RESUMEN
The migration of circulating leukocytes into the central nervous system (CNS) is a key driver of multiple sclerosis (MS) pathogenesis. The monoclonal antibody natalizumab proved that pharmaceutically obstructing this process is an effective therapeutic approach for treating relapsing-remitting MS (RRMS). Unfortunately, the clinical efficacy of natalizumab is somewhat offset by its incapacity to control the progressive forms of MS (PMS) and by life-threatening side effects in RRMS rising from the expression of its molecular target, very late antigen 4 (VLA4), on most immune cells and consequent impairment of CNS immunosurveillance. Here, we identified dual immunoglobulin domain containing cell adhesion molecule (DICAM) as a cell trafficking molecule preferentially expressed by T helper 17 (TH17)polarized CD4+ T lymphocytes. We found that DICAM expression on circulating CD4+ T cells was increased in patients with active RRMS and PMS disease courses, and expression of DICAM ligands was increased on the blood-brain barrier endothelium upon inflammation and in MS lesions. Last, we demonstrated that pharmaceutically neutralizing DICAM reduced murine and human TH17 cell trafficking across the blood-brain barrier in vitro and in vivo, and alleviated disease symptoms in four distinct murine autoimmune encephalomyelitis models, including relapsing-remitting and progressive disease models. Collectively, our data highlight DICAM as a candidate therapeutic target to impede the migration of disease-inducing leukocytes into the CNS in both RRMS and PMS and suggest that blocking DICAM with a monoclonal antibody may be a promising therapeutic approach.
Asunto(s)
Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Animales , Barrera Hematoencefálica/metabolismo , Moléculas de Adhesión Celular/metabolismo , Humanos , Ratones , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/metabolismo , Natalizumab/metabolismo , Natalizumab/farmacología , Natalizumab/uso terapéutico , Enfermedades Neuroinflamatorias , Linfocitos T/metabolismo , Células Th17RESUMEN
There are an increasing number of treatments available for multiple sclerosis (MS). The early identification of optimal responders to individual treatments is important to achieve individualized therapy. With this aim, we performed a multicenter retrospective longitudinal study including 186 MS patients treated with natalizumab who were followed for 2 years. We analyzed the following variables at recruitment: sex, current age, age at disease onset, disease duration, EDSS, number of T2 and Gd + lesions, IgG and IgM oligoclonal bands, HLA class II (DR, DRB, DQA, DQB, and DRB1*15:01), IgG and IgM antibody titers against human herpesvirus 6 (HHV-6) and the antibody response to Epstein-Barr virus (EBV) through the measurement of the anti-EBNA-1 and anti-VCA IgG titers, in relation to clinical response (no relapses or disability progression), and to NEDA-3 (no evidence of disease activity in terms of clinical response and no changes in MRI scans either) after 2-years follow-up. Baseline EDSS score, baseline EBNA-1 IgG titers and percentage change of HHV6 IgG titers between baseline and 6 month visits were significantly different in clinical responders and in NEDA-3 status (all of them remained significant in the multivariate analysis). We identified three variables for the early identification of natalizumab optimal responders in a rapid and cost-effective approach.
Asunto(s)
Biomarcadores Farmacológicos/análisis , Esclerosis Múltiple/tratamiento farmacológico , Natalizumab/uso terapéutico , Adulto , Formación de Anticuerpos , Biomarcadores Farmacológicos/sangre , Proteínas de la Cápside/análisis , Proteínas de la Cápside/inmunología , Progresión de la Enfermedad , Infecciones por Virus de Epstein-Barr/inmunología , Antígenos Nucleares del Virus de Epstein-Barr/análisis , Femenino , Antígenos HLA/análisis , Herpesvirus Humano 4/inmunología , Herpesvirus Humano 6/inmunología , Humanos , Inmunoglobulina G/análisis , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/inmunología , Natalizumab/metabolismo , Pronóstico , Recurrencia , Estudios Retrospectivos , EspañaRESUMEN
OBJECTIVE: To assess possible adverse effects on breastfed infants of mothers receiving monoclonal antibodies (MAbs) during pregnancy and/or lactation. METHODS: We identified 23 patients from the German Multiple Sclerosis and Pregnancy Registry (DMSKW) who received MAbs (17 natalizumab and 6 anti-CD20) during lactation. Thirteen were already exposed to natalizumab during the third trimester of pregnancy, and 1 received ocrelizumab during pregnancy. Data were obtained from standardized, telephone-administered questionnaires completed by the mother during pregnancy and at 1, 3, 6, and 12 months postpartum. Natalizumab concentration in mother's milk was analyzed in 3 patients and natalizumab serum concentration in 2 of these patients and their breastfed infants. RESULTS: We did not observe a negative impact on infant health and development attributable to breast milk exposure after a median follow-up of 1 year. Infants exposed to natalizumab during the third trimester had a lower birth weight and more hospitalizations in the first year of life. The concentration of natalizumab in breast milk and serum of infants was low; B cells normal in infants breastfed under anti-CD20. CONCLUSION: More data on the effect of Mab exposure during pregnancy are needed. Otherwise, our data suggest that treatment with natalizumab, ocrelizumab, or rituximab during lactation might be safe for breastfed infants.
