RESUMEN
BACKGROUND & AIMS: In celiac disease (CeD), gluten induces immune activation, leading to enteropathy. TAK-101, gluten protein (gliadin) encapsulated in negatively charged poly(dl-lactide-co-glycolic acid) nanoparticles, is designed to induce gluten-specific tolerance. METHODS: TAK-101 was evaluated in phase 1 dose escalation safety and phase 2a double-blind, randomized, placebo-controlled studies. Primary endpoints included pharmacokinetics, safety, and tolerability of TAK-101 (phase 1) and change from baseline in circulating gliadin-specific interferon-γ-producing cells at day 6 of gluten challenge, in patients with CeD (phase 2a). Secondary endpoints in the phase 2a study included changes from baseline in enteropathy (villus height to crypt depth ratio [Vh:Cd]), and frequency of intestinal intraepithelial lymphocytes and peripheral gut-homing T cells. RESULTS: In phase 2a, 33 randomized patients completed the 14-day gluten challenge. TAK-101 induced an 88% reduction in change from baseline in interferon-γ spot-forming units vs placebo (2.01 vs 17.58, P = .006). Vh:Cd deteriorated in the placebo group (-0.63, P = .002), but not in the TAK-101 group (-0.18, P = .110), although the intergroup change from baseline was not significant (P = .08). Intraepithelial lymphocyte numbers remained equal. TAK-101 reduced changes in circulating α4ß7+CD4+ (0.26 vs 1.05, P = .032), αEß7+CD8+ (0.69 vs 3.64, P = .003), and γδ (0.15 vs 1.59, P = .010) effector memory T cells. TAK-101 (up to 8 mg/kg) induced no clinically meaningful changes in vital signs or routine clinical laboratory evaluations. No serious adverse events occurred. CONCLUSIONS: TAK-101 was well tolerated and prevented gluten-induced immune activation in CeD. The findings from the present clinical trial suggest that antigen-specific tolerance was induced and represent a novel approach translatable to other immune-mediated diseases. ClinicalTrials.gov identifiers: NCT03486990 and NCT03738475.
Asunto(s)
Enfermedad Celíaca/inmunología , Gliadina/inmunología , Tolerancia Inmunológica/inmunología , Nanopartículas/administración & dosificación , Enfermedad Celíaca/patología , Método Doble Ciego , Gliadina/administración & dosificación , Glicolatos/administración & dosificación , Humanos , Infusiones IntravenosasRESUMEN
BACKGROUND & AIMS: Celiac disease could be treated, and potentially cured, by restoring T-cell tolerance to gliadin. We investigated the safety and efficacy of negatively charged 500-nm poly(lactide-co-glycolide) nanoparticles encapsulating gliadin protein (TIMP-GLIA) in 3 mouse models of celiac disease. Uptake of these nanoparticles by antigen-presenting cells was shown to induce immune tolerance in other animal models of autoimmune disease. METHODS: We performed studies with C57BL/6; RAG1-/- (C57BL/6); and HLA-DQ8, huCD4 transgenic Ab0 NOD mice. Mice were given 1 or 2 tail-vein injections of TIMP-GLIA or control nanoparticles. Some mice were given intradermal injections of gliadin in complete Freund's adjuvant (immunization) or of soluble gliadin or ovalbumin (ear challenge). RAG-/- mice were given intraperitoneal injections of CD4+CD62L-CD44hi T cells from gliadin-immunized C57BL/6 mice and were fed with an AIN-76A-based diet containing wheat gluten (oral challenge) or without gluten. Spleen or lymph node cells were analyzed in proliferation and cytokine secretion assays or by flow cytometry, RNA sequencing, or real-time quantitative polymerase chain reaction. Serum samples were analyzed by gliadin antibody enzyme-linked immunosorbent assay, and intestinal tissues were analyzed by histology. Human peripheral blood mononuclear cells, or immature dendritic cells derived from human peripheral blood mononuclear cells, were cultured in medium containing TIMP-GLIA, anti-CD3 antibody, or lipopolysaccharide (controls) and analyzed in proliferation and cytokine secretion assays or by flow cytometry. Whole blood or plasma from healthy volunteers was incubated with TIMP-GLIA, and hemolysis, platelet activation and aggregation, and complement activation or coagulation were analyzed. RESULTS: TIMP-GLIA did not increase markers of maturation on cultured human dendritic cells or induce activation of T cells from patients with active or treated celiac disease. In the delayed-type hypersensitivity (model 1), the HLA-DQ8 transgenic (model 2), and the gliadin memory T-cell enteropathy (model 3) models of celiac disease, intravenous injections of TIMP-GLIA significantly decreased gliadin-specific T-cell proliferation (in models 1 and 2), inflammatory cytokine secretion (in models 1, 2, and 3), circulating gliadin-specific IgG/IgG2c (in models 1 and 2), ear swelling (in model 1), gluten-dependent enteropathy (in model 3), and body weight loss (in model 3). In model 1, the effects were shown to be dose dependent. Splenocytes from HLA-DQ8 transgenic mice given TIMP-GLIA nanoparticles, but not control nanoparticles, had increased levels of FOXP3 and gene expression signatures associated with tolerance induction. CONCLUSIONS: In mice with gliadin sensitivity, injection of TIMP-GLIA nanoparticles induced unresponsiveness to gliadin and reduced markers of inflammation and enteropathy. This strategy might be developed for the treatment of celiac disease.
