RESUMO
The neonatal fragment crystallizable (Fc) receptor (FcRn) functions as a recycling mechanism to prevent degradation and extend the half-life of IgG and albumin in the circulation. Several FcRn inhibitors selectively targeting IgG recycling are now moving rapidly toward clinical practice in neurology and hematology. These molecules accelerate the destruction of IgG, reducing pathogenic IgG and IgG immune complexes, with no anticipated effects on IgA, IgM, IgE, complement, plasma cells, B cells, or other cells of the innate or adaptive immune systems. FcRn inhibitors have potential for future use in a much wider variety of antibody-mediated autoimmune diseases. Given the imminent clinical use, potential for broader utility, and novel mechanism of action of FcRn inhibitors, here we review data from 4 main sources: (a) currently available activity, safety, and mechanism-of-action data from clinical trials of FcRn inhibitors; (b) other procedures and treatments that also remove IgG (plasma donation, plasma exchange, immunoadsorption); (c) diseases resulting in loss of IgG; and (d) primary immunodeficiencies with potential mechanistic similarities to those induced by FcRn inhibitors. These data have been evaluated to provide practical considerations for the assessment, monitoring, and reduction of any potential infection risk associated with FcRn inhibition, in addition to highlighting areas for future research.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Doenças Autoimunes/terapia , Antígenos de Histocompatibilidade Classe I/metabolismo , Receptores Fc/metabolismo , Anticorpos Bloqueadores , Autoanticorpos/metabolismo , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Imunomodulação , Terapia de Alvo Molecular , Guias de Prática Clínica como Assunto , Receptores Fc/imunologia , Risco , Medição de RiscoRESUMO
OBJECTIVE: The objective of the present trial was to assess efficacy and safety of intravenous (IV) brivaracetam (BRV) vs. lorazepam (LZP) in patients with epilepsy undergoing evaluation in an epilepsy monitoring unit (EMU) who experienced seizures requiring acute treatment. METHODS: This was a phase 2, open-label, randomized, active-control, proof-of-concept trial (EP0087; NCT03021018). Patients (18-70â¯years) admitted to EMU were randomized 1:1:1 to single-dose bolus IV LZP (dose per investigator's practice), IV BRV 100â¯mg, or IV BRV 200â¯mg. Trial medication had to be administered within 30â¯min of qualifying seizure. Primary efficacy outcome was time to next seizure (clinical observation with electroencephalogram [EEG] confirmation) or to rescue medication use within 12â¯h of trial medication administration. Secondary outcomes included seizure freedom and rescue medication use within 12â¯h of trial medication administration. Safety and tolerability outcomes included treatment-emergent adverse events (TEAEs). RESULTS: Overall, 46 patients were randomized, and 45 received trial medication for a qualifying seizure. Patients in the LZP arm had doses from 1 to 4â¯mg (median: 1â¯mg). Eleven of 45 patients had a seizure within 12â¯h of trial medication administration (LZP 5/15 [median time to next seizure: 5.55â¯h], BRV 100â¯mg 3/15 [5.97â¯h], BRV 200â¯mg 3/15 [3.60â¯h]). No patients received additional rescue medication to control their qualifying seizure. Most patients were seizure-free over 12â¯h (LZP 9/15 [60.0%], BRV 100â¯mg 12/15 [80.0%], BRV 200â¯mg 12/15 [80.0%]). Rescue medication use within 12â¯h was numerically higher for LZP (6/15 [40.0%]) vs. BRV 100â¯mg (1/15 [6.7%]) and vs. BRV 200â¯mg (2/15 [13.3%]). Treatment-emergent adverse events were reported by 5/16 (31.3%), 6/15 (40.0%), and 3/15 (20.0%) of LZP, BRV 100â¯mg, and BRV 200â¯mg patients; one LZP patient had a serious TEAE (seizure cluster). Most common TEAEs (≥10% of patients) were sedation and somnolence with LZP, and dizziness, headache, and nausea with BRV. SIGNIFICANCE: Intravenous LZP, IV BRV 100â¯mg, and IV BRV 200â¯mg showed similar efficacy in controlling acute seizure activity in the EMU. Treatment-emergent adverse events were as expected for each medication. Although this trial should be interpreted with caution because of small patient numbers, it suggests a possible role of BRV in the acute treatment of increased seizure activity.
