Janine Rupp1, Johannes Fessler2, Silvia Hayer3, Barbara Dreo4, Angelika Lackner2, Patrizia Fasching2, Wolfgang Helmberg2, Peter Schlenke2, Jens Thiel5, Guenter Steiner6, Cornelia M. Weyand7 and Martin Stradner2, 1Medical University Graz, Rochester, MN, 2Medical University of Graz, Graz, Austria, 3Medical University of VIenna, Vienna, Austria, 4Division of Rheumatology and Immunology, Medical University of Graz, Graz, Austria, 5University Hospital Freiburg, Freiburg, Germany, 6Division of Rheumatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria, 7Mayo Clinic School of Medicine and Stanford University, Rochester, MN
Background/Purpose: T cells play an important role in the genesis of rheumatoid arthritis (RA). HLA class II genes, such as HLA-DRB1*0401 (HLA-DR4), confer the strongest genetic risk and suggest involvement of CD4+ T cells. However, the exact pathogenesis of RA is still elusive. Existing mouse models mimic specific aspects of the disease but do not fully recapitulate the human immune system. Thereby current research is limited and would profit from a humanized mouse model. We aimed to identify arthritogenic cells by transferring HLA-DR4+ peripheral blood mononuclear cells (PBMC) of RA patients into NSG-DR4 mice. Thereby generating a novel mouse model with inflammatory joint disease, only triggered by the transfer of human immune cells.
Methods: Humanized NSG-DR4 mice (NSG-AB0 Tg(HLA-DR4)) were generated by injecting PBMC of HLA-DR4 positive patients or controls. Engraftment within peripheral blood, bone marrow, skin, liver, and spleen was assessed comprehensively using multicolor flow cytometry. Development of RA was monitored by examination of the joints, followed by micro computed tomography analysis and histology. Joints were analyzed regarding pannus formation, bone erosions, cartilage damage, and human cell infiltration.
Results: Here, we show that DR4+ T cells of the peripheral blood of RA patients are capable of inducing an RA-like disease in NSG-DR4 mice. These mice recapitulate different hallmarks of the disease including immune cell infiltration, pannus formation, increased osteoclastogenesis, cartilage damage, and bone erosions. Compared to healthy controls, cells of RA patients are more likely to develop inflammatory joint disease in these mice (RA donor 70% vs. healthy control 20%, p=0.00196). 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. Transfer of in vitro Th1 polarized T cells increased arthritis incidence.
Conclusion: Arthritogenic cells found in the peripheral blood of RA patients are capable of inducing an RA-like disease in NSG-DR4 mice. This novel mouse model will allow to identify these cells on a patient-personalized level.
J. Rupp: None; J. Fessler: None; S. Hayer: None; B. Dreo: None; A. Lackner: None; P. Fasching: None; W. Helmberg: None; P. Schlenke: None; J. Thiel: None; G. Steiner: None; C. Weyand: None; M. Stradner: None.