Asunto(s)
Enfermedad Celíaca/tratamiento farmacológico , Gliadina/administración & dosificación , Tolerancia Inmunológica/efectos de los fármacos , Nanopartículas/administración & dosificación , Administración Intravenosa , Animales , Linfocitos T CD4-Positivos , Enfermedad Celíaca/sangre , Enfermedad Celíaca/inmunología , Células Cultivadas , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Femenino , Gliadina/inmunología , Gliadina/toxicidad , Glútenes/administración & dosificación , Glútenes/inmunología , Antígenos HLA-DQ/genética , Antígenos HLA-DQ/inmunología , Humanos , Mucosa Intestinal , Leucocitos Mononucleares , Ratones , Ratones Transgénicos , Nanopartículas/química , Nanopartículas/toxicidad , Poliglactina 910/química , Cultivo Primario de Células , Pruebas de Toxicidad AgudaRESUMEN
BACKGROUND: Interleukin 23 is a critical cytokine in the pathogenesis of multiple sclerosis. But the local impact of interleukin 23 on the course of neuroinflammation is still not well defined. To further characterize the effect of interleukin 23 on CNS inflammation, we recently described a transgenic mouse model with astrocyte-specific expression of interleukin 23 (GF-IL23 mice). The GF-IL23 mice spontaneously develop a progressive ataxic phenotype with cerebellar tissue destruction and inflammatory infiltrates with high amounts of B cells most prominent in the subarachnoid and perivascular space. METHODS: To further elucidate the local impact of the CNS-specific interleukin 23 synthesis in autoimmune neuroinflammation, we induced a MOG35-55 experimental autoimmune encephalomyelitis (EAE) in GF-IL23 mice and WT mice and analyzed the mice by histology, flow cytometry, and transcriptome analysis. RESULTS: We were able to demonstrate that local interleukin 23 production in the CNS leads to aggravation and chronification of the EAE course with a severe paraparesis and an ataxic phenotype. Moreover, enhanced multilocular neuroinflammation was present not only in the spinal cord, but also in the forebrain, brainstem, and predominantly in the cerebellum accompanied by persisting demyelination. Thereby, interleukin 23 creates a pronounced proinflammatory response with accumulation of leukocytes, in particular B cells, CD4+ cells, but also γδ T cells and activated microglia/macrophages. Furthermore, transcriptome analysis revealed an enhanced proinflammatory cytokine milieu with upregulation of lymphocyte activation markers, co-stimulatory markers, chemokines, and components of the complement system. CONCLUSION: Taken together, the GF-IL23 model allowed a further breakdown of the different mechanisms how IL-23 drives neuroinflammation in the EAE model and proved to be a useful tool to further dissect the impact of interleukin 23 on neuroinflammatory models.
Asunto(s)
Astrocitos/inmunología , Linfocitos B/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Inflamación/inmunología , Interleucina-23/inmunología , Animales , Astrocitos/metabolismo , Encefalomielitis Autoinmune Experimental/metabolismo , Encefalomielitis Autoinmune Experimental/patología , Inflamación/metabolismo , Interleucina-23/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , FenotipoRESUMEN
Autoimmune diseases, such as celiac disease, multiple sclerosis, and type 1 diabetes, are leading causes of morbidity and mortality in the United States. In these disease states, immune regulatory mechanisms fail that result in T and B cell-mediated destruction of self-tissues. The known role of T cells in mediating autoimmune diseases has led to the emergence of numerous therapies aimed at inactivating T cells, however successful 'tolerance-inducing' strategies have not yet emerged for approved standard-of-care clinical use. In this review, we describe relevant examples of antigen-specific tolerance approaches that have been applied in clinical trials for human diseases. Furthermore, we describe the evolution of biomaterial approaches from cell-based therapies to induce immune tolerance with a focus on the Tolerogenic Immune-Modifying nanoParticle (TIMP) platform. The TIMP platform can be designed to treat various autoimmune conditions and is currently in clinical trials testing its ability to reverse celiac disease.
