1165: Pathogenicity of IL-17 Producing Cells in HLA-B27 Transgenic Rat Model of Spondyloarthritis

Marie Beaufrère¹, Manon Jacoutot¹, Amel Ait Ali Said¹, Roula Said-Nahal², Gina Cosentino³, Chiara Rizzo³, Maxime Breban⁴ and Simon Glatigny⁴, ¹Paris Saclay University / INSERM 1173, Montigny-le-Bretonneux, France, ²Rheumatology Division - Ambroise Pare Hospital, APHP, Boulogne-Billancourt, France, ³INSERM 1173, Montigny-le-Bretonneux, France, ⁴1INSERM U1173, UFR Simone Veil, Versailles-Saint Quentin / Paris-Saclay University, Montigny-le-Bretonneux, France

Background/Purpose: Spondylarthritis (SpA) is a group of chronic inflammatory disorders with osteoarticular and extraarticular symptoms, including colitis, highly associated with the human leukocyte antigen (HLA) class I allele HLA-B27. A strong association of SpA with HLA-B27 has been known for nearly 50 years but its pathogenic role remains largely unexplained. Transgenic rats expressing HLA-B27 and human b2-microglobulin (B27-rat) develop clinical manifestations resembling human SpA (rat SpA). Previous studies revealed that IL-17 and TNF-a are two major cytokines implicated in both SpA and rat SpA.

In this study, we aimed to determine which cell subset(s) produce key proinflammatory cytokines IL-17 and TNF-α during rat SpA and characterize their tissue distribution. Then, we evaluated if chemokine receptor can be used to isolate these subsets. Finally, we tested the pathogenicity of these proinflammatory cell subsets by transfer in athymic (nude) B27-rats.

Methods: Lymphoid cells were isolated from both inflamed tissues and lymphoid organs draining those tissues before and during rat SpA development and were characterized. Nontransgenic (NTG) littermates were used as control. Blood samples were used to translate B27-rat findings to HLA-B27⁺ SpA patients. Pathogenicity of purified CD4⁺ T cell subsets was assessed by transfer of 40,000 purified cell subsets in SpA-resistant athymic nude B27-rats.

Results: First, we showed that conventional T cells (CD4⁺ Foxp3^-) were the main producers of both IL-17 and TNF-α and coproduced these cytokines during rat SpA. Importantly, those Th17 cells were already significantly expanded in the blood, bone marrow (BM), and colon of premorbid B27-rats. Then, we showed that CCR6 was a reliable marker to isolate all Th17 cells in rat. Similar findings were observed in SpA patients. Finally, transfer of HLA-B27⁺ purified Th17 (CCR6⁺) – but not Th1 - cells induced SpA symptoms (arthritis and colitis) in athymic B27-rats, providing the first direct evidence of a specific proarthritogenic role of Th17 cells in SpA.

Conclusion: Our study demonstrates that IL-17⁺TNFa⁺ Th17 cells are already expanded before disease development and are involved in SpA development. Further studies are required to determine the mechanism leading to the generation of these cells in colon and BM to identify new therapeutic targets.

Disclosures: M. Beaufrère, None; M. Jacoutot, None; A. Ait Ali Said, None; R. Said-Nahal, None; G. Cosentino, None; C. Rizzo, None; M. Breban, None; S. Glatigny, None.