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1.
Brain ; 147(4): 1344-1361, 2024 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-37931066

RESUMO

Neuromyelitis optica spectrum disorder (NMOSD) is a CNS autoimmune inflammatory disease mediated by T helper 17 (Th17) and antibody responses to the water channel protein, aquaporin 4 (AQP4), and associated with astrocytopathy, demyelination and axonal loss. Knowledge about disease pathogenesis is limited and the search for new therapies impeded by the absence of a reliable animal model. In our work, we determined that NMOSD is characterized by decreased IFN-γ receptor signalling and that IFN-γ depletion in AQP4201-220-immunized C57BL/6 mice results in severe clinical disease resembling human NMOSD. Pathologically, the disease causes autoimmune astrocytic and CNS injury secondary to cellular and humoral inflammation. Immunologically, the absence of IFN-γ allows for increased expression of IL-6 in B cells and activation of Th17 cells, and generation of a robust autoimmune inflammatory response. Consistent with NMOSD, the experimental disease is exacerbated by administration of IFN-ß, whereas repletion of IFN-γ, as well as therapeutic targeting of IL-17A, IL-6R and B cells, ameliorates it. We also demonstrate that immune tolerization with AQP4201-220-coupled poly(lactic-co-glycolic acid) nanoparticles could both prevent and effectively treat the disease. Our findings enhance the understanding of NMOSD pathogenesis and provide a platform for the development of immune tolerance-based therapies, avoiding the limitations of the current immunosuppressive therapies.


Assuntos
Neuromielite Óptica , Humanos , Animais , Camundongos , Neuromielite Óptica/patologia , Aquaporina 4 , Interferon gama/metabolismo , Camundongos Endogâmicos C57BL , Linfócitos B , Autoanticorpos/metabolismo
2.
J Allergy Clin Immunol ; 153(3): 549-559, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37926124

RESUMO

Food allergy is a growing public health issue among children and adults that can lead to life-threatening anaphylaxis following allergen exposure. The criterion standard for disease management includes food avoidance and emergency epinephrine administration because current allergen-specific immunotherapy treatments are limited by adverse events and unsustained desensitization. A promising approach to remedy these shortcomings is the use of nanoparticle-based therapies that disrupt disease-driving immune mechanisms and induce more sustained tolerogenic immune pathways. The pathophysiology of food allergy includes multifaceted interactions between effector immune cells, including lymphocytes, antigen-presenting cells, mast cells, and basophils, mainly characterized by a TH2 cell response. Regulatory T cells, TH1 cell responses, and suppression of other major allergic effector cells have been found to be major drivers of beneficial outcomes in these nanoparticle therapies. Engineered nanoparticle formulations that have shown efficacy at reducing allergic responses and revealed new mechanisms of tolerance include polymeric-, lipid-, and emulsion-based nanotherapeutics. This review highlights the recent engineering design of these nanoparticles, the mechanisms induced by them, and their future potential therapeutic targets.


Assuntos
Hipersensibilidade Alimentar , Nanopartículas , Criança , Adulto , Humanos , Dessensibilização Imunológica , Alimentos , Alérgenos
3.
J Immunol ; 209(3): 465-475, 2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35725270

RESUMO

Type 1 diabetes (T1D) is an autoimmune disease characterized by T and B cell responses to proteins expressed by insulin-producing pancreatic ß cells, inflammatory lesions within islets (insulitis), and ß cell loss. We previously showed that Ag-specific tolerance targeting single ß cell protein epitopes is effective in preventing T1D induced by transfer of monospecific diabetogenic CD4 and CD8 transgenic T cells to NOD.scid mice. However, tolerance induction to individual diabetogenic proteins, for example, GAD65 (glutamic acid decarboxylase 65) or insulin, has failed to ameliorate T1D both in wild-type NOD mice and in the clinic. Initiation and progression of T1D is likely due to activation of T cells specific for multiple diabetogenic epitopes. To test this hypothesis, recombinant insulin, GAD65, and chromogranin A proteins were encapsulated within poly(d,l-lactic-co-glycolic acid) (PLGA) nanoparticles (COUR CNPs) to assess regulatory T cell induction, inhibition of Ag-specific T cell responses, and blockade of T1D induction/progression in NOD mice. Whereas treatment of NOD mice with CNPs containing a single protein inhibited the corresponding Ag-specific T cell response, inhibition of overt T1D development only occurred when all three diabetogenic proteins were included within the CNPs (CNP-T1D). Blockade of T1D following CNP-T1D tolerization was characterized by regulatory T cell induction and a significant decrease in both peri-insulitis and immune cell infiltration into pancreatic islets. As we have recently published that CNP treatment is both safe and induced Ag-specific tolerance in a phase 1/2a celiac disease clinical trial, Ag-specific tolerance induced by nanoparticles encapsulating multiple diabetogenic proteins is a promising approach to T1D treatment.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Células Secretoras de Insulina , Nanopartículas , Animais , Diabetes Mellitus Experimental/patologia , Epitopos , Insulina , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Proteínas
4.
Biotechnol Bioeng ; 120(1): 284-296, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36221192