Asunto(s)
Autoinmunidad , Tolerancia Inmunológica , Nanopartículas/química , Animales , Antígenos/inmunología , Apoptosis , Humanos , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/químicaRESUMEN
Specific immunotherapy (SIT) is the most widely used treatment for allergic diseases that directly targets the T helper 2 (Th2) bias underlying allergy. However, the most widespread clinical applications of SIT require a long period of dose escalation with soluble antigen (Ag) and carry a significant risk of adverse reactions, particularly in highly sensitized patients who stand to benefit most from a curative treatment. Thus, the development of safer, more efficient methods to induce Ag-specific immune tolerance is critical to advancing allergy treatment. We hypothesized that antigen-associated nanoparticles (Ag-NPs), which we have used to prevent and treat Th1/Th17-mediated autoimmune disease, would also be effective for the induction of tolerance in a murine model of Th2-mediated ovalbumin/alum-induced allergic airway inflammation. We demonstrate here that antigen-conjugated polystyrene (Ag-PS) NPs, although effective for the prophylactic induction of tolerance, induce anaphylaxis in presensitized mice. Antigen-conjugated NPs made of biodegradable poly(lactide-co-glycolide) (Ag-PLG) are similarly effective prophylactically, are well tolerated by sensitized animals, but only partially inhibit Th2 responses when administered therapeutically. PLG NPs containing encapsulated antigen [PLG(Ag)], however, were well tolerated and effectively inhibited Th2 responses and airway inflammation both prophylactically and therapeutically. Thus, we illustrate progression toward PLG(Ag) as a biodegradable Ag carrier platform for the safe and effective inhibition of allergic airway inflammation without the need for nonspecific immunosuppression in animals with established Th2 sensitization.
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Antígenos/administración & dosificación , Antígenos/inmunología , Asma/inmunología , Asma/terapia , Implantes de Medicamentos/administración & dosificación , Nanocápsulas/administración & dosificación , Células Th2/inmunología , Implantes Absorbibles , Animales , Asma/diagnóstico , Femenino , Inmunización/métodos , Inyecciones Intravenosas , Ratones , Ratones Endogámicos BALB C , Tamaño de la Partícula , Poliglactina 910/administración & dosificación , Poliglactina 910/química , Células Th2/efectos de los fármacos , Resultado del TratamientoRESUMEN
Type 1 diabetes (T1D) is mediated by destruction of pancreatic ß cells by autoantigen-specific CD4+ and CD8+ T cells, thus the ideal solution for T1D is the restoration of immune tolerance to ß cell antigens. We demonstrate the ability of carboxylated 500 nm biodegradable poly(lactide-co-glycolide) (PLG) nanoparticles PLG nanoparticles (either surface coupled with or encapsulating the cognate diabetogenic peptides) to rapidly and efficiently restore tolerance in NOD.SCID recipients of both activated diabetogenic CD4+ BDC2.5 chromagranin A-specific and CD8+ NY8.3 islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)-specific TCR transgenic T cells in an antigen-specific manner. Further, initiation and maintenance of Ag-PLG tolerance operates via several overlapping, but independent, pathways including regulation via negative-co-stimulatory molecules (CTLA-4 and PD-1) and the systemic induction of peptide-specific Tregs which were critical for long-term maintenance of tolerance by controlling both trafficking of effector T cells to, and their release of pro-inflammatory cytokines within the pancreas, concomitant with selective retention of effector cells in the spleens of recipient mice.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Diabetes Mellitus Tipo 1/inmunología , Células Secretoras de Insulina/patología , Nanopartículas/uso terapéutico , Animales , Autoantígenos/química , Autoantígenos/inmunología , Células Cultivadas , Diabetes Mellitus Tipo 1/terapia , Modelos Animales de Enfermedad , Femenino , Glucosa-6-Fosfatasa/química , Glucosa-6-Fosfatasa/genética , Glucosa-6-Fosfatasa/inmunología , Tolerancia Inmunológica , Ratones , Ratones Endogámicos NOD , Ratones Transgénicos , Nanopartículas/química , Péptidos/química , Péptidos/inmunología , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Receptores de Antígenos de Linfocitos T alfa-beta/genéticaRESUMEN
Recent approaches using nanoparticles engineered for immune regulation have yielded promising results in preclinical models of disease. The number of nanoparticle therapies is growing, fueled by innovations in nanotechnology and advances in understanding of the underlying pathogenesis of immune-mediated diseases. In particular, recent mechanistic insight into the ways in which nanoparticles interact with the mononuclear phagocyte system and impact its function during homeostasis and inflammation have highlighted the potential of nanoparticle-based therapies for controlling severe inflammation while concurrently restoring peripheral immune tolerance in autoimmune disease. Here we review recent advances in nanoparticle-based approaches aimed at immune-modulation, and discuss these in the context of concepts in polymeric nanoparticle development, including particle modification, delivery and the factors associated with successful clinical deployment.