Assuntos
Anticonvulsivantes/administração & dosagem , Epilepsia/tratamento farmacológico , Lorazepam/administração & dosagem , Pirrolidinonas/administração & dosagem , Convulsões/tratamento farmacológico , Administração Intravenosa , Adolescente , Adulto , Idoso , Anticonvulsivantes/efeitos adversos , Tontura/induzido quimicamente , Método Duplo-Cego , Eletroencefalografia/efeitos dos fármacos , Eletroencefalografia/métodos , Epilepsia/diagnóstico , Feminino , Humanos , Lorazepam/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estudo de Prova de Conceito , Pirrolidinonas/efeitos adversos , Convulsões/diagnóstico , Sonolência , Resultado do Tratamento , Adulto JovemRESUMO
Experimental autoimmune encephalomyelitis (EAE) is a widely used model of multiple sclerosis. In NOD mice, EAE develops as a relapsing-remitting disease that transitions to a chronic progressive disease, making the NOD model the only mouse model that recapitulates the full clinical disease course observed in most multiple sclerosis patients. We have generated a TCR transgenic mouse that expresses the α- and ß-chains of a myelin oligodendrocyte glycoprotein (MOG) 35-55-reactive TCR (1C6) on the NOD background. 1C6 TCR transgenic mice spontaneously generate both CD4(+) and CD8(+) T cells that recognize MOG and produce proinflammatory cytokines, allowing for the first time to our knowledge the simultaneous examination of myelin-reactive CD4(+) and CD8(+) T cells in the same host. 1C6 CD8(+) T cells alone can induce optic neuritis and mild EAE with delayed onset; however, 1C6 CD4(+) T cells alone induce severe EAE and predominate in driving disease when both cell types are present. When 1C6 mice are crossed with mice bearing an IgH specific for MOG, the mice develop spontaneous EAE with high incidence, but surprisingly the disease pattern does not resemble the neuromyelitis optica-like disease observed in mice bearing CD4(+) T cells and B cells reactive to MOG on the C57BL/6 background. Collectively, our data show that although myelin-reactive CD8(+) T cells contribute to disease, disease is primarily driven by myelin-reactive CD4(+) T cells and that the coexistence of myelin-reactive T and B cells does not necessarily result in a distinct pathological phenotype.
Assuntos
Subpopulações de Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Sequência de Aminoácidos , Animais , Subpopulações de Linfócitos B/metabolismo , Subpopulações de Linfócitos B/patologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Feminino , Técnicas de Introdução de Genes , Glicoproteínas/administração & dosagem , Glicoproteínas/toxicidade , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Dados de Sequência Molecular , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/toxicidadeRESUMO
Neural stem/progenitor cells (NSPCs) have the ability to migrate into the central nervous system (CNS) to replace damaged cells. In inflammatory CNS disease, cytokine transduced neural stem cells may be used as vehicles to specifically reduce inflammation and promote cell replacement. In this study, we used NSPCs overexpressing IL-10, an immunomodulatory cytokine, in an animal model for CNS inflammation and multiple sclerosis (MS). Intravenous injection of IL-10 transduced neural stem/progenitor cells (NSPC(IL-10)) suppressed myelin oligodendrocyte glycoprotein aa 35-55 (MOG35-55)- induced experimental autoimmune encephalomyelitis (EAE) and, following intravenous injection, NSPC(IL-10) migrated to peripheral lymphoid organs and into the CNS. NSPC(IL-10 )suppressed antigen-specific proliferation and proinflammatory cytokine production of lymph node cells obtained from MOG35-55 peptide immunized mice. In this model, IL-10 producing NSPCs act via a peripheral immunosuppressive effect to attenuate EAE.
Assuntos
Encefalomielite Autoimune Experimental/imunologia , Interleucina-10/imunologia , Células-Tronco Neurais/imunologia , Células-Tronco Neurais/transplante , Transplante de Células-Tronco/métodos , Animais , Ensaio de Imunoadsorção Enzimática , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução GenéticaRESUMO
BACKGROUND: Cognitive impairment is a common symptom of multiple sclerosis (MS), but little is known about cognitive decline in patients in the long-term course of progressive MS. Because advancing age is the most significant risk factor for Alzheimer's Disease (AD), AD-related pathology must be considered in elderly patients with MS. Amnestic mild cognitive impairment (aMCI) represents the prodromal phase of AD with subjects showing memory impairment that does not improve with recognition testing. OBJECTIVE: We sought to identify disease-dependent deterioration patterns by comparing elderly patients with secondary progressive MS (SPMS) and with aMCI using the Consortium to Establish a Registry for Alzheimer's Disease test battery. METHODS: This study included 120 age-, education- and gender-matched participants, including healthy controls (n=40), SPMS patients (n=40), and aMCI patients (n=40). RESULTS: Episodic memory deficits appeared in the long-term course of SPMS. Deficits were associated with deterioration of executive function, but not impairment of memory storage as recognition was preserved in SPMS in contrast to the patients with aMCI. CONCLUSION: Through neuropsychological testing, MS-related episodic memory impairment due to deteriorated executive function can be distinguished from AD-related encoding and storage deficits. Hence, neuropsychological testing may help to identify AD-related pathology in SPMS patients.
Assuntos
Envelhecimento/psicologia , Amnésia/psicologia , Cognição , Disfunção Cognitiva/psicologia , Memória Episódica , Esclerose Múltipla Crônica Progressiva/psicologia , Reconhecimento Psicológico , Fatores Etários , Idoso , Amnésia/diagnóstico , Estudos de Casos e Controles , Disfunção Cognitiva/diagnóstico , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Crônica Progressiva/diagnóstico , Testes Neuropsicológicos , Valor Preditivo dos Testes , Fatores de TempoRESUMO
BACKGROUND: Generalised myasthenia gravis is a chronic, unpredictable, and debilitating autoimmune disease. New treatments for this disease are needed because conventional therapies have limitations, such as side-effects (eg, increased infection risk) or inadequate control of symptoms. Rozanolixizumab is a neonatal Fc receptor blocker that might provide a novel therapeutic option for myasthenia gravis. We aimed to assess the safety and efficacy of rozanolixizumab for generalised myasthenia gravis. METHODS: MycarinG is a randomised, double-blind, placebo-controlled, adaptive phase 3 study done at 81 outpatient centres and hospitals in Asia, Europe, and North America. We enrolled patients (aged ≥18 years) with acetylcholine receptor (AChR) or muscle-specific kinase (MuSK) autoantibody-positive generalised myasthenia gravis (Myasthenia Gravis Foundation of America class II-IVa), a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of at least 3 (non-ocular symptoms), and a quantitative myasthenia gravis score of at least 11. Patients were randomly assigned (1:1:1) to receive subcutaneous infusions once a week for 6 weeks of either rozanolixizumab 7 mg/kg, rozanolixizumab 10 mg/kg, or placebo. Randomisation was stratified by AChR and MuSK autoantibody status. Investigators, patients, and people assessing outcomes were masked to random assignments. The primary efficacy endpoint was change from baseline to day 43 in MG-ADL score, assessed in the intention-to-treat population. Treatment-emergent adverse events (TEAEs) were assessed in all randomly assigned patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT03971422) and EudraCT (2019-000968-18); an open-label extension study has been completed (NCT04124965; EudraCT 2019-000969-21) and another is underway (NCT04650854; EudraCT 2020-003230-20). FINDINGS: Between June 3, 2019, and June 30, 2021, 300 patients were assessed for eligibility, of whom 200 were enrolled. 66 (33%) were randomly assigned to rozanolixizumab 7 mg/kg, 67 (34%) to rozanolixizumab 10 mg/kg, and 67 (34%) to placebo. Reductions in MG-ADL score from baseline to day 43 were greater in the rozanolixizumab 7 mg/kg group (least-squares mean change -3·37 [SE 0·49]) and in the rozanolixizumab 10 mg/kg group (-3·40 [0·49]) than with placebo (-0·78 [0·49]; for 7 mg/kg, least-squares mean difference -2·59 [95% CI -4·09 to -1·25], p<0·0001; for 10 mg/kg, -2·62 [-3·99 to -1·16], p<0·0001). TEAEs were experienced by 52 (81%) of 64 patients treated with rozanolixizumab 7 mg/kg, 57 (83%) of 69 treated with rozanolixizumab 10 mg/kg, and 45 (67%) of 67 treated with placebo. The most frequent TEAEs were headache (29 [45%] patients in the rozanolixizumab 7 mg/kg group, 26 [38%] in the rozanolixizumab 10 mg/kg group, and 13 [19%] in the placebo group), diarrhoea (16 [25%], 11 [16%], and nine [13%]), and pyrexia (eight [13%], 14 [20%], and one [1%]). Five (8%) patients in the rozanolixizumab 7 mg/kg group, seven (10%) in the rozanolixizumab 10 mg/kg group, and six (9%) in the placebo group had a serious TEAE. No deaths occurred. INTERPRETATION: Rozanolixizumab showed clinically meaningful improvements in patient-reported and investigator-assessed outcomes in patients with generalised myasthenia gravis, for both 7 mg/kg and 10 mg/kg doses. Both doses were generally well tolerated. These findings support the mechanism of action of neonatal Fc receptor inhibition in generalised myasthenia gravis. Rozanolixizumab represents a potential additional treatment option for patients with generalised myasthenia gravis. FUNDING: UCB Pharma.
Assuntos
Atividades Cotidianas , Miastenia Gravis , Recém-Nascido , Humanos , Adolescente , Adulto , Miastenia Gravis/tratamento farmacológico , Receptores Colinérgicos , Autoanticorpos , Método Duplo-Cego , Resultado do TratamentoRESUMO
OBJECTIVE: To explore the clinical efficacy and safety of subcutaneous (SC) rozanolixizumab, an anti-neonatal Fc receptor humanized monoclonal antibody, in patients with generalized myasthenia gravis (gMG). METHODS: In this phase 2a, randomized, double-blind, placebo-controlled, 2-period, multicenter trial (NCT03052751), patients were randomized (1:1) in period 1 (days 1-29) to 3 once-weekly (Q1W) SC infusions of rozanolixizumab 7 mg/kg or placebo. In period 2 (days 29-43), patients were re-randomized to either rozanolixizumab 7 mg/kg or 4 mg/kg (3 Q1W SC infusions), followed by an observation period (days 44-99). Primary endpoint was change from baseline to day 29 in Quantitative Myasthenia Gravis (QMG) score. Secondary endpoints were change from baseline to day 29 in MG-Activities of Daily Living (MG-ADL) and MG-Composite (MGC) scores and safety. RESULTS: Forty-three patients were randomized (rozanolixizumab 21, placebo 22 [period 1]). Least squares (LS) mean change from baseline to day 29 for rozanolixizumab vs placebo was as follows: QMG (LS mean -1.8 vs -1.2, difference -0.7, 95% upper confidence limit [UCL] 0.8; p = 0.221; not statistically significant), MG-ADL (LS mean -1.8 vs -0.4, difference -1.4, 95% UCL -0.4), and MGC (LS mean -3.1 vs -1.2, difference -1.8, 95% UCL 0.4) scores. Efficacy measures continued to improve with rozanolixizumab 7 mg/kg in period 2. The most common adverse event in period 1 was headache (rozanolixizumab 57%, placebo 14%). CONCLUSION: Whereas change from baseline in QMG was not statistically significant, the data overall suggest rozanolixizumab may provide clinical benefit in patients with gMG and was generally well tolerated. Phase 3 evaluation is ongoing (NCT03971422). CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with gMG, rozanolixizumab is well-tolerated, but did not significantly improve QMG score.
Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Imunossupressores/farmacologia , Miastenia Gravis/tratamento farmacológico , Avaliação de Resultados em Cuidados de Saúde , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Neutrophil cytosolic factor 1, p47phox (NCF1) is a component of the leukocyte NADPH oxidase complex mediating formation of reactive oxygen intermediates (ROI) which play an important role in host defense and autoimmunity. An individual genomic pattern of ncf1 and its two types of pseudogenes (reflected by the DeltaGT/GTGT ratio) may influence the individual capacity to produce ROI. METHODS: NCF1DeltaGT/GTGT ratios were correlated with clinical parameters and ROI production during Plasmodium falciparum malaria and with susceptibility to the autoimmune disease multiple sclerosis (MS). RESULTS: Among Gabonese children with severe malaria, ROI production from peripheral blood tended to be higher in individuals with a DeltaGT/GTGT ratio = 1:1. DeltaGT/GTGT ratios were not associated with susceptibility to MS, but to age-of-onset among MS patients. CONCLUSION: The genomic pattern of NCF1 and its pseudogenes might influence ROI production but only marginally influence susceptibility to and outcome of malaria and MS.
Assuntos
Malária Falciparum/genética , Esclerose Múltipla/genética , NADPH Oxidases/genética , Pseudogenes , Espécies Reativas de Oxigênio/metabolismo , Idade de Início , Autoimunidade , Estudos de Casos e Controles , Criança , Gabão/epidemiologia , Predisposição Genética para Doença , Alemanha/epidemiologia , Granulócitos/metabolismo , Humanos , Malária Falciparum/epidemiologia , Malária Falciparum/imunologia , Esclerose Múltipla/epidemiologia , Polônia/epidemiologiaRESUMO
After encounter with a central nervous system (CNS)-derived autoantigen, lymphocytes leave the lymph nodes and enter the CNS. This event leads only rarely to subsequent tissue damage. Genes relevant to CNS pathology after cell infiltration are largely undefined. Myelin-oligodendrocyte-glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS), a chronic autoimmune disease of the CNS that results in disability. To assess genes that are involved in encephalitogenicity and subsequent tissue damage mediated by CNS-infiltrating cells, we performed a DNA microarray analysis from cells derived from lymph nodes and eluted from CNS in LEW.1AV1 (RT1av1) rats immunized with MOG 91-108. The data was compared to immunizations with adjuvant alone or naive rats and to immunizations with the immunogenic but not encephalitogenic MOG 73-90 peptide. Here, we show involvement of Cd38, Cxcr4 and Akt and confirm these findings by the use of Cd38-knockout (B6.129P2-Cd38tm1Lnd/J) mice, S1P-receptor modulation during EAE and quantitative expression analysis in individuals with MS. The hereby-defined underlying pathways indicate cellular activation and migration pathways mediated by G-protein-coupled receptors as crucial events in CNS tissue damage. These pathways can be further explored for novel therapeutic interventions.
Assuntos
Encefalomielite Autoimune Experimental/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Esclerose Múltipla/genética , ADP-Ribosil Ciclase 1/metabolismo , Animais , Movimento Celular/efeitos dos fármacos , Quimiocina CXCL12/metabolismo , Encefalomielite Autoimune Experimental/patologia , Feminino , Cloridrato de Fingolimode/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Imunização , Linfonodos/efeitos dos fármacos , Linfonodos/patologia , Camundongos Endogâmicos C57BL , Esclerose Múltipla/patologia , Glicoproteína Mielina-Oligodendrócito , Peptídeos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologiaRESUMO
Genetic variation in the intracellular tyrosine phosphatase PTPN22 has been recently associated with susceptibility to various autoimmune diseases. Myasthenia gravis (MG) is a complex genetic disease with a distinct clinical and pathological heterogeneity. We conducted a case-control association study for the PTPN22 1858C/T polymorphism in Hungarian and German MG patients (n = 282) and regional controls (n = 379). We detected an association of the PTPN22 1858T allele with MG in the subgroup of nonthymoma patients with anti-titin antibodies present (n = 50; T allele frequency 21% vs 11% in controls; p = 0.005, odds ratio 2.1, 95% confidence interval 1.23-3.58). This overrepresentation was reported independently in both Hungarian and German MG patients compared with regional controls. We conclude that the common autoimmune polymorphism PTPN22 1858C/T may account for disease susceptibility in a subset of nonthymoma MG patients with anti-titin antibodies present.
Assuntos
Autoanticorpos/imunologia , Proteínas Musculares/imunologia , Miastenia Gravis/genética , Polimorfismo de Nucleotídeo Único/genética , Proteínas Quinases/imunologia , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Autoimunidade , Estudos de Casos e Controles , Conectina , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Alemanha , Humanos , Hungria , Desequilíbrio de Ligação , Miastenia Gravis/imunologia , Polimorfismo de Nucleotídeo Único/imunologiaRESUMO
Polymorphisms in the CTLA4 gene region have been associated with susceptibility to autoimmune diseases. The recently described single nucleotide polymorphism CT60, located in the 3' untranslated region of CTLA4 is associated with Graves' disease, thyroiditis, autoimmune diabetes and other autoimmune diseases. A case-control association study was conducted in German, Hungarian and Polish multiple sclerosis (MS) patients and regional control individuals for the CTLA4 CT60 and +49A/G polymorphisms. No significant association of these polymorphisms or respective haplotypes with MS was found. No association of CT60 genotypes with T cell expression of ICOS and CTLA-4 after in vitro stimulation was detected.
Assuntos
Antígenos CD/genética , Antígenos CD/imunologia , Esclerose Múltipla/genética , Esclerose Múltipla/imunologia , Polimorfismo Genético , Autoimunidade/genética , Antígeno CTLA-4 , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Alemanha , Humanos , Hungria , PolôniaRESUMO
The NF-kappaB family of transcription factors plays a pivotal role in T cell activation and survival during (auto) immune responses. IkappaB kinase 2/beta (IKK2) is part of the IkappaB kinase complex, a central component of the intracellular signaling pathway mediating NF-kappaB activation. We studied the role of IKK2 in autoantigen-specific T cell activation and induction of autoimmune disease using mice that lack this kinase specifically in T cells (IKK2(DeltaT cell) mice). We found highly impaired myelin-oligodendrocyte-glycoprotein (MOG)(35-55)-specific T cell activation in vitro and complete resistance to MOG(35-55)-induced experimental autoimmune encephalomyelitis (EAE) in IKK2(DeltaT cell) C57BL/6 mice in vivo. By contrast, transgenic expression of a pathogenic MOG(35-55)-specific TCR (2D2 TCR) rendered IKK2(DeltaT cell) mice susceptible to MOG(35-55)-induced EAE and restored in vitro MOG(35-55)-specific T cell responses, indicating an expansion defect in IKK2-deficient T cells. Treatment with the IKK2-inhibitory compound PS-1145 reduced MOG(35-55)-specific proliferation and cytokine production of 2D2 transgenic spleen cells in vitro and diminished clinical signs of EAE in vivo. Our data underscore the potential of therapeutic IKK inhibition in autoimmune diseases.