RESUMO

Immune-mediated hypersensitivities such as autoimmunity, allergy, and allogeneic graft rejection are treated with therapeutics that suppress the immune system, and the lack of specificity is associated with significant side effects. The delivery of disease-relevant antigens (Ags) by carrier systems such as poly(lactide-co-glycolide) nanoparticles (PLG-Ag) and carbodiimide (ECDI)-fixed splenocytes (SP-Ag) has demonstrated Ag-specific tolerance induction in model systems of these diseases. Despite therapeutic outcomes by both platforms, tolerance is conferred with different efficacy. This investigation evaluated Ag loading and total particle dose of PLG-Ag on Ag presentation in a coculture system of dendritic cells (DCs) and Ag-restricted T cells, with SP-Ag employed as a control. CD25 expression was observed in nearly all T cells even at low concentrations of PLG-Ag, indicating efficient presentation of Ag by dendritic cells. However, the secretion of IL-2, Th1, and Th2 cytokines (IFNγ and IL-4, respectively) varied depending on PLG-Ag concentration and Ag loading. Concentration escalation of soluble Ag resulted in an increase in IL-2 and IFNγ and a decrease in IL-4. Treatment with PLG-Ag followed a similar trend but with lower levels of IL-2 and IFNγ secreted. Transcriptional Activity CEll ARrays (TRACER) were employed to measure the real-time transcription factor (TF) activity in Ag-presenting DCs. The kinetics and magnitude of TF activity was dependent on the Ag delivery method, concentration, and Ag loading. Ag positively regulated IRF1 activity and, as carriers, NPs and ECDI-treated SP negatively regulated this signaling. The effect of Ag loading and dose on tolerance induction were corroborated in vivo using the delayed-type hypersensitivity (DTH) and experimental autoimmune encephalomyelitis (EAE) mouse models where a threshold of 8 µg/mg Ag loading and 0.5 mg PLG-Ag dose were required for tolerance. Together, the effect of Ag loading and dosing on in vitro and in vivo immune regulation provide useful insights for translating Ag-carrier systems for the clinical treatment of immune disorders.


Assuntos
Encefalomielite Autoimune Experimental , Nanopartículas , Animais , Camundongos , Linfócitos T , Interleucina-2 , Interleucina-4/uso terapêutico , Antígenos , Encefalomielite Autoimune Experimental/tratamento farmacológico
5.
Glia ; 70(10): 1950-1970, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35809238

RESUMO

Multiple sclerosis (MS) is a central nervous system (CNS) autoimmune disease characterized by inflammation, demyelination, and neurodegeneration. The ideal MS therapy would both specifically inhibit the underlying autoimmune response and promote repair/regeneration of myelin as well as maintenance of axonal integrity. Currently approved MS therapies consist of non-specific immunosuppressive molecules/antibodies which block activation or CNS homing of autoreactive T cells, but there are no approved therapies for stimulation of remyelination nor maintenance of axonal integrity. In an effort to repurpose an FDA-approved medication for myelin repair, we chose to examine the effectiveness of digoxin, a cardiac glycoside (Na+ /K+ ATPase inhibitor), originally identified as pro-myelinating in an in vitro screen. We found that digoxin regulated multiple genes in oligodendrocyte progenitor cells (OPCs) essential for oligodendrocyte (OL) differentiation in vitro, promoted OL differentiation both in vitro and in vivo in female naïve C57BL/6J (B6) mice, and stimulated recovery of myelinated axons in B6 mice following demyelination in the corpus callosum induced by cuprizone and spinal cord demyelination induced by lysophosphatidylcholine (LPC), respectively. More relevant to treatment of MS, we show that digoxin treatment of mice with established MOG35-55 -induced Th1/Th17-mediated chronic EAE combined with tolerance induced by the i.v. infusion of biodegradable poly(lactide-co-glycolide) nanoparticles coupled with MOG35-55 (PLG-MOG35-55 ) completely ameliorated clinical disease symptoms and stimulated recovery of OL lineage cell numbers. These findings provide critical pre-clinical evidence supporting future clinical trials of myelin-specific tolerance with myelin repair/regeneration drugs, such as digoxin, in MS patients.