Asunto(s)
Inmunoterapia/métodos , Nanopartículas/química , Animales , Sistemas de Liberación de Medicamentos , Humanos , Inmunoterapia/instrumentación , Tamaño de la Partícula , Propiedades de SuperficieRESUMEN
Polymeric nanoparticles (NPs) have demonstrated their potential to induce antigen (Ag)-specific immunological tolerance in multiple immune models and are at various stages of commercial development. Association of Ag with NPs is typically achieved through surface coupling or encapsulation methods. However, these methods have limitations that include high polydispersity, uncontrollable Ag loading and release, and possible immunogenicity. Here, using antigenic peptides conjugated to poly(lactide-co-glycolide), we developed Ag-polymer conjugate NPs (acNPs) with modular loading of single or multiple Ags, negligible burst release, and minimally exposed surface Ag. Tolerogenic responses of acNPs were studied in vitro to decouple the role of NP size, concentration, and Ag loading on regulatory T cell (Treg) induction. CD4+CD25+Foxp3+ Treg induction was dependent on NP size, but CD25 expression of CD4+ T cells was not. NP concentration and Ag loading could be modulated to achieve maximal levels of Treg induction. In relapsing-remitting experimental autoimmune encephalomyelitis (R-EAE), a murine model of multiple sclerosis, acNPs were effective in inhibiting disease induced by a single peptide or multiple peptides. The acNPs provide a simple, modular, and well-defined platform, and the NP physicochemical properties offer potential to design and answer complex mechanistic questions surrounding NP-induced tolerance.
Asunto(s)
Antígenos/farmacología , Preparaciones de Acción Retardada/química , Encefalomielitis Autoinmune Experimental/terapia , Inmunoconjugados/farmacología , Proteína Proteolipídica de la Mielina/farmacología , Nanopartículas/química , Ovalbúmina/farmacología , Animales , Antígenos/química , Antígenos/inmunología , Biomarcadores/metabolismo , Antígenos CD4/genética , Antígenos CD4/inmunología , Preparaciones de Acción Retardada/administración & dosificación , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/patología , Femenino , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/inmunología , Expresión Génica , Tolerancia Inmunológica/efectos de los fármacos , Inmunoconjugados/química , Inmunoconjugados/metabolismo , Subunidad alfa del Receptor de Interleucina-2/genética , Subunidad alfa del Receptor de Interleucina-2/inmunología , Ratones , Ratones Endogámicos C57BL , Proteína Proteolipídica de la Mielina/química , Proteína Proteolipídica de la Mielina/inmunología , Nanopartículas/administración & dosificación , Ovalbúmina/química , Ovalbúmina/inmunología , Tamaño de la Partícula , Poliglactina 910/química , Poliglactina 910/metabolismo , Cultivo Primario de Células , Bazo/efectos de los fármacos , Bazo/inmunología , Bazo/patología , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/patologíaRESUMEN
Herpes simplex virus type 1 (HSV-1) encephalitis (HSE) is the most common fatal sporadic encephalitis in developed countries. There is evidence from HSE animal models that not only direct virus-mediated damage caused but also the host's immune response contributes to the high mortality of the disease. Chemokines modulate and orchestrate this immune response. Previous experimental studies in HSE models identified the chemokine receptor CXCR3 and its ligands as molecules with a high impact on the course of HSE in mouse models. In this study, the role of the chemokine receptor CXCR3 was evaluated after intranasal infection with the encephalitogenic HSV-1 strain 17 syn+ using CXCR3-deficient mice (CXCR3-/-) and wild-type controls. We demonstrated a neurotropic viral spread into the CNS of after intranasal infection. Although viral load and histological distribution of infected neurons were independent from CXCR3 signaling early after infection, CXCR3-deficient mice cleared HSV-1 more efficiently 14 days after infection. Furthermore, CXCR3 deficiency led to a decreased weight loss in mice after HSV-1 infection. T cell infiltration and microglial activation was prominently reduced by inhibition of CXCR3 signaling. Quantitative PCR of proinflammatory cytokines and chemokines confirmed the reduced neuroinflammatory response in CXCR3-deficient mice during HSE. Our results demonstrate that the recruitment of peripheral immune cells into the CNS, induction of neuroinflammation, and consecutive weight loss during herpes encephalitis is modulated by CXCR3 signaling. Interruption of the CXCR3 pathway ameliorates the detrimental host immune response and in turn, leads paradoxically to an enhanced viral clearance after intranasal infection. Our data gives further insight into the role of CXCR3 during HSE after intranasal infection.