Asunto(s)
Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/metabolismo , Peso al Nacer/efectos de los fármacos , Factores Inmunológicos/efectos adversos , Factores Inmunológicos/metabolismo , Lactancia , Leche Humana/metabolismo , Esclerosis Múltiple/tratamiento farmacológico , Neuromielitis Óptica/tratamiento farmacológico , Complicaciones del Embarazo/tratamiento farmacológico , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Sistema de Registros , Adulto , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/metabolismo , Antígenos CD20/inmunología , Lactancia Materna , Femenino , Estudios de Seguimiento , Hospitalización , Humanos , Lactante , Masculino , Natalizumab/efectos adversos , Natalizumab/metabolismo , Periodo Posparto , Embarazo , Tercer Trimestre del Embarazo , Rituximab/efectos adversos , Rituximab/metabolismoRESUMEN
INTRODUCTION: Multiple sclerosis (MS) is an immune-mediated and neurodegenerative disease with an unpredictable outcome. Immune-modulatory treatment aims at decreasing long-term disability. With the increasing number of treatment options, it is essential to fully digest the possible side effects of the available therapeutics and to monitor patients is essential. AREAS COVERED: All approved disease-modifying drugs (DMD) for MS are discussed in this review. Mode of action, adverse effects, reported risks for infections and malignancies, and pregnancy related issues are discussed in the review. The authors also provide suggestions for monitoring therapy. For all approved DMDs the pivotal studies have been included for possible side effects, as well as reports by health authorities. For this manuscript, PubMed was checked for reports on side effects for various drugs. EXPERT OPINION: Treatment options in MS are manifold, each carrying different risks. The safety-risk profile for approved agents is favorable. Knowing and monitoring these possible side effects is essential to minimize risks associated with treatment. Presently, the long-term experience for some of these therapies is missing and this must be addressed.
Asunto(s)
Factores Inmunológicos/efectos adversos , Inmunosupresores/efectos adversos , Alemtuzumab/efectos adversos , Alemtuzumab/metabolismo , Alemtuzumab/uso terapéutico , Cladribina/efectos adversos , Cladribina/metabolismo , Cladribina/uso terapéutico , Crotonatos/efectos adversos , Crotonatos/metabolismo , Crotonatos/uso terapéutico , Clorhidrato de Fingolimod/efectos adversos , Clorhidrato de Fingolimod/metabolismo , Clorhidrato de Fingolimod/uso terapéutico , Acetato de Glatiramer/efectos adversos , Acetato de Glatiramer/metabolismo , Acetato de Glatiramer/uso terapéutico , Humanos , Hidroxibutiratos , Factores Inmunológicos/uso terapéutico , Inmunosupresores/uso terapéutico , Interferón beta/efectos adversos , Interferón beta/metabolismo , Interferón beta/uso terapéutico , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/patología , Natalizumab/efectos adversos , Natalizumab/metabolismo , Natalizumab/uso terapéutico , Neoplasias/etiología , Nitrilos , Toluidinas/efectos adversos , Toluidinas/metabolismo , Toluidinas/uso terapéuticoRESUMEN
Very Late Antigen-4 (VLA-4, α4ß1-integrin, ITGA4) orchestrates cell-cell and cell-endothelium adhesion. Given the proposed role of VLA-4 in sickle cell disease (SCD) pathophysiology, we evaluated the ability of the VLA-4 blocking antibody natalizumab to inhibit SCD blood cell adhesion. Natalizumab recognized surface VLA-4 on leucocytes and reticulocytes in whole blood from SCD subjects. SCD reticulocytes were positive for VLA-4, while VLA-4 staining of non-SCD reticulocytes was undetectable. Titrations with natalizumab revealed the presence of saturable levels of VLA-4 on both SCD reticulocytes and leucocytes similar to healthy subject leucocytes. Under physiological flow conditions, the adhesion of SCD whole blood cells and isolated SCD leucocytes to immobilized vascular cell adhesion molecule 1 (VCAM-1) was blocked by natalizumab in a dose-dependent manner, which correlated with cell surface receptor binding. Natalizumab also inhibited >50% of whole blood cell binding to TNF-α activated human umbilical vein endothelial cell monolayers under physiological flow at clinically relevant concentrations (10 to 100 µg/ml). This indicates that VLA-4 is the dominant receptor that drives SCD reticulocyte and mononuclear cell adhesion to VCAM-1 and that the VLA-4 adhesion to VCAM-1 is a significant contributor to SCD blood cell adhesion to endothelium. Thus, VLA-4 blockade may be beneficial in sickle cell disease.