Assuntos
Glicosídeos Cardíacos , Doenças Desmielinizantes , Esclerose Múltipla , Animais , Glicosídeos Cardíacos/efeitos adversos , Diferenciação Celular , Cuprizona , Doenças Desmielinizantes/induzido quimicamente , Digoxina/efeitos adversos , Modelos Animais de Doenças , Reposicionamento de Medicamentos , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/tratamento farmacológico , Bainha de Mielina/fisiologia , Oligodendroglia/fisiologia
6.
Gastroenterology ; 161(1): 66-80.e8, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33722583

RESUMO

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.


Assuntos
Doença Celíaca/imunologia , Gliadina/imunologia , Tolerância Imunológica/imunologia , Nanopartículas/administração & dosagem , Doença Celíaca/patologia , Método Duplo-Cego , Gliadina/administração & dosagem , Glicolatos/administração & dosagem , Humanos , Infusões Intravenosas
7.
Gastroenterology ; 158(6): 1667-1681.e12, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32032584

RESUMO

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.


Assuntos
Doença Celíaca/tratamento farmacológico , Gliadina/administração & dosagem , Tolerância Imunológica/efeitos dos fármacos , Nanopartículas/administração & dosagem , Administração Intravenosa , Animais , Linfócitos T CD4-Positivos , Doença Celíaca/sangue , Doença Celíaca/imunologia , Células Cultivadas , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Feminino , Gliadina/imunologia , Gliadina/toxicidade , Glutens/administração & dosagem , Glutens/imunologia , Antígenos HLA-DQ/genética , Antígenos HLA-DQ/imunologia , Humanos , Mucosa Intestinal , Leucócitos Mononucleares , Camundongos , Camundongos Transgênicos , Nanopartículas/química , Nanopartículas/toxicidade , Poliglactina 910/química , Cultura Primária de Células , Testes de Toxicidade Aguda
8.
Nature ; 522(7555): 216-20, 2015 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-25896324

RESUMO

Multiple sclerosis involves an aberrant autoimmune response and progressive failure of remyelination in the central nervous system. Prevention of neural degeneration and subsequent disability requires remyelination through the generation of new oligodendrocytes, but current treatments exclusively target the immune system. Oligodendrocyte progenitor cells are stem cells in the central nervous system and the principal source of myelinating oligodendrocytes. These cells are abundant in demyelinated regions of patients with multiple sclerosis, yet fail to differentiate, thereby representing a cellular target for pharmacological intervention. To discover therapeutic compounds for enhancing myelination from endogenous oligodendrocyte progenitor cells, we screened a library of bioactive small molecules on mouse pluripotent epiblast stem-cell-derived oligodendrocyte progenitor cells. Here we show seven drugs function at nanomolar doses selectively to enhance the generation of mature oligodendrocytes from progenitor cells in vitro. Two drugs, miconazole and clobetasol, are effective in promoting precocious myelination in organotypic cerebellar slice cultures, and in vivo in early postnatal mouse pups. Systemic delivery of each of the two drugs significantly increases the number of new oligodendrocytes and enhances remyelination in a lysolecithin-induced mouse model of focal demyelination. Administering each of the two drugs at the peak of disease in an experimental autoimmune encephalomyelitis mouse model of chronic progressive multiple sclerosis results in striking reversal of disease severity. Immune response assays show that miconazole functions directly as a remyelinating drug with no effect on the immune system, whereas clobetasol is a potent immunosuppressant as well as a remyelinating agent. Mechanistic studies show that miconazole and clobetasol function in oligodendrocyte progenitor cells through mitogen-activated protein kinase and glucocorticoid receptor signalling, respectively. Furthermore, both drugs enhance the generation of human oligodendrocytes from human oligodendrocyte progenitor cells in vitro. Collectively, our results provide a rationale for testing miconazole and clobetasol, or structurally modified derivatives, to enhance remyelination in patients.