Asunto(s)
Encéfalo/inmunología , Resistencia a la Enfermedad/genética , Encefalitis por Herpes Simple/inmunología , Herpesvirus Humano 1/inmunología , Receptores CXCR3/deficiencia , Administración Intranasal , Animales , Encéfalo/virología , Movimiento Celular , Quimiocina CXCL10/genética , Quimiocina CXCL10/inmunología , ADN Viral/genética , ADN Viral/inmunología , Modelos Animales de Enfermedad , Encefalitis por Herpes Simple/patología , Encefalitis por Herpes Simple/virología , Regulación de la Expresión Génica , Herpesvirus Humano 1/crecimiento & desarrollo , Humanos , Interferón gamma/genética , Interferón gamma/inmunología , Leucocitos/inmunología , Leucocitos/virología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microglía/inmunología , Microglía/virología , Receptores CXCR3/genética , Receptores CXCR3/inmunología , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunología , Carga Viral , Pérdida de Peso/inmunologíaRESUMEN
As a group of disorders, autoimmunity ranks as the third most prevalent cause of morbidity and mortality in the Western World. However, the etiology of most autoimmune diseases remains unknown. Although genetic linkage studies support a critical underlying role for genetics, the geographic distribution of these disorders as well as the low concordance rates in monozygotic twins suggest that a combination of other factors including environmental ones are involved. Virus infection is a primary factor that has been implicated in the initiation of autoimmune disease. Infection triggers a robust and usually well-coordinated immune response that is critical for viral clearance. However, in some instances, immune regulatory mechanisms may falter, culminating in the breakdown of self-tolerance, resulting in immune-mediated attack directed against both viral and self-antigens. Traditionally, cross-reactive T-cell recognition, known as molecular mimicry, as well as bystander T-cell activation, culminating in epitope spreading, have been the predominant mechanisms elucidated through which infection may culminate in an T-cell-mediated autoimmune response. However, other hypotheses including virus-induced decoy of the immune system also warrant discussion in regard to their potential for triggering autoimmunity. In this review, we discuss the mechanisms by which virus infection and antiviral immunity contribute to the development of autoimmunity.
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Autoinmunidad , Virosis/inmunología , Virus/inmunología , Animales , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/metabolismo , Enfermedades Autoinmunes/virología , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/patología , Sistema Nervioso Central/virología , Humanos , Virosis/metabolismoRESUMEN
Lipocalin 2 (Lcn2) is a bacteriostatic factor produced during the innate immune response to bacterial infection. Whether Lcn2 has a function in viral infection is unknown. We investigated the regulation and function of Lcn2 in the central nervous system (CNS) of mice during West Nile virus (WNV) encephalitis. Lcn2 mRNA and protein were induced in the brain by day 5, and this induction increased further by day 7 postinfection but was delayed compared with the induction of the toll-like receptor 3 (TLR3) gene, retinoic acid-inducible gene 1 (RIG-I), and melanoma differentiation-associated protein 5 (MDA5) gene. The Lcn2 mRNA and protein were both found at high levels in the choroid plexus, vascular endothelium, macrophage/microglia, and astrocytes. However, some neuronal subsets contained Lcn2 protein but no detectable mRNA. In Lcn2 knockout (KO) mice, with the exception of CXC motif chemokine 5 (CXCL5), which was significantly more downregulated than in wild-type (WT) mice, expression levels of a number of other host response genes were similar in the two genotypes. The brain from Lcn2 and WT mice with WNV encephalitis contained similar numbers of infiltrating macrophages, granulocytes, and T cells. Lcn2 KO and WT mice had no significant difference in tissue viral loads or survival after infection with different doses of WNV. We conclude that Lcn2 gene expression is induced to high levels in a time-dependent fashion in a variety of cells and regions of the CNS of mice with WNV encephalitis. The function of Lcn2 in the host response to WNV infection remains largely unknown, but our data indicate that it is dispensable as an antiviral or immunoregulatory factor in WNV encephalitis.
