RESUMEN
The strong association of HLA-DR2b (DRB1*1501) with multiple sclerosis (MS) suggests this molecule as prime target for specific immunotherapy. Inhibition of HLA-DR2b-restricted myelin-specific T cells has the potential to selectively prevent CNS pathology mediated by these MHC molecules without undesired global immunosuppression. In this study, we report development of a highly selective small molecule inhibitor of peptide binding and presentation by HLA-DR2b. PV-267, the candidate molecule used in these studies, inhibited cytokine production and proliferation of myelin-specific HLA-DR2b-restricted T cells. PV-267 had no significant effect on T cell responses mediated by other MHC class II molecules, including HLA-DR1, -DR4, or -DR9. Importantly, PV-267 did not induce nonspecific immune activation of human PBMC. Lastly, PV-267 showed treatment efficacy both in preventing experimental autoimmune encephalomyelitis and in treating established disease. The results suggest that blocking the MS-associated HLA-DR2b allele with small molecule inhibitors may be a promising therapeutic strategy for the treatment of MS.
Asunto(s)
Encefalomielitis Autoinmune Experimental/prevención & control , Encefalomielitis Autoinmune Experimental/terapia , Antígeno HLA-DR2/metabolismo , Linfocitos T/metabolismo , Animales , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Encefalomielitis Autoinmune Experimental/inmunología , Antígeno HLA-DR2/efectos de los fármacos , Antígeno HLA-DR2/inmunología , Humanos , Leucocitos Mononucleares/inmunología , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , Ratones , Ratones Transgénicos , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/terapia , Proteína Básica de Mielina , Péptidos/farmacología , Linfocitos T/efectos de los fármacosRESUMEN
OBJECTIVE: To study the frequency of HLA DR2 status of patients with aplastic anemia and their response to immunosuppressive therapy at a tertiary care hospital. METHODS: Thirty eight consecutive patients of acquired aplastic anemia were evaluated with respect to demographic features, severity of HLA DR2 status and response outcome to immunosuppressive therapy. RESULTS: The mean age of the patients was 24.6 years + 16.4 with a male to female ratio of 2.8:1. Positivity of HLA DR2 was markedly high in acquired aplastic anemia patients. Twenty four (65%) out of 38 patients as compared to 45 (15%) of 300 healthy controls (p<0.0001) were positive for HLA DR2. Response to immunosuppressive therapy, which included antilymphocyte globulin, cyclosporin and methylprednisolone, was available in sixteen HLA DR2 positive patients and was found satisfactory in 12/16 (75%) patients. CONCLUSION: HLA DR2 was significantly higher in patients with acquired aplastic anemia and favourable response to immunosuppressive therapy was also associated with HLA DR2 positivity.