Assuntos
Clobetasol/farmacologia , Miconazol/farmacologia , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/metabolismo , Bainha de Mielina/efeitos dos fármacos , Bainha de Mielina/metabolismo , Células-Tronco Pluripotentes/efeitos dos fármacos , Animais , Diferenciação Celular/efeitos dos fármacos , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Cerebelo/patologia , Doenças Desmielinizantes/tratamento farmacológico , Doenças Desmielinizantes/metabolismo , Doenças Desmielinizantes/patologia , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Feminino , Camadas Germinativas/efeitos dos fármacos , Camadas Germinativas/metabolismo , Camadas Germinativas/patologia , Humanos , Lisofosfatidilcolinas , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Esclerose Múltipla/patologia , Oligodendroglia/citologia , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/metabolismo , Fenótipo , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/metabolismo , Receptores de Glucocorticoides/metabolismo , Regeneração/efeitos dos fármacos , Técnicas de Cultura de Tecidos
9.
Immunol Rev ; 276(1): 40-51, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28258701

RESUMO

Observations noting the presence of white blood cell infiltrates within tumors date back more than a century, however the cellular and molecular mechanisms regulating tumor immunity continue to be elucidated. The recent successful use of monoclonal antibodies to block immune regulatory pathways to enhance tumor-specific immune responses for the treatment of cancer has encouraged the identification of additional immune regulatory receptor/ligand pathways. Over the past several years, a growing body of data has identified B7-H4 (VTCN1/B7x/B7S1) as a potential therapeutic target for the treatment of cancer. The potential clinical significance of B7-H4 is supported by the high levels of B7-H4 expression found in numerous tumor tissues and correlation of the level of expression on tumor cells with adverse clinical and pathologic features, including tumor aggressiveness. The biological activity of B7-H4 has been associated with decreased inflammatory CD4+ T-cell responses and a correlation between B7-H4-expressing tumor-associated macrophages and FoxP3+ regulatory T cells (Tregs) within the tumor microenvironment. Since B7-H4 is expressed on tumor cells and tumor-associated macrophages in various cancer types, therapeutic blockade of B7-H4 could favorably alter the tumor microenvironment allowing for antigen-specific clearance tumor cells. The present review highlights the therapeutic potential of targeting B7-H4.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antígenos de Neoplasias/metabolismo , Imunoterapia/métodos , Macrófagos/imunologia , Neoplasias/terapia , Linfócitos T Reguladores/imunologia , Inibidor 1 da Ativação de Células T com Domínio V-Set/metabolismo , Animais , Antígenos de Neoplasias/imunologia , Fatores de Transcrição Forkhead/metabolismo , Humanos , Neoplasias/imunologia , Evasão Tumoral , Microambiente Tumoral , Inibidor 1 da Ativação de Células T com Domínio V-Set/imunologia
10.
J Immunol ; 200(6): 2013-2024, 2018 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-29431690

RESUMO

ILDR2 is a member of the Ig superfamily, which is implicated in tricellular tight junctions, and has a putative role in pancreatic islet health and survival. We recently found a novel role for ILDR2 in delivering inhibitory signals to T cells. In this article, we show that short-term treatment with ILDR2-Fc results in long-term durable beneficial effects in the relapsing-remitting experimental autoimmune encephalomyelitis and NOD type 1 diabetes models. ILDR2-Fc also promotes transplant engraftment in a minor mismatch bone marrow transplantation model. ILDR2-Fc displays a unique mode of action, combining immunomodulation, regulation of immune homeostasis, and re-establishment of Ag-specific immune tolerance via regulatory T cell induction. These findings support the potential of ILDR-Fc to provide a promising therapeutic approach for the treatment of autoimmune diseases.