Asunto(s)
Proteínas de Fase Aguda/metabolismo , Sistema Nervioso Central/metabolismo , Lipocalinas/metabolismo , Proteínas Oncogénicas/metabolismo , Fiebre del Nilo Occidental/metabolismo , Animales , Hibridación in Situ , Lipocalina 2 , Ratones , Ratones Endogámicos C57BL , Regulación hacia Arriba , Fiebre del Nilo Occidental/genéticaRESUMEN
Immune tolerance remains the most promising yet elusive strategy for treating immune-mediated diseases. An experimental strategy showing promise in phase 1 clinical studies is the delivery of Ag cross-linked to apoptotic leukocytes using ethylene carbodiimide. This approach originated from demonstration of the profound tolerance-inducing ability of i.v. administered Ag-coupled splenocytes (Ag-SP) in mice, which has been demonstrated to treat T cell-mediated disorders including autoimmunity, allergy, and transplant rejection. Recent studies have defined the intricate interplay between the innate and adaptive immune systems in Ag-SP tolerance induction. Innate mechanisms include scavenger receptor-mediated uptake of Ag-SP by host APCs, Ag representation, and the required upregulation of PD-L1 expression and IL-10 production by splenic marginal zone macrophages leading to Ag-specific T cell regulation via the combined effects of cell-intrinsic anergy and regulatory T cell induction. In this paper, we discuss the history, advantages, current mechanistic understanding, and clinical potential of tolerance induction using apoptotic Ag-coupled apoptotic leukocytes.
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Traslado Adoptivo , Enfermedades del Sistema Inmune/terapia , Tolerancia Inmunológica , Terapia de Inmunosupresión/métodos , Subgrupos de Linfocitos T/inmunología , Linfocitos T Reguladores/inmunología , Inmunidad Adaptativa , Animales , Presentación de Antígeno , Antígenos/inmunología , Apoptosis , Antígeno B7-H1/inmunología , Ensayos Clínicos Fase I como Asunto , Anergia Clonal , Humanos , Enfermedades del Sistema Inmune/inmunología , Inmunidad Innata , Terapia de Inmunosupresión/tendencias , Interleucina-10/inmunología , Ratones , Receptores Depuradores/inmunología , Subgrupos de Linfocitos T/trasplante , Linfocitos T Reguladores/trasplanteRESUMEN
Monoclonal antibody (mAb) technology has revolutionized treatment options for T cell mediated diseases. However, a safe, clinically available anti-T cell antibody (ab) remains elusive. Experience with anti-T cell agents and their propensity for causing immune-mediated toxicities have hampered the development of anti-T cell mAb's. Furthermore, misunderstanding regarding mechanism(s) of action of particular antibodies can influence development and clinical prescription habits. For example, the anti-CD3 Ab OKT3 is consistently described as a depleting Ab even though original studies showed the mechanism to be non-lytic. Future anti-T cell mAbs are likely to be non-depletional and focused on the expansion of regulatory T cells. This review discusses how the properties of Abs can be exploited for manipulating pathological T cell responses in the clinic.
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Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/uso terapéutico , Inmunoterapia/métodos , Linfocitos T/inmunología , Animales , Antígenos de Diferenciación de Linfocitos T/inmunología , Autoinmunidad/inmunología , Citotoxicidad Inmunológica , Humanos , Activación de Linfocitos , Linfocitos T/citología , Linfocitos T/patologíaRESUMEN
Ag-specific tolerance is a highly desired therapy for immune-mediated diseases. Intravenous infusion of protein/peptide Ags linked to syngeneic splenic leukocytes with ethylene carbodiimide (Ag-coupled splenocytes [Ag-SP]) has been demonstrated to be a highly efficient method for inducing peripheral, Ag-specific T cell tolerance for treatment of autoimmune disease. However, little is understood about the mechanisms underlying this therapy. In this study, we show that apoptotic Ag-SP accumulate in the splenic marginal zone, where their uptake by F4/80(+) macrophages induces production of IL-10, which upregulates the expression of the immunomodulatory costimulatory molecule PD-L1 that is essential for Ag-SP tolerance induction. Ag-SP infusion also induces T regulatory cells that are dispensable for tolerance induction but required for long-term tolerance maintenance. Collectively, these results indicate that Ag-SP tolerance recapitulates how tolerance is normally maintained in the hematopoietic compartment and highlight the interplay between the innate and adaptive immune systems in the induction of Ag-SP tolerance. To our knowledge, we show for the first time that tolerance results from the synergistic effects of two distinct mechanisms, PD-L1-dependent T cell-intrinsic unresponsiveness and the activation of T regulatory cells. These findings are particularly relevant as this tolerance protocol is currently being tested in a Phase I/IIa clinical trial in new-onset relapsing-remitting multiple sclerosis.
