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1.
Front Immunol ; 11: 599083, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33281825

RESUMO

Toll-like receptors (TLRs) are essential components of innate immunity and provide defensive inflammatory responses to invading pathogens. Located within the plasma membranes of cells and also intracellular endosomes, TLRs can detect a range of pathogen associated molecular patterns from bacteria, viruses and fungi. TLR activation on dendritic cells can propagate to an adaptive immune response, making them attractive targets for the development of both prophylactic and therapeutic vaccines. In contrast to conventional adjuvants such as aluminium salts, TLR agonists have a clear immunomodulatory profile that favours anti-allergic T lymphocyte responses. Consequently, the potential use of TLRs as adjuvants in Allergen Immunotherapy (AIT) for allergic rhinitis and asthma remains of great interest. Allergic Rhinitis is a Th2-driven, IgE-mediated disease that occurs in atopic individuals in response to exposure to otherwise harmless aeroallergens such as pollens, house dust mite and animal dander. AIT is indicated in subjects with allergic rhinitis whose symptoms are inadequately controlled by antihistamines and nasal corticosteroids. Unlike anti-allergic drugs, AIT is disease-modifying and may induce long-term disease remission through mechanisms involving upregulation of IgG and IgG4 antibodies, induction of regulatory T and B cells, and immune deviation in favour of Th1 responses that are maintained after treatment discontinuation. This process takes up to three years however, highlighting an unmet need for a more efficacious therapy with faster onset. Agonists targeting different TLRs to treat allergy are at different stages of development. Synthetic TLR4, and TLR9 agonists have progressed to clinical trials, while TLR2, TLR5 and TLR7 agonists been shown to have potent anti-allergic effects in human in vitro experiments and in vivo in animal studies. The anti-allergic properties of TLRs are broadly characterised by a combination of enhanced Th1 deviation, regulatory responses, and induction of blocking antibodies. While promising, a durable effect in larger clinical trials is yet to be observed and further long-term studies and comparative trials with conventional AIT are required before TLR adjuvants can be considered for inclusion in AIT. Here we critically evaluate experimental and clinical studies investigating TLRs and discuss their potential role in the future of AIT.


Assuntos
Adjuvantes Imunológicos/uso terapêutico , Alérgenos , Asma , Dessensibilização Imunológica , Rinite Alérgica , Receptores Toll-Like , Imunidade Adaptativa , Alérgenos/imunologia , Alérgenos/uso terapêutico , Animais , Asma/imunologia , Asma/terapia , Humanos , Imunidade Inata , Rinite Alérgica/imunologia , Rinite Alérgica/terapia , Receptores Toll-Like/agonistas , Receptores Toll-Like/imunologia
2.
J Med Chem ; 59(5): 1711-26, 2016 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-26861551

RESUMO

Induction of IFNα in the upper airways via activation of TLR7 represents a novel immunomodulatory approach to the treatment of allergic asthma. Exploration of 8-oxoadenine derivatives bearing saturated oxygen or nitrogen heterocycles in the N-9 substituent has revealed a remarkable selective enhancement in IFNα inducing potency in the nitrogen series. Further potency enhancement was achieved with the novel (S)-pentyloxy substitution at C-2 leading to the selection of GSK2245035 (32) as an intranasal development candidate. In human cell cultures, compound 32 resulted in suppression of Th2 cytokine responses to allergens, while in vivo intranasal administration at very low doses led to local upregulation of TLR7-mediated cytokines (IP-10). Target engagement was confirmed in humans following single intranasal doses of 32 of ≥20 ng, and reproducible pharmacological response was demonstrated following repeat intranasal dosing at weekly intervals.


