In experimental autoimmune anti-glomerular basement membrane glomerulonephritis, HLADR15 inhibition blocks autoreactivity to the immunodominant T cell epitope, alpha3135-145, and prevents disease.

Anti-glomerular basement membrane (GBM) disease is an autoimmune disease that manifests as rapidly progressive glomerulonephritis. It has a strong HLA association with the DR15 allele (odds ratio: 8.5) and the immunodominant, DR15-restricted T-cell epitope has been defined. A DR15 specific inhibitor, PV-267, has potential as a targeted therapy, as current treatments are non-specific and have detrimental side effects. Using humanised HLA transgenic mice expressing DR15, this study tests the hypotheses that administration of PV-267 will inhibit autoreactivity to the immunodominant T cell epitope, alpha3135-145, and prevent disease in experimental autoimmune anti-GBM disease. Autoreactivity to alpha3135-145 was determined by immunizing mice with alpha3135-145, then measuring recall responses ex vivo 10 days later by [3H]-T proliferation and IFN-gamma and IL-17 ELISPOTs. Experimental anti-GBM disease was induced by immunizing DR15 transgenic mice (backcrossed onto an FcgammaRIIb-/- background) with three weekly injections of alpha3135-145, then functional and histological endpoints measured at 6 weeks. Compared with mice that received vehicle control, DR15 transgenic mice that received PV-267 daily (30mg/kg) from day -1 developed markedly reduced alpha3135-145-specific proliferation (SI: 9.5+/-0.9 vs 2.2+/-0.5, P< 0.001) as well as reduced numbers of IFN-gamma and IL-17 spots. In experimental anti-GBM disease, DR15 transgenic mice that received PV-267 (30mg/kg) on alternate days from day -1 had markedly reduced 24 hour albuminuria (mg: 1064+/-313 vs 42+/-29, P< 0.01) and reduced glomerular segmental necrosis and glomerular crescent formation. In conclusion, PV-267 effectively prevents experimental autoimmune anti-GBM disease, and highlights the potential for specific MHCII inhibitors as a targeted therapy for autoimmune disease.