Assuntos
Autoantígenos/imunologia , Proliferação de Células , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/prevenção & controle , Quinase I-kappa B/deficiência , Quinase I-kappa B/genética , Subpopulações de Linfócitos T/enzimologia , Subpopulações de Linfócitos T/patologia , Sequência de Aminoácidos , Animais , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/enzimologia , Epitopos de Linfócito T/imunologia , Feminino , Glicoproteínas/toxicidade , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Quinase I-kappa B/antagonistas & inibidores , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Dados de Sequência Molecular , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Peptídeos/toxicidade , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Subpopulações de Linfócitos T/imunologiaRESUMO
Nonobese diabetic (NOD) mice develop multi-organ autoimmune diseases, including type 1 diabetes. We hypothesized that backcrossing the MHC region from SJL (H-2(s)) mice, which have an endogenous PLP(139-151)-reactive repertoire, onto the background of autoimmune-prone NOD mice would result in a mouse strain that is highly susceptible to experimental autoimmune encephalomyelitis (EAE). Unexpectedly, although we detected an endogenous PLP(139-151) repertoire in the NOD.S mice, they did not develop spontaneous EAE and were relatively resistant to PLP(139-151)-induced EAE when compared to SJL mice. This resistance was associated with lower production of proinflammatory cytokines and a decreased expansion of PLP(139-151)-specific CD4(+) T cells after immunization and restimulation with PLP peptide in vitro. V(beta) chain usage among PLP(139-151)-reactive T cells differed between SJL and NOD.S mice. Furthermore, NOD.S mice were resistant to the development of insulitis and cyclophosphamide-induced diabetes, but not sialadenitis. Altogether, even though NOD mice develop spontaneous autoimmune diseases, they become relatively resistant to induction of EAE even when they express the EAE-permissive class II molecule I-A(s). Our data show that certain combinations of otherwise susceptibility-conferring MHC and non-MHC genes can mediate autoimmune-disease resistance when they are paired together. These findings do not support the "shared autoimmune gene" hypothesis.
Assuntos
Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/imunologia , Predisposição Genética para Doença/genética , Haplótipos/genética , Complexo Principal de Histocompatibilidade/genética , Animais , Animais Congênicos , Linfócitos T CD4-Positivos/imunologia , Células Cultivadas , Ciclofosfamida/farmacologia , Citocinas/biossíntese , Citocinas/imunologia , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/patologia , Encefalomielite Autoimune Experimental/patologia , Antígenos de Histocompatibilidade/genética , Antígenos de Histocompatibilidade/metabolismo , Imunização , Camundongos , Camundongos Endogâmicos NOD , Proteína Proteolipídica de Mielina/química , Proteína Proteolipídica de Mielina/imunologia , Linfócitos T/imunologiaRESUMO
Antibodies against native glycosylated myelin-oligodendrocyte-glycoprotein (MOG) were measured by ELISA in patients with multiple sclerosis (MS) and controls. Anti-MOG IgM antibodies were elevated during the first demyelinating event. Higher MOG-specific IgG antibodies were found in patients during relapses and in secondary chronic progressive MS compared to patients in remission and healthy controls. Antibodies against native MOG may be a potential biomarker for MS.
Assuntos
Autoanticorpos/imunologia , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Esclerose Múltipla Crônica Progressiva/imunologia , Esclerose Múltipla Recidivante-Remitente/imunologia , Glicoproteína Associada a Mielina/imunologia , Processamento de Proteína Pós-Traducional , Adulto , Idoso , Animais , Especificidade de Anticorpos , Autoanticorpos/sangue , Doenças Desmielinizantes , Feminino , Glicosilação , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Masculino , Camundongos , Pessoa de Meia-Idade , Proteínas da Mielina , Glicoproteína Associada a Mielina/química , Glicoproteína Associada a Mielina/isolamento & purificação , Glicoproteína Mielina-OligodendrócitoRESUMO
Linkage analysis and congenic mapping in NOD mice have identified a susceptibility locus for type 1 diabetes, Idd5.1 on mouse chromosome 1, which includes the Ctla4 and Icos genes. Besides type 1 diabetes, numerous autoimmune diseases have been mapped to a syntenic region on human chromosome 2q33. In this study we determined how the costimulatory molecules encoded by these genes contribute to the immunopathogenesis of experimental autoimmune encephalomyelitis (EAE). When we compared levels of expression of costimulatory molecules on T cells, we found higher ICOS and lower full-length CTLA-4 expression on activated NOD T cells compared with C57BL/6 (B6) and C57BL/10 (B10) T cells. Using NOD.B10 Idd5 congenic strains, we determined that a 2.1-Mb region controls the observed expression differences of ICOS. Although Idd5.1 congenic mice are resistant to diabetes, we found them more susceptible to myelin oligodendrocyte glycoprotein 35-55-induced EAE compared with NOD mice. Our data demonstrate that higher ICOS expression correlates with more IL-10 production by NOD-derived T cells, and this may be responsible for the less severe EAE in NOD mice compared with Idd5.1 congenic mice. Paradoxically, alleles at the Idd5.1 locus have opposite effects on two autoimmune diseases, diabetes and EAE. This may reflect differential roles for costimulatory pathways in inducing autoimmune responses depending upon the origin (tissue) of the target Ag.
