POS0408 TRANSFER OF HUMAN RHEUMATOID ARTHRITIS MONONUCLEAR CELLS INDUCES ARTHRITIS IN IMMUNODEFICIENT HLA-DR4 TRANSGENIC MICE

BackgroundRheumatoid arthritis (RA) is a systemic autoimmune disease leading to erosive joint destruction. Although the exact pathogenesis is still elusive, the strong association of certain HLA class II molecules, such as HLA-DRB1*0401 (HLA-DR4), suggest involvement of CD4+ T cells (1,2). Mouse models of RA mimic specific aspects of the disease but are limited by the differences between human and murine immune systems.ObjectivesWe aimed to establish a humanized mouse model (humice) carrying DR4+ RA PBMCs to study its role in the pathogenesis of RA without putting patients at risk.MethodsPeripheral blood mononuclear cells (PBMC) of HLA-DR4 positive RA patients or controls were isolated and injected into NSG-Ab0 DR4 mice (NOD-scid IL2Rgammanull mice lacking MHC class II while expressing the human HLA-DR4) to create humice. Human immune cell composition within humice was profiled using flow cytometry. Development of RA was monitored by examination of the joints and micro computed tomography analysis. Joints were analysed by histology regarding pannus formation, bone erosions, cartilage damage, and human cell infiltration.ResultsTransfer of RA PBMCs induced arthritis in humice recapitulating hallmarks of RA including immune cell infiltration, pannus formation, increased osteoclastogenesis, cartilage damage, and bone erosions. Arthritis was dependent on the implanted human cells as NSG-Ab0 DR4 mice without transfer of human PBMCs did not develop arthritis. T-helper 1 (Th1) cells, dominated the human immune cell composition in humice, while regulatory T cells (Tregs) were diminished compared to donor PBMC composition. Mice humanized with cells from RA patients were more likely to develop inflammatory joint disease, compared to healthy HLA-DR4 positive controls (RA donor 70% vs. healthy control 20%, p=0.00196). CTLA-4 Ig treatment prevented arthritis development in this model (p=0.0055).ConclusionHumice carrying DR4+ RA PBMCs developed an RA-like erosive joint disease driven by the implanted human immune system. The data implies that the disease can be transferred by arthritogenic cells found in the peripheral blood of RA patients. This model will allow new insights into the pathogenesis of RA.References[1]Goulielmos GN, Zervou MI, Myrthianou E, Burska A, Niewold TB, Ponchel F. Genetic data: The new challenge of personalized medicine, insights for rheumatoid arthritis patients. Gene Available from: http://www.ncbi.nlm.nih.gov/pubmed/26869316[2]Holoshitz J. The rheumatoid arthritis HLA–DRB1 shared epitope. Curr Opin Rheumatol Available from: http://www.ncbi.nlm.nih.gov/pubmed/20061955Disclosure of InterestsNone declared.