Assuntos
Antígenos/imunologia , Homeostase/imunologia , Tolerância Imunológica/imunologia , Fragmentos Fc das Imunoglobulinas/imunologia , Proteínas de Membrana/imunologia , Animais , Transplante de Medula Óssea/métodos , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Tipo 1/imunologia , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD
11.
J Immunol ; 201(3): 897-907, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29898965

RESUMO

The potent immune regulatory function of an agonistic B7-H4-Ig fusion protein (B7-H4Ig) has been demonstrated in multiple experimental autoimmune models; however, the identity of a functional B7-H4 receptor remained unknown. The biological activity of B7-H4 is associated with decreased inflammatory CD4+ T cell responses as supported by a correlation between B7-H4-expressing tumor-associated macrophages and Foxp3+ T cells within the tumor microenvironment. Recent data indicate that members of the semaphorin (Sema)/plexin/neuropilin (Nrp) family of proteins both positively and negatively modulate immune cell function. In this study, we show that B7-H4 binds the soluble Sema family member Sema3a. Additionally, B7-H4Ig-induced inhibition of inflammatory CD4+ T cell responses is lost in both Sema3a functional mutant mice and mice lacking Nrp-1 expression in Foxp3+ T cells. These findings indicate that B7-H4Ig binds to Sema3a, which acts as a functional bridge to stimulate an Nrp-1/Plexin A4 heterodimer to form a functional immunoregulatory receptor complex resulting in increased levels of phosphorylated PTEN and enhanced regulatory CD4+ T cell number and function.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Neuropilina-1/metabolismo , Receptores de Superfície Celular/metabolismo , Semaforina-3A/metabolismo , Inibidor 1 da Ativação de Células T com Domínio V-Set/metabolismo , Animais , Linfócitos T CD4-Positivos/imunologia , Células Cultivadas , Feminino , Fatores de Transcrição Forkhead/metabolismo , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , PTEN Fosfo-Hidrolase/metabolismo , Microambiente Tumoral/imunologia
12.
J Immunol ; 200(6): 2025-2037, 2018 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-29431694

RESUMO

The B7-like protein family members play critical immunomodulatory roles and constitute attractive targets for the development of novel therapies for human diseases. We identified Ig-like domain-containing receptor (ILDR)2 as a novel B7-like protein with robust T cell inhibitory activity, expressed in immune cells and in immune-privileged and inflamed tissues. A fusion protein, consisting of ILDR2 extracellular domain with an Fc fragment, that binds to a putative counterpart on activated T cells showed a beneficial effect in the collagen-induced arthritis model and abrogated the production of proinflammatory cytokines and chemokines in autologous synovial-like cocultures of macrophages and cytokine-stimulated T cells. Collectively, these findings point to ILDR2 as a novel negative regulator for T cells, with potential roles in the development of immune-related diseases, including autoimmunity and cancer.


Assuntos
Antígenos B7/imunologia , Proteínas de Membrana/imunologia , Linfócitos T/imunologia , Animais , Células Cultivadas , Citocinas/imunologia , Humanos , Domínios de Imunoglobulina/imunologia , Fragmentos Fc das Imunoglobulinas/imunologia , Ativação Linfocitária/imunologia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C
13.
Brain ; 142(2): 344-361, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30657878