Assuntos
Antígenos de Diferenciação de Linfócitos T/genética , Mapeamento Cromossômico , Diabetes Mellitus Tipo 1/genética , Encefalomielite Autoimune Experimental/etiologia , Regulação da Expressão Gênica , Predisposição Genética para Doença , Animais , Antígenos CD , Antígenos de Diferenciação/genética , Antígeno CTLA-4 , Citocinas/biossíntese , Encefalomielite Autoimune Experimental/genética , Proteína Coestimuladora de Linfócitos T Induzíveis , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos NOD , Linfócitos T/imunologiaRESUMO
B7 costimulatory molecules play an important role in inducing autoimmunity, tumor immunity, and transplant rejection, and therapeutic manipulation of B7 is being investigated in human diseases. To determine whether B7 costimulation is essential for inducing autoimmunity on different genetic backgrounds, we backcrossed B7.1/B7.2 deficient ((-/-)) mice on to the C57BL/6 (B6) and SJL backgrounds and induced experimental autoimmune encephalomyelitis (EAE) in these mice. B7.1/B7.2(-/-) mice on the B6 background were resistant to EAE induced with MOG 35-55, whereas the SJL B7.1/B7.2(-/-) mice were susceptible to PLP 139-151 or PLP 178-191-induced EAE. The SJL B7.1/B7.2(-/-) mice had a qualitatively different lesion pattern in that they showed increased white matter vacuolation compared to wild-type SJL mice when immunized with either PLP 139-151 or PLP 178-191. (B6xSJL)F1 B7.1/B7.2(+/+) mice were susceptible to EAE whereas (B6xSJL)F1 B7.1/B7.2(-/-) mice were resistant to EAE induced with either encephalitogenic peptide. Thus, genetic background determines the B7 requirement for inducing autoimmunity. These data have important implications for developing B7-based immunotherapies for human diseases.
Assuntos
Antígenos CD/fisiologia , Antígeno B7-1/fisiologia , Encefalomielite Autoimune Experimental/genética , Imunoconjugados , Glicoproteínas de Membrana/fisiologia , Abatacepte , Sequência de Aminoácidos , Animais , Antígenos CD/genética , Antígenos de Diferenciação/imunologia , Autoimunidade/genética , Antígeno B7-1/genética , Antígeno B7-2 , Antígeno CTLA-4 , Cruzamentos Genéticos , Encefalomielite Autoimune Experimental/etiologia , Encefalomielite Autoimune Experimental/imunologia , Feminino , Predisposição Genética para Doença , Glicoproteínas/imunologia , Glicoproteínas/toxicidade , Imunização , Linfonodos/patologia , Ativação Linfocitária , Masculino , Glicoproteínas de Membrana/deficiência , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Proteína Proteolipídica de Mielina/imunologia , Proteína Proteolipídica de Mielina/toxicidade , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/toxicidadeRESUMO
Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) plays a critical role in downregulating T cell responses. A number of autoimmune diseases have shown genetic linkage to the CTLA-4 locus. We have cloned and expressed an alternatively spliced form of CTLA-4 that has genetic linkage with type I diabetes in the NOD mice. This splice variant of CTLA-4, named ligand-independent CTLA-4 (liCTLA-4), lacks exon2 including the MYPPPY motif essential for binding to the costimulatory ligands B7-1 and B7-2. Here we show that liCTLA-4 is expressed as a protein in primary T cells and strongly inhibits T cell responses by binding and dephosphorylating the TcRzeta chain. Expression of liCTLA-4, but not full-length CTLA-4 (flCTLA-4), was higher in memory/regulatory T cells from diabetes-resistant NOD congenic mice compared to susceptible NOD mice. These data suggest that increased expression and negative signaling delivered by the liCTLA-4 may regulate development of T cell-mediated autoimmune diseases.