HLA-DR15 inhibition attenuates experimental autoimmune anti-glomerular basement membrane disease.

Anti-GBM disease is a form of small vessel vasculitis that manifests as rapidly progressive glomerulonephritis. It has a strong association with the HLA-DR15 allele (odds ratio: 8.5), and the immunodominant T cell epitope a3135-145 is restricted to HLA-DR15. A DR15-specific inhibitor, PV-267, has potential as a targeted therapy, as current treatment is broadly immunosuppressive and has detrimental side effects. This study aims to demonstrate that specific inhibition of HLA-DR15 prevents autoreactivity to the immunodominant T cell epitope and attenuates injury in experimental autoimmune anti-glomerular basement membrane (GBM) disease. HLA-DR15 transgenic mice (backcrossed onto an FcgRIIb-/-background) were used in this study. Autoreactivity to a3135-145 was determined by immunising mice with a3135-145 at day 0, while administering PV-267 daily (30mg/kg) from day-1 to day 10, then measuring recall responses ex vivo by [3H]-thymidine proliferation and IFNg and IL-17A ELISPOTs. Experimental autoimmune anti-GBM disease was induced in mice by immunisations of a3135-145 at days 0, 7, and 14. In a prevention model, mice were administered PV-267 every second day (30mg/kg) from day-1 to day 42. In a treatment model, PV-267 was administered daily (50mg/kg) from day 28 to day 42. Mice were culled at day 42. Functional and histological endpoints, as well as immune cell infiltration were determined. Compared with mice that received vehicle control, mice that received PV-267 had reduced a3135-145-specific proliferation (SI: 9.5+/-0.9 vs 2.2+/-0.5, P<0.001) as well as reduced numbers of IFNg and IL-17A spots. In the prevention model of disease, mice given PV-267 had fewer infiltrating glomerular CD4+ T-cells (0.90+/-0.12 vs 0.36+/-0.03 cells/glomerular cross section, P<0.01), reduced albuminuria (albumin/creatinine ratio: 0.215+/-0.056 vs 0.010+/-0.007 mg/mmol, P<0.01), and reduced glomerular segmental necrosis and crescents. In the treatment model, there was no difference in album