RESUMO

Multiple sclerosis is a chronic autoimmune demyelinating disorder of the CNS. Immune-mediated oligodendrocyte cell loss contributes to multiple sclerosis pathogenesis, such that oligodendrocyte-protective strategies represent a promising therapeutic approach. The integrated stress response, which is an innate cellular protective signalling pathway, reduces the cytotoxic impact of inflammation on oligodendrocytes. This response is initiated by phosphorylation of eIF2α to diminish global protein translation and selectively allow for the synthesis of protective proteins. The integrated stress response is terminated by dephosphorylation of eIF2α. The small molecule Sephin1 inhibits eIF2α dephosphorylation, thereby prolonging the protective response. Herein, we tested the effectiveness of Sephin1 in shielding oligodendrocytes against inflammatory stress. We confirmed that Sephin1 prolonged eIF2α phosphorylation in stressed primary oligodendrocyte cultures. Moreover, by using a mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis, we demonstrated that Sephin1 delayed the onset of clinical symptoms, which correlated with a prolonged integrated stress response, reduced oligodendrocyte and axon loss, as well as diminished T cell presence in the CNS. Sephin1 is reportedly a selective inhibitor of GADD34 (PPP1R15A), which is a stress-induced regulatory subunit of protein phosphatase 1 complex that dephosphorylates eIF2α. Consistent with this possibility, GADD34 mutant mice presented with a similar ameliorated experimental autoimmune encephalomyelitis phenotype as Sephin1-treated mice, and Sephin1 did not provide additional therapeutic benefit to the GADD34 mutant animals. Results presented from the adoptive transfer of encephalitogenic T cells between wild-type and GADD34 mutant mice further indicate that the beneficial effects of Sephin1 are mediated through a direct protective effect on the CNS. Of particular therapeutic relevance, Sephin1 provided additive therapeutic benefit when combined with the first line multiple sclerosis drug, interferon ß. Together, our results suggest that a neuroprotective treatment based on the enhancement of the integrated stress response would likely have significant therapeutic value for multiple sclerosis patients.


Assuntos
Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/imunologia , Guanabenzo/análogos & derivados , Imunidade Inata/fisiologia , Oligodendroglia/imunologia , Animais , Células Cultivadas , Encefalomielite Autoimune Experimental/metabolismo , Feminino , Guanabenzo/farmacologia , Guanabenzo/uso terapêutico , Humanos , Imunidade Inata/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/imunologia , Esclerose Múltipla/metabolismo , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/metabolismo , Ratos
14.
Nanomedicine ; 18: 282-291, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30352312

RESUMO

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.


Assuntos
Autoimunidade , Tolerância Imunológica , Nanopartículas/química , Animais , Antígenos/imunologia , Apoptose , Humanos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química
15.
J Autoimmun ; 89: 112-124, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29258717

RESUMO

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.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Diabetes Mellitus Tipo 1/imunologia , Células Secretoras de Insulina/patologia , Nanopartículas/uso terapêutico , Animais , Autoantígenos/química , Autoantígenos/imunologia , Células Cultivadas , Diabetes Mellitus Tipo 1/terapia , Modelos Animais de Doenças , Feminino , Glucose-6-Fosfatase/química , Glucose-6-Fosfatase/genética , Glucose-6-Fosfatase/imunologia , Tolerância Imunológica , Camundongos , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Nanopartículas/química , Peptídeos/química , Peptídeos/imunologia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Receptores de Antígenos de Linfócitos T alfa-beta/genética
16.
J Immunol ; 196(4): 1443-8, 2016 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-26773145

RESUMO

Leukocyte trafficking into the CNS is a prominent feature driving the immunopathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis. Blocking the recruitment of inflammatory leukocytes into the CNS represents an exploitable therapeutic target; however, the adhesion molecules that specifically regulate the step of leukocyte diapedesis into the CNS remain poorly understood. We report that CD99 is critical for lymphocyte transmigration without affecting adhesion in a human blood-brain barrier model. CD99 blockade in vivo ameliorated experimental autoimmune encephalomyelitis and decreased the accumulation of CNS inflammatory infiltrates, including dendritic cells, B cells, and CD4(+) and CD8(+) T cells. Anti-CD99 therapy was effective when administered after the onset of disease symptoms and blocked relapse when administered therapeutically after disease symptoms had recurred. These findings underscore an important role for CD99 in the pathogenesis of CNS autoimmunity and suggest that it may serve as a novel therapeutic target for controlling neuroinflammation.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antígenos CD/imunologia , Linfócitos T CD8-Positivos/imunologia , Moléculas de Adesão Celular/imunologia , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/terapia , Antígeno 12E7 , Animais , Antígenos CD/fisiologia , Linfócitos B , Barreira Hematoencefálica/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/fisiologia , Adesão Celular , Moléculas de Adesão Celular/antagonistas & inibidores , Moléculas de Adesão Celular/fisiologia , Movimento Celular/imunologia , Células Dendríticas , Modelos Animais de Doenças , Humanos , Inflamação/imunologia , Inflamação/terapia , Camundongos
17.
J Neurosci ; 35(48): 15921-33, 2015 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-26631473