Asunto(s)
Tolerancia Inmunológica/inmunología , Macrófagos/inmunología , Proteína Proteolipídica de la Mielina/inmunología , Fragmentos de Péptidos/inmunología , Bazo/inmunología , Linfocitos T Reguladores/inmunología , Animales , Antígenos/inmunología , Apoptosis/inmunología , Antígeno B7-1/biosíntesis , Antígeno B7-1/inmunología , Antígeno B7-H1 , Separación Celular , Encefalomielitis Autoinmune Experimental/inmunología , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Inmunohistoquímica , Interleucina-10/biosíntesis , Interleucina-10/inmunología , Activación de Linfocitos/inmunología , Linfocitos/inmunología , Activación de Macrófagos/inmunología , Macrófagos/metabolismo , Glicoproteínas de Membrana/biosíntesis , Glicoproteínas de Membrana/inmunología , Ratones , Ratones Endogámicos C57BL , Péptidos/inmunología , Bazo/citologíaRESUMEN
Mosquito-borne flaviviruses are a major current and emerging threat, affecting millions of people worldwide. Global climate change, combined with increasing proximity of humans to animals and mosquito vectors by expansion into natural habitats, coupled with the increase in international travel, have resulted in significant spread and concomitant increase in the incidence of infection and severe disease. Although neuroinvasive disease has been well described for some viral infections such as Japanese Encephalitis virus (JEV) and West Nile virus (WNV), others such as dengue virus (DENV) have recently displayed an emerging pattern of neuroinvasive disease, distinct from the previously observed, systemically-induced encephalomyelopathy. In this setting, the immune response is a crucial component of host defence, in preventing viral dissemination and invasion of the central nervous system (CNS). However, subversion of the anti-viral activities of macrophages by flaviviruses can facilitate viral replication and spread, enhancing the intensity of immune responses, leading to severe immune-mediated disease which may be further exacerbated during the subsequent infection with some flaviviruses. Furthermore, in the CNS myeloid cells may be responsible for inducing specific inflammatory changes, which can lead to significant pathological damage during encephalitis. The interaction of virus and cells of the myeloid lineage is complex, and this interaction is likely responsible at least in part, for crucial differences between viral clearance and pathology. Recent studies on the role of myeloid cells in innate immunity and viral control, and the mechanisms of evasion and subversion used by flaviviruses are rapidly advancing our understanding of the immunopathological mechanisms involved in flavivirus encephalitis and will lead to the development of therapeutic strategies previously not considered.
Asunto(s)
Encefalitis/inmunología , Infecciones por Flavivirus/inmunología , Inmunidad Innata , Macrófagos/inmunología , Animales , Virus del Dengue/inmunología , Virus del Dengue/patogenicidad , Encefalitis/virología , Virus de la Encefalitis Japonesa (Especie)/inmunología , Virus de la Encefalitis Japonesa (Especie)/patogenicidad , Flavivirus/inmunología , Flavivirus/patogenicidad , Infecciones por Flavivirus/transmisión , Infecciones por Flavivirus/virología , Humanos , Células Mieloides/inmunología , Virus del Nilo Occidental/inmunología , Virus del Nilo Occidental/patogenicidadRESUMEN
Monocytes are a heterogeneous population of bone marrow-derived cells that are recruited to sites of infection and inflammation in many models of human diseases, including those of the central nervous system (CNS). Ly6Chi/CCR2(hi) inflammatory monocytes have been identified as the circulating precursors of brain macrophages, dendritic cells and arguably microglia in experimental autoimmune encephalomyelitis; Alzheimer's disease; stroke; and more recently in CNS infection caused by Herpes simplex virus, murine hepatitis virus, Theiler's murine encephalomyelitis virus, Japanese encephalitis virus and West Nile virus. The precise differentiation pathways and functions of inflammatory monocyte-derived populations in the inflamed CNS remains a contentious issue, especially in regard to the existence of monocyte-derived microglia. Furthermore, the contributions of monocyte-derived subsets to viral clearance and immunopathology are not well-defined. Thus, understanding the pathways through which inflammatory monocytes migrate to the brain and their functional capacity within the CNS is critical to inform future therapeutic strategies. This review discusses some of the key aspects of inflammatory monocyte trafficking to the brain and addresses the role of these cells in viral encephalitis.
