Search

Aim: This study aims to demonstrate that HLA-DR15 blockade inhibits auto reactivity to the immunodominant T-cell epitope, alpha3135-145 and attenuates disease in experimental autoimmune anti-glomerular basement membrane (GBM) disease. Background(s): Anti-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 nonspecific and have detrimental side effects. Method(s): HLA-DR15 transgenic mice were used to examine the potential of PV-267 in attenuating DR15-mediated autoreactivity and disease. Autoreactivity to alpha3135-145 was determined by immunizing mice with alpha3135-145, then measuring recall responses ex vivo 10 days later by 3[H]-T proliferation and IFN-gamma and IL-17 ELISPOTs. Experimental autoimmune anti-GBM disease was induced by immunizing mice (backcrossed onto an FcgammaRIIb-/- background) with three weekly injections of alpha3135-145; functional and histological endpoints, as well as immune cell infiltration, were determined at 6weeks. Result(s): Compared with mice that received vehicle control, DR15 transgenic mice that received PV-267 daily (30mg/kg) from day 1 had 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 fewer infiltrating glomerular Tcells (cells/glomerular cross section: 0.90+/- 0.12 vs 0.36+/- 0.03, P<0.01), reduced 24-hour albuminuria (mug: 1064+/- 313 vs 42+/- 29, P<0.01), and reduced glomerular segmental necrosis and crescent formation. Conclusion(s): HLA-DR15 inhibition effectively attenuates experimental autoimmune anti-GBM disease and highlights t

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.