RESUMO

Myelinating cells synthesize large amounts of membrane protein through the secretory pathway, which makes these cells particularly sensitive to perturbations of the endoplasmic reticulum (ER). Ig binding protein (BiP), also known as glucose-regulated protein 78 (GRP78), is a critical ER chaperone that also plays a pivotal role in controlling the cellular response to ER stress. To examine the potential importance of BiP to myelinating cells, we used a conditional knock-out approach to BiP gene inactivation in oligodendrocytes during development, in adulthood, and in response to experimental autoimmune encephalomyelitis (EAE), an animal model of the inflammatory demyelinating disorder multiple sclerosis (MS). During development, mice lacking functional BiP gene expression in oligodendrocytes developed tremors and ataxia and died before reaching maturity. When BiP gene inactivation in oligodendrocytes was initiated in adulthood, the mice displayed severe neurological symptoms including tremors and hind-limb paralysis. The inactivation of BiP in oligodendrocytes during development or in adulthood resulted in oligodendrocyte loss and corresponding severe myelin abnormalities. Mice heterozygous for the oligodendrocyte-specific inactivation of BiP, which were phenotypically normal without evidence of neuropathology, displayed an exacerbated response to EAE that correlated with an increased loss of oligodendrocytes. Furthermore, mice in which the BiP gene was specifically inactivated in developing Schwann cells displayed tremor that progressed to hindlimb paralysis, which correlated with diminished numbers of myelinating Schwann cells and severe PNS hypomyelination. These studies demonstrate that BiP is critical for myelinating cell survival and contributes to the protective response of oligodendrocyte against inflammatory demyelination.


Assuntos
Encefalomielite Autoimune Experimental/patologia , Encefalomielite Autoimune Experimental/prevenção & controle , Bainha de Mielina/metabolismo , Oligodendroglia/patologia , Oligopeptídeos/metabolismo , 2',3'-Nucleotídeo Cíclico 3'-Fosfodiesterase/genética , 2',3'-Nucleotídeo Cíclico 3'-Fosfodiesterase/metabolismo , Animais , Animais Recém-Nascidos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/fisiopatologia , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/patologia , Retículo Endoplasmático/ultraestrutura , Chaperona BiP do Retículo Endoplasmático , Feminino , Adjuvante de Freund/toxicidade , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/genética , Camundongos , Camundongos Endogâmicos C57BL , Proteínas da Mielina/metabolismo , Glicoproteína Mielina-Oligodendrócito/imunologia , Oligodendroglia/ultraestrutura , Oligopeptídeos/genética , Fragmentos de Peptídeos/imunologia , Nervos Periféricos/patologia , Fator de Transcrição CHOP/metabolismo
18.
Adv Healthc Mater ; : e2400237, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38691819

RESUMO

Food allergy is a prevalent, potentially deadly disease caused by inadvertent sensitization to benign food antigens. Pathogenic Th2 cells are a major driver for disease, and allergen-specific immunotherapies (AIT) aim to increase the allergen threshold required to elicit severe allergic symptoms. However, the majority of AIT approaches require lengthy treatments and convey transient disease suppression, likely due to insufficient targeting of pathogenic Th2 responses. Here, the ability of allergen-encapsulating nanoparticles to directly suppress pathogenic Th2 responses and reactivity is investigated in a mouse model of food allergy. NPs associate with pro-tolerogenic antigen presenting cells, provoking accumulation of antigen-specific, functionally suppressive regulatory T cells in the small intestine lamina propria. Two intravenous doses of allergen encapsulated in poly(lactide-co-glycolide) nanoparticles (NPs) significantly reduces oral food challenge (OFC)-induced anaphylaxis. Importantly, NP treatment alters the fates of pathogenic allergen-specific Th2 cells, reprogramming these cells toward CD25+FoxP3+ regulatory and CD73+FR4+ anergic phenotypes. NP-mediated reductions in the frequency of effector cells in the gut and mast cell degranulation following OFC are also demonstrated. These studies reveal mechanisms by which an allergen-encapsulating NP therapy and, more broadly, allergen-specific immunotherapies, can rapidly attenuate allergic responses by targeting pathogenic Th2 cells.