Assuntos
Adenina/análogos & derivados , Asma/tratamento farmacológico , Descoberta de Drogas , Piperidinas/administração & dosagem , Piperidinas/farmacologia , Receptor 7 Toll-Like/agonistas , Adenina/administração & dosagem , Adenina/química , Adenina/farmacologia , Administração Intranasal , Asma/metabolismo , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Piperidinas/química , Relação Estrutura-Atividade
3.
Br J Clin Pharmacol ; 77(5): 777-88, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-23909699

RESUMO

AIMS: To assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of intranasal SB-705498, a selective TRPV1 antagonist. METHODS: Two randomized, double-blind, placebo-controlled, clinical studies were performed: (i) an intranasal SB-705498 first time in human study to examine the safety and PK of five single escalating doses from 0.5 to 12 mg and of repeat dosing with 6 mg and 12 mg twice daily for 14 days and (ii) a PD efficacy study in subjects with non-allergic rhinitis (NAR) to evaluate the effect of 12 mg intranasal SB-705498 against nasal capsaicin challenge. RESULTS: Single and repeat dosing with intranasal SB-705498 was safe and well tolerated. The overall frequency of adverse events was similar for SB-705498 and placebo and no dose-dependent increase was observed. Administration of SB-705498 resulted in less than dose proportional AUC(0,12 h) and Cmax , while repeat dosing from day 1 to day 14 led to its accumulation. SB-705498 receptor occupancy in nasal tissue was estimated to be high (>80%). Administration of 12 mg SB-705498 to patients with NAR induced a marked reduction in total symptom scores triggered by nasal capsaicin challenge. Inhibition of rhinorrhoea, nasal congestion and burning sensation was associated with 2- to 4-fold shift in capsaicin potency. CONCLUSIONS: Intranasal SB-705498 has an appropriate safety and PK profile for development in humans and achieves clinically relevant attenuation of capsaicin-provoked rhinitis symptoms in patients with NAR. The potential impact intranasal SB-705498 may have in rhinitis treatment deserves further evaluation.


Assuntos
Capsaicina/antagonistas & inibidores , Pirrolidinas/farmacologia , Rinite/tratamento farmacológico , Canais de Cátion TRPV/antagonistas & inibidores , Ureia/análogos & derivados , Adolescente , Adulto , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pirrolidinas/efeitos adversos , Pirrolidinas/farmacocinética , Ureia/efeitos adversos , Ureia/farmacocinética , Ureia/farmacologia , Escala Visual Analógica
4.
Ann N Y Acad Sci ; 1088: 100-15, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17192559

RESUMO

Allergies are the result of aberrant immune reactivity against common innocuous environmental proteins (allergens). A pivotal component of allergic pathogenesis is the generation of allergen-specific Th cells with an effector phenotype. These Th cells activate a complex immune cascade that triggers the release of potent mediators and enhances the mobilization of several inflammatory cells types, which in turn elicit the acute allergic reactions and promote the development of chronic inflammation. The current therapies for allergic diseases focus primarily on pharmacological control of symptoms and suppression of inflammation. This approach is beneficial, but not curative, since the underlying immune pathology is not inhibited. In an attempt to develop more effective therapeutic strategies, the scientific interest has been directed toward methods down-modulating the immune mechanisms that initiate and maintain the allergic cascade. Today, the only widely used disease-modifying form of allergy treatment is the specific immunotherapy with allergen extracts. More recently the use of anti-IgE has been approved for patients with allergic asthma. Other immunomodulatory methods being currently explored are the administration of microbial adjuvants that inhibit Th2 reactivity and the design of molecules that interrupt the activity of key allergic cytokines, chemokines, or other Th2 effector mediators.


Assuntos
Hipersensibilidade/imunologia , Hipersensibilidade/terapia , Fatores Imunológicos/uso terapêutico , Imunoterapia/tendências , Neuroimunomodulação/imunologia , Animais , Humanos , Imunoglobulina E/imunologia , Fatores Imunológicos/imunologia , Linfócitos T/imunologia
5.
J Clin Invest ; 113(4): 619-27, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-14966571

RESUMO

Glucocorticoids have potent immunosuppressive properties, but their effects are often modulated by the conditions prevailing in the local immune milieu. In this study we determined whether the action of glucocorticoids is influenced by the degree of signaling during T cell activation. We found that dexamethasone (Dex) effectively suppressed T cell receptor-induced (TCR-induced) proliferation of naive CD4+ T cells, through a mechanism involving downregulation of c-Fos expression and inhibition of activator protein-1 (AP-1), nuclear factor of activated T cells (NF-AT), and NF-kappaB transcriptional activity. However, enhancement of TCR signaling by CD28- or IL-2-mediated costimulation abrogated the suppressive effect of Dex on c-Fos expression and AP-1 function and restored cellular proliferation. The amount of signaling through the MAPK pathway was critical in determining the effect of Dex on T cell activation. In particular, costimulatory signaling via MAPK kinase (MEK) and extracellular signal-regulated kinase (ERK) was essential for the development of T cell resistance to Dex. Selective blockade of MEK/ERK signal transduction abolished the costimulation-induced resistance. In contrast, transmission of IL-2 signals via STAT5 and CD28 signals via NF-kappaB remained inhibited by Dex. These results imply that the immune system, by regulating the degree of local costimulation through MEK/ERK, can modify the effect of glucocorticoids on T cells. Moreover, these findings suggest that MAPK inhibitors may offer a therapeutic solution for glucocorticoid resistance.


Assuntos
Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Glucocorticoides/farmacologia , Sistema de Sinalização das MAP Quinases/fisiologia , Proteínas do Leite , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Animais , Antígenos CD28/imunologia , Antígenos CD28/metabolismo , Complexo CD3/imunologia , Complexo CD3/metabolismo , Linfócitos T CD4-Positivos/citologia , Células Cultivadas , Proteínas de Ligação a DNA/metabolismo , Dexametasona/metabolismo , Dexametasona/farmacologia , Ativação Enzimática , Glucocorticoides/metabolismo , Humanos , Interleucina-2/imunologia , Interleucina-2/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Fator de Transcrição STAT5 , Transativadores/metabolismo , Fator de Transcrição AP-1/metabolismo
6.
Int Immunol ; 14(6): 659-67, 2002 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12039917

RESUMO

Respiratory exposure to allergen induces the development of allergen-specific CD4(+) T cell tolerance that effectively protects against the development of allergic-sensitization and T(h)2-biased immunity. The establishment of T cell unresponsiveness to aeroallergens is an active process preceded by a transient phase of T cell activation that requires T cell co-stimulation and is critically influenced by the antigen-presenting cell type. In this study we examined the role of B cells in the development of respiratory tolerance following intranasal (i.n.) exposure to a prototypic protein antigen. We found that respiratory exposure of BCR-transgenic (Tg) mice to minute quantities of cognate antigen effectively induced T cell unresponsiveness, indicating that antigen presentation by antigen-specific B cells greatly enhanced the development of respiratory tolerance. In contrast, respiratory T cell unresponsiveness could not be induced in B cell-deficient JHD mice exposed to i.n. antigen, although T cell tolerance developed in JHD mice reconstituted with B cells, suggesting that B cells are required for the induction of respiratory T cell tolerance. Respiratory exposure of BCR-Tg mice to cognate antigen induced activation of antigen-specific T cells and partial activation of antigen-specific B cells, as demonstrated by enhanced expression by B cells of class II MHC and B7 molecules but lack of antibody secretion. Our data indicate that B cells critically influence the immune response to inhaled allergens and are required for the development of allergen-specific T cell unresponsiveness induced by respiratory allergen.


Assuntos
Alérgenos/administração & dosagem , Linfócitos B/imunologia , Tolerância Imunológica , Linfócitos T/imunologia , Administração Intranasal , Animais , Formação de Anticorpos , Linfócitos T CD4-Positivos/imunologia , Imunidade nas Mucosas , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Muramidase/administração & dosagem , Muramidase/imunologia , Ovalbumina/administração & dosagem , Ovalbumina/imunologia , Receptores de Antígenos de Linfócitos B/genética , Mucosa Respiratória/imunologia
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