Asunto(s)
Infarto Encefálico/patología , Citocinas/metabolismo , Encefalitis Viral/patología , Monocitos/patología , Animales , Células de la Médula Ósea/patología , Infarto Encefálico/complicaciones , Infarto Encefálico/inmunología , Infarto Encefálico/virología , Diferenciación Celular , Encefalitis Viral/complicaciones , Humanos , Monocitos/clasificación , Monocitos/inmunologíaRESUMEN
Infiltration of Ly6C(hi) monocytes from the blood is a hallmark of viral encephalitis. In mice with lethal encephalitis caused by West Nile virus (WNV), an emerging neurotropic flavivirus, inhibition of Ly6C(hi) monocyte trafficking into the brain by anti-very late antigen (VLA)-4 integrin antibody blockade at the time of first weight loss and leukocyte influx resulted in long-term survival of up to 60% of infected mice, with subsequent sterilizing immunity. This treatment had no effect on viral titers but appeared to be due to inhibition of Ly6C(hi) macrophage immigration. Although macrophages isolated from the infected brain induced WNV-specific CD4(+) T-cell proliferation, T cells did not directly contribute to pathology, but are likely to be important in viral control, as antibody-mediated T-cell depletion could not reproduce the therapeutic benefit of anti-VLA-4. Instead, 70% of infiltrating inflammatory monocyte-derived macrophages were found to be making nitric oxide (NO). Furthermore, aminoguanidine-mediated inhibition of induced NO synthase activity in infiltrating macrophages significantly prolonged survival, indicating involvement of NO in the immunopathology. These data show for the first time the therapeutic effects of temporally targeting pathogenic NO-producing macrophages during neurotropic viral encephalitis.
Asunto(s)
Integrina alfa4beta1/inmunología , Integrina alfa4beta1/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Fiebre del Nilo Occidental , Animales , Antígenos CD/metabolismo , Encéfalo/patología , Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular/metabolismo , Modelos Animales de Enfermedad , Femenino , Regulación Viral de la Expresión Génica/fisiología , Proteína Ácida Fibrilar de la Glía/metabolismo , Integrinas/genética , Integrinas/metabolismo , Antígeno-1 Asociado a Función de Linfocito/genética , Antígeno-1 Asociado a Función de Linfocito/metabolismo , Macrófagos/virología , Ratones , Ratones Endogámicos C57BL , Infiltración Neutrófila/inmunología , Óxido Nítrico Sintasa de Tipo II , Fiebre del Nilo Occidental/inmunología , Fiebre del Nilo Occidental/metabolismo , Fiebre del Nilo Occidental/patologíaRESUMEN
Guillain-Barre syndrome (GBS) is an autoimmune disease of demyelination and inflammation of peripheral nerves. Current treatments are limited to plasma exchange and intravenous immunoglobulins. Cargo-free nanoparticles (NPs) have been evaluated here for their therapeutic benefit on the disease course of experimental autoimmune neuritis (EAN), mimicking the human GBS. NPs prepared from poly-lactic co-glycolic acid (PLGA) with variable size and surface charge (i.e., 500 nm vs. 130 nm, polyvinyl alcohol (PVA) vs. sodium cholate), were intravenously administered in before- or early-onset treatment schedules in a rat EAN model. NP treatment mitigated distinctly the clinical severity of EAN as compared to the P2-peptide control group (P2) in all treatments and reduced the trafficking of inflammatory monocytes at inflammatory loci and diverted them towards the spleen. Therapeutic treatment with NPs reduced the expression of proinflammatory markers (CD68 (P2: 34.8 ± 6.6 vs. NP: 11.9 ± 2.3), IL-1ß (P2: 18.3 ± 0.8 vs. NP: 5.8 ± 2.2), TNF-α (P2: 23.5 ± 3.7 vs. NP: 8.3 ± 1.7) and elevated the expression levels of anti-inflammatory markers CD163 (P2: 19.7 ± 3.0 vs. NP: 41.1 ± 6.5; all for NP-PVA of 130 nm; relative to healthy control). These results highlight the therapeutic potential of such cargo-free NPs in treating EAN, which would be easily translatable into clinical use due to their well-known low-toxicity profile.
RESUMEN
Interleukin (IL)-23 is one of the critical cytokines in autoimmune neuroinflammation. To further clarify the local function of IL-23 on the course of neuroinflammation, we recently established a transgenic mouse model with astrocyte-specific expression of IL-23 (GF-IL23). The GF-IL23 mice spontaneously developed a progressive ataxic phenotype with cerebellar infiltration with high amounts of B cells most prominent in the subarachnoid and perivascular space. To enlighten the B cell role in GF-IL23 mice, we generated GF-IL23 mice on a B cell knockout (k.o.) background (GF-IL23 B cell k.o.). GF-IL23 B cell k.o. mice compared with GF-IL23 mice had no infiltrates or only minor infiltration, and no antibody deposition was detected in the cerebellum. Furthermore, microglia, astrocyte activation, hypervascularization and demyelination were reduced in GF-IL23 B cell k.o. mice compared with GF-IL23 mice. Cytokines and chemokine receptors like IL-12a, cerebrospinal fluid 2 and CXCR3 were downregulated. Our study indicates that B cells are essential in IL-23-dependent neuroinflammation in the GF-IL23 model.