectin, an anti-inflammatory adipose tissue-derived cytokine, and PEPITEM (a novel PEPtide Inhibitor of T-cell Migration) to regulate the migration of T-cells <i>in vitro</i> and <i>in vivo</i>. <h3>Methods</h3> Peripheral blood lymphocytes were isolated from healthy controls or from treatment naive patients with a new onset of clinically apparent RA. Lymphocytes were treated in the presence or absence of adiponectin (15μg/ml) or PEPITEM (10ng/ml). <i>Ex vivo</i>, lymphocyte migration across tumour necrosis factor alpha and interferon gamma stimulated endothelial cells was assessed using phase-contrast microscopy. <i>In vivo</i>, lymphocyte migration was assessed in a model of zymosan-driven peritoneal inflammation. <h3>Results</h3> We observed that adiponectin inhibited the migration of human lymphocytes across inflamed endothelium in a dose dependent manner. This effect was lost when B-cells were absent, but could be regained by the addition of supernatants from adiponectin-stimulated B-cells. Mass spectrometry identified the adiponectin induced B-cell-derived agent as a small peptide, subsequently named PEPITEM. <i>In vitro</i>, PEPITEM blocks T-cell migration by stimulating endothelial cells to release sphingosine-1-phosphate, a known regulator of T-cell migration. In zymosan-induced peritonitis, T-cell recruitment was significantly increased in B-cell deficient animals compared to wild-type controls, and this was ameliorated by treatment with synthetic PEPITEM. B-cells isolated from patients with early RA expressed lower levels of adiponectin receptors compared to healthy controls and were unable to respond to adiponectin. Consequently, T-cells from patients with early RA were released from the inhibitory effects of adiponectin on transmigration. Excitingly the full effect of adiponectin was rescued <i>in vitro</i> by the therapeutic use of exogenous PEPITEM. <h3>Conclusions</h3> We have identified a novel endogenous peptide (PEPITEM) mediated pathway that suppresses T-cell recruitment across inflamed endothelium, which is dysfunctional in patients with early RA. We believe this leads to a loss of PEPITEM-mediated suppression of T-cell migration, resulting in the inappropriate accumulation of T-cells in the rheumatoid joint. Thus, deregulation of the adiponectin-PEPITEM axis during early development and/or progression of disease could directly contribute to pathology in RA. Re-establishing PEPITEM function to “turn off” pathological recruitment of T-cells represents a novel and potentially powerful approach to treating patients with early rheumatoid arthritis. <h3>Acknowledgements</h3> HMM and MC contributed equally to this work. <h3>Disclosure of Interest</h3> None declared