RESUMEN
Antigen-presenting cell-associated four-domain MHC class II (MHC-II) molecules play a central role in activating autoreactive CD4(+) T cells involved in multiple sclerosis (MS) and type 1 diabetes (T1D). In contrast, two-domain MHC-II structures with the same covalently attached self-peptide (recombinant T-cell receptor ligands (RTLs)) can regulate pathogenic CD4(+) T cells and reverse clinical signs of experimental autoimmune diseases. RTL1000, which is composed of the ß1α1 domains of human leukocyte antigen (HLA)-DR2 linked to the encephalitogenic human myelin oligodendrocyte glycoprotein (MOG)-35-55 peptide, was recently shown to be safe and well tolerated in a phase I clinical trial in MS. To evaluate the opposing biological effects of four- versus two-domain MHC-II structures, we screened phage Fab antibodies (Abs) for the neutralizing activity of RTL1000. Five different TCR-like Abs were identified that could distinguish between the two- versus four-domain MHC-peptide complexes while the cognate TCR was unable to make such a distinction. Moreover, Fab detection of native two-domain HLA-DR structures in human plasma implies that there are naturally occurring regulatory MHC-peptide complexes. These results demonstrate for the first time distinct conformational determinants characteristic of activating versus tolerogenic MHC-peptide complexes involved in human autoimmunity.
Asunto(s)
Células Presentadoras de Antígenos/inmunología , Linfocitos T CD4-Positivos/inmunología , Antígenos de Histocompatibilidad Clase II/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Animales , Autoinmunidad/inmunología , Diabetes Mellitus Tipo 1/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/terapia , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Glicoproteínas , Antígeno HLA-DR2/química , Antígeno HLA-DR2/genética , Antígeno HLA-DR2/inmunología , Humanos , Tolerancia Inmunológica , Fragmentos Fab de Inmunoglobulinas/inmunología , Complejo Mayor de Histocompatibilidad/inmunología , Ratones , Ratones Transgénicos , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/terapia , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Péptidos , Proteínas Recombinantes de Fusión/sangre , Proteínas Recombinantes de Fusión/inmunología , Proteínas Recombinantes/inmunologíaRESUMEN
A human recombinant T cell receptor ligand (RTL1000) consisting of DR2 α1 and ß1 domains linked covalently to MOG-35-55 peptide can reverse clinical and histological signs of experimental autoimmune encephalomyelitis (EAE), and was evaluated for safety in a Phase 1 randomized, placebo-controlled, escalating dose study in 34 subjects with multiple sclerosis (MS). RTL1000 was safe and well tolerated at a dose of ≤60 mg that is well within the effective dose range for EAE and did not cause worsening of MS disease at doses ≤200 mg. RTL1000 represents a novel approach for the treatment of MS that promises potent immunoregulation and CNS repair without global immunosuppression.