19.
J Autoimmun ; 44: 71-81, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23683881

RESUMO

We evaluated the therapeutic efficacy and mechanisms of action of both mouse and human B7-H4 Immunoglobulin fusion proteins (mB7-H4Ig; hB7-H4Ig) in treating EAE. The present data show that mB7-H4Ig both directly and indirectly (via increasing Treg function) inhibited CD4⁺ T-cell proliferation and differentiation in both Th1- and Th17-cell promoting conditions while inducing production of IL-10. B7-H4Ig treatment effectively ameliorated progression of both relapsing (R-EAE) and chronic EAE correlating with decreased numbers of activated CD4⁺ T-cells within the CNS and spleen, and a concurrent increase in number and function of Tregs. The functional requirement for Treg activation in treating EAE was demonstrated by a loss of therapeutic efficacy of hB7-H4Ig in R-EAE following inactivation of Treg function either by anti-CD25 treatment or blockade of IL-10. Significant to the eventual translation of this treatment into clinical practice, hB7-H4Ig similarly inhibited the in vitro differentiation of naïve human CD4⁺ T-cells in both Th1- and Th17-promoting conditions, while promoting the production of IL-10. B7-H4Ig thus regulates pro-inflammatory T-cell responses by a unique dual mechanism of action and demonstrates significant promise as a therapeutic for autoimmune diseases, including MS.


Assuntos
Encefalomielite Autoimune Experimental/tratamento farmacológico , Imunoglobulinas/farmacologia , Interleucina-10/imunologia , Linfócitos T/efeitos dos fármacos , Inibidor 1 da Ativação de Células T com Domínio V-Set/farmacologia , Animais , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Encefalomielite Autoimune Experimental/imunologia , Feminino , Humanos , Imunoglobulinas/imunologia , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Camundongos , Linfócitos T/imunologia , Inibidor 1 da Ativação de Células T com Domínio V-Set/imunologia
20.
Immunol Rev ; 229(1): 337-55, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19426232

RESUMO

SUMMARY: Pro-inflammatory CD4(+) T-cell-mediated autoimmune diseases, such as multiple sclerosis and type 1 diabetes, are hypothesized to be initiated and maintained by activated antigen-presenting cells presenting self antigen to self-reactive interferon-gamma and interleukin-17-producing CD4(+) T-helper (Th) type 1/Th17 cells. To date, the majority of Food and Drug Administration-approved therapies for autoimmune disease primarily focus on the global inhibition of immune inflammatory activity. The goal of ongoing research in this field is to develop both therapies that inhibit/eliminate activated autoreactive cells as well as antigen-specific treatments, which allow for the directed blockade of the deleterious effects of self-reactive immune cell function. According to the two-signal hypothesis, activation of a naive antigen-specific CD4(+) T cell requires both stimulation of the T-cell receptor (TCR) (signal 1) and stimulation of costimulatory molecules (signal 2). There also exists a balance between pro-inflammatory and anti-inflammatory immune cell activity, which is regulated by the type and strength of the activating signal as well as the local cytokine milieu in which the naive CD4(+) T cell is activated. To this end, the majority of ongoing research is focused on the delivery of suboptimal TCR stimulation in the absence of costimulatory molecule stimulation, or potential blockade of stimulatory accessory molecules. Therefore, the signaling pathways involved in the induction of CD4(+) T-cell anergy, as apposed to activation, are topics of intense interest.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Doenças Autoimunes/tratamento farmacológico , Linfócitos T CD4-Positivos/imunologia , Imunossupressores/uso terapêutico , Receptores de Antígenos de Linfócitos T/imunologia , Animais , Anticorpos Monoclonais/imunologia , Antígenos CD/imunologia , Antígenos CD/metabolismo , Doenças Autoimunes/imunologia , Antígeno B7-1/imunologia , Antígeno B7-1/metabolismo , Antígenos CD28/imunologia , Antígenos CD28/metabolismo , Linfócitos T CD4-Positivos/efeitos dos fármacos , Antígeno CTLA-4 , Ensaios Clínicos como Assunto , Humanos , Imunossupressores/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Fatores de Transcrição NFATC/imunologia , Fatores de Transcrição NFATC/metabolismo , Proteínas Quinases/imunologia , Proteínas Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia
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