RESUMO
In this review, we discuss small-molecule, carbohydrate-based immunostimulants that target Toll-like receptor 4 (TLR-4) and cluster of differentiation 1D (CD1d) receptors. The design and use of these molecules in immunotherapy as well as results from their use in clinical trials are described. How these molecules work and their utilization as vaccine adjuvants are also discussed. Future applications and extensions for the use of these analogues as therapeutic agents will be outlined.
Assuntos
Adjuvantes Imunológicos/química , Carboidratos/química , Adjuvantes Imunológicos/uso terapêutico , Animais , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Antígenos CD1d/química , Antígenos CD1d/metabolismo , Humanos , Hipersensibilidade/imunologia , Hipersensibilidade/patologia , Hipersensibilidade/terapia , Imunoterapia , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/terapia , Receptor 4 Toll-Like/agonistas , Receptor 4 Toll-Like/antagonistas & inibidores , Receptor 4 Toll-Like/metabolismo , Viroses/imunologia , Viroses/prevenção & controleRESUMO
The ability of different glycosphingolipids (GSLs) to activate type I natural killer T cells (NKT cells) has been known for 2 decades. The possible therapeutic use of these GSLs has been studied in many ways; however, studies are needed in which the efficacy of promising GSLs is compared under identical conditions. Here, we compare five unique GSLs structurally derived from α-galactosylceramide. We employed biophysical and biological assays, as well as x-ray crystallography to study the impact of the chemical modifications of the antigen on type I NKT cell activation. Although all glycolipids are bound by the T cell receptor of type I NKT cells in real time binding assays with high affinity, only a few activate type I NKT cells in in vivo or in vitro experiments. The differences in biological responses are likely a result of different pharmacokinetic properties of each lipid, which carry modifications at different parts of the molecule. Our results indicate a need to perform a variety of assays to ascertain the therapeutic potential of type I NKT cell GSL activators.
Assuntos
Galactosilceramidas/química , Galactosilceramidas/imunologia , Células T Matadoras Naturais/imunologia , Animais , Apresentação de Antígeno , Antígenos CD1d/química , Antígenos CD1d/metabolismo , Sítios de Ligação , Linhagem Celular , Cristalografia por Raios X , Galactosilceramidas/metabolismo , Glicoesfingolipídeos/química , Glicoesfingolipídeos/imunologia , Glicoesfingolipídeos/metabolismo , Humanos , Cinética , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Estrutura Molecular , Complexos Multiproteicos/química , Complexos Multiproteicos/metabolismo , Células T Matadoras Naturais/classificação , Receptores de Antígenos de Linfócitos T alfa-beta/química , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Ressonância de Plasmônio de SuperfícieRESUMO
Invariant natural killer T (iNKT) cells are known to have marked immunomodulatory capacity due to their ability to produce copious amounts of effector cytokines. Here, we report the structure and function of a novel class of aromatic α-galactosylceramide structurally related glycolipids with marked Th1 bias in both mice and men, leading to superior tumour protection in vivo. The strength of the Th1 response correlates well with enhanced lipid binding to CD1d as a result of an induced fit mechanism that binds the aromatic substitution as a third anchor, in addition to the two lipid chains. This induced fit is in contrast to another Th1-biasing glycolipid, α-C-GalCer, whose CD1d binding follows a conventional key-lock principle. These findings highlight the previously unexploited flexibility of CD1d in accommodating galactose-modified glycolipids and broaden the range of glycolipids that can stimulate iNKT cells. We speculate that glycolipids can be designed that induce a similar fit, thereby leading to superior and more sustained iNKT cell responses in vivo.
Assuntos
Antígenos CD1d/metabolismo , Galactosilceramidas/metabolismo , Células T Matadoras Naturais/imunologia , Metástase Neoplásica/prevenção & controle , Neoplasias/prevenção & controle , Animais , Camundongos , Metástase Neoplásica/imunologia , Neoplasias/imunologia , Ligação ProteicaRESUMO
NKT cells respond to a variety of CD1d-restricted glycolipid Ags that are structurally related to the prototypic Ag α-galactosylceramide (α-GalCer). A modified analog of α-GalCer with a carbon-based glycosidic linkage (α-C-GalCer) has generated great interest because of its apparent ability to promote prolonged, Th1-biased immune responses. In this study, we report the activation of spleen NKT cells to α-C-GalCer, and related C-glycoside ligands, is weaker than that of α-GalCer. Furthermore, the Vß8.2 and Vß7 NKT TCR affinity for CD1d-α-C-GalCer, and some related analogs, is â¼10-fold lower than that for the NKT TCR-CD1d-α-GalCer interaction. Nevertheless, the crystal structure of the Vß8.2 NKT TCR-CD1d-α-C-GalCer complex is similar to that of the corresponding NKT TCR-CD1d-α-GalCer complex, although subtle differences at the interface provide a basis for understanding the lower affinity of the NKT TCR-CD1d-α-C-GalCer interaction. Our findings support the concept that for CD1d-restricted NKT cells, altered glycolipid ligands can promote markedly different responses while adopting similar TCR-docking topologies.
Assuntos
Antígenos CD1d/metabolismo , Galactosilceramidas/metabolismo , Células T Matadoras Naturais/metabolismo , Fragmentos de Peptídeos/metabolismo , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Animais , Antígenos CD1d/imunologia , Configuração de Carboidratos , Células Cultivadas , Cristalografia por Raios X , Galactosilceramidas/imunologia , Ligantes , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Células T Matadoras Naturais/imunologia , Fragmentos de Peptídeos/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologiaRESUMO
Certain glycolipid Ags for Valpha14i NKT cells can direct the overall cytokine balance of the immune response. Th2-biasing OCH has a lower TCR avidity than the most potent agonist known, alpha-galactosylceramide. Although the CD1d-exposed portions of OCH and alpha-galactosylceramide are identical, structural analysis indicates that there are subtle CD1d conformational differences due to differences in the buried lipid portion of these two Ags, likely accounting for the difference in antigenic potency. Th1-biasing C-glycoside/CD1d has even weaker TCR interactions than OCH/CD1d. Despite this, C-glycoside caused a greater downstream activation of NK cells to produce IFN-gamma, accounting for its promotion of Th1 responses. We found that this difference correlated with the finding that C-glycoside/CD1d complexes survive much longer in vivo. Therefore, we suggest that the pharmacokinetic properties of glycolipids are a major determinant of cytokine skewing, suggesting a pathway for designing therapeutic glycolipids for modulating invariant NKT cell responses.
Assuntos
Antígenos CD1d/imunologia , Citocinas/imunologia , Galactosilceramidas/imunologia , Glicolipídeos/imunologia , Monossacarídeos/imunologia , Células T Matadoras Naturais/imunologia , Animais , Apresentação de Antígeno/imunologia , Antígenos/química , Antígenos/imunologia , Antígenos CD1d/química , Citometria de Fluxo , Galactosilceramidas/química , Glicolipídeos/química , Glicosídeos , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Monossacarídeos/química , Transdução de Sinais/imunologia , Ressonância de Plasmônio de Superfície , Ativação TranscricionalRESUMO
A synthetic C-glycoside, α-C-galactosylceramide, is an active immunostimulant in mice. It displays better activity than α-O-galactosylceramide in several disease models. Syntheses of several α-C-galactosylceramides are described. Experiments that probe its immunostimulant activity are outlined. Possible explanations for its superior activity are discussed.
RESUMO
C-glycoside analogues of alpha-galactosylceramide were shown to activate both human and mouse invariant NKT (iNKT) cells. Among these analogues, GCK152, which has an aromatic ring in the acyl chain, exhibited a stronger stimulatory activity against human iNKT cells and a much weaker activity against murine iNKT cells than GCK127 that has an almost identical fatty acyl chain as alpha-galactosylceramide. In this study, we have found that invariant TCR (invTCR) expressed by iNKT cells, but not CD1d expressed by APCs, command the species-specific preferential activity of C-glycosides, and that their preferential activity against human vs murine iNKT cells correlate with the binding affinity of glycolipid-CD1d complex to invTCR of respective iNKT cells rather than that of glycolipid to human or murine CD1d molecules. Overall, the structural difference of invTCR appears to supersede those of CD1d molecule in shaping the strength of the biological activity of C-glycoside analogues.
Assuntos
Apresentação de Antígeno/imunologia , Antígenos CD1d/fisiologia , Monossacarídeos/imunologia , Células T Matadoras Naturais/imunologia , Receptores de Antígenos de Linfócitos T/fisiologia , Animais , Apresentação de Antígeno/efeitos dos fármacos , Apresentação de Antígeno/genética , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Antígenos CD1d/biossíntese , Antígenos CD1d/genética , Sequência de Carboidratos , Diferenciação Celular/imunologia , Linhagem Celular , Técnicas de Cocultura , Feminino , Galactosilceramidas/imunologia , Galactosilceramidas/metabolismo , Galactosilceramidas/farmacologia , Rearranjo Gênico da Cadeia alfa dos Receptores de Antígenos dos Linfócitos T/imunologia , Glicosídeos , Células HeLa , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Monossacarídeos/metabolismo , Células T Matadoras Naturais/efeitos dos fármacos , Células T Matadoras Naturais/metabolismo , Ligação Proteica/genética , Ligação Proteica/imunologia , Receptores de Antígenos de Linfócitos T/biossíntese , Receptores de Antígenos de Linfócitos T/genética , Especificidade da EspécieRESUMO
alpha-Galactosylceramide (alpha-GalCer) is a glycolipid that stimulates natural killer T cells to produce both T helper (Th) 1 and Th2 cytokines. This property enables alpha-GalCer to ameliorate a wide variety of infectious, neoplastic, and autoimmune diseases; however, its effectiveness against any one disease is limited by the opposing activities of the induced Th1 and Th2 cytokines. Here, we report that a synthetic C-glycoside analogue of alpha-GalCer, alpha-C-galactosylceramide (alpha-C-GalCer), acts as natural killer T cell ligand in vivo, and stimulates an enhanced Th1-type response in mice. In two disease models requiring Th1-type responses for control, namely malaria and melanoma metastases, alpha-C-GalCer exhibited a 1,000-fold more potent antimalaria activity and a 100-fold more potent antimetastatic activity than alpha-GalCer. Moreover, alpha-C-GalCer consistently stimulated prolonged production of the Th1 cytokines interferon-gamma and interleukin (IL)-12, and decreased production of the Th2 cytokine IL-4 compared with alpha-GalCer. Finally, alpha-C-GalCer's enhanced therapeutic activity required the presence of IL-12, which was needed to stimulate natural killer cells for optimal interferon-gamma production, but did not affect IL-4. Overall, our results suggest that alpha-C-GalCer may one day be an excellent therapeutic option for diseases resolved by Th1-type responses.
Assuntos
Galactosilceramidas/imunologia , Células Matadoras Naturais/imunologia , Malária/imunologia , Melanoma Experimental/patologia , Metástase Neoplásica/imunologia , Animais , Sequência de Bases , Primers do DNA , Feminino , Interferon gama/biossíntese , Células Matadoras Naturais/metabolismo , Ligantes , Camundongos , Camundongos Endogâmicos BALB CRESUMO
We have previously shown that the C-glycoside analog of alpha-galactosylceramide (alpha-GalCer), alpha-C-GalCer, displays a superior inhibitory activity against the liver stages of the rodent malaria parasite Plasmodium yoelii than its parental glycolipid, alpha-GalCer. In this study, we demonstrate that NK cells, as well as IL-12, are a key contributor for the superior activity displayed by alpha-C-GalCer. Surprisingly, the diminished production of Th2 cytokines, including IL-4, by alpha-C-GalCer has no affect on its superior therapeutic activity relative to alpha-GalCer. Finally, we show that the in vivo administration of alpha-C-GalCer induces prolonged maturation of dendritic cells (DCs), as well as an enhanced proliferative response of mouse invariant Valpha14 (Valpha14i) NKT cells, both of which may also contribute to some degree to the superior activity of alpha-C-GalCer in vivo.
Assuntos
Antimaláricos/farmacologia , Galactosilceramidas/farmacologia , Monossacarídeos/farmacologia , Animais , Antimaláricos/uso terapêutico , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Dendríticas/citologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Regulação para Baixo/efeitos dos fármacos , Galactosilceramidas/química , Galactosilceramidas/uso terapêutico , Glicosídeos , Interleucina-10/metabolismo , Interleucina-12/metabolismo , Interleucina-4/metabolismo , Células Matadoras Naturais/citologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Ativação Linfocitária/efeitos dos fármacos , Malária/tratamento farmacológico , Malária/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Modelos Imunológicos , Monossacarídeos/química , Monossacarídeos/uso terapêutico , Receptores de Antígenos de Linfócitos T/metabolismo , Células Th2/efeitos dos fármacos , Células Th2/metabolismoRESUMO
Invariant NKT cells (iNKT cells) have been reported to play a role not only in innate immunity but also to regulate several models of autoimmunity. Furthermore, iNKT cells are necessary for the generation of the prototypic eye-related immune regulatory phenomenon, anterior chamber associated immune deviation (ACAID). In this study, we explore the role of iNKT cells in regulation of autoimmunity to retina, using a model of experimental autoimmune uveitis (EAU) in mice immunized with a uveitogenic regimen of the retinal Ag, interphotoreceptor retinoid-binding protein. Natural strain-specific variation in iNKT number or induced genetic deficiencies in iNKT did not alter baseline susceptibility to EAU. However, iNKT function seemed to correlate with susceptibility and its pharmacological enhancement in vivo by treatment with iNKT TCR ligands at the time of uveitogenic immunization reproducibly ameliorated disease scores. Use of different iNKT TCR ligands revealed dependence on the elicited cytokine profile. Surprisingly, superior protection against EAU was achieved with alpha-C-GalCer, which induces a strong IFN-gamma but only a weak IL-4 production by iNKT cells, in contrast to the ligands alpha-GalCer (both IFN-gamma and IL-4) and OCH (primarily IL-4). The protective effect of alpha-C-GalCer was associated with a reduction of adaptive Ag-specific IFN-gamma and IL-17 production and was negated by systemic neutralization of IFN-gamma. These data suggest that pharmacological activation of iNKT cells protects from EAU at least in part by a mechanism involving innate production of IFN-gamma and a consequent dampening of the Th1 as well as the Th17 effector responses.
Assuntos
Doenças Autoimunes/terapia , Interferon gama/biossíntese , Interleucina-17/fisiologia , Ativação Linfocitária/imunologia , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/metabolismo , Células Th1/imunologia , Uveíte/terapia , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/prevenção & controle , Bovinos , Suscetibilidade a Doenças/imunologia , Proteínas do Olho/administração & dosagem , Proteínas do Olho/imunologia , Imunidade Inata , Interferon gama/metabolismo , Interferon gama/fisiologia , Interleucina-17/antagonistas & inibidores , Interleucina-4/metabolismo , Ligantes , Camundongos , Camundongos Endogâmicos AKR , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Proteínas de Ligação ao Retinol/administração & dosagem , Proteínas de Ligação ao Retinol/imunologia , Especificidade da Espécie , Células Th1/metabolismo , Uveíte/imunologia , Uveíte/prevenção & controleRESUMO
We have recently shown that alpha-C-galactosylceramide (alpha-C-GalCer) stimulates invariant natural killer T (iNKT) cells and preferentially induces a T helper 1 (Th1)-type response in mice. However, alpha-C-GalCer was found to be a rather weak ligand against human iNKT cells in vitro. Therefore, in this study, we sought to identify a compound that displays a strong stimulatory activity against human iNKT cells, by determining the biological activities of several C-glycoside analogues. From the in vitro screening assays, we found that almost all C-glycoside analogues, which have an E-alkene linker between sugar and lipid moieties, are able to activate human iNKT cells and to induce the maturation and activation of human dendritic cells through iNKT-cell activation. In summary, although alpha-galactosylceramide (alpha-GalCer) remains the strongest iNKT-cell ligand, our study identified E-alkene-linked C-glycoside analogues as potent human iNKT-cell stimulants, and indicated that these analogues could be used as a therapeutic agent in the future for diseases resolved by Th1-type responses.
Assuntos
Monossacarídeos/farmacologia , Células T Matadoras Naturais/efeitos dos fármacos , Adulto , Idoso , Animais , Apresentação de Antígeno/imunologia , Antígenos CD1d/análise , Diferenciação Celular/imunologia , Linhagem Celular , Citocinas/biossíntese , Células Dendríticas/imunologia , Feminino , Glicolipídeos/imunologia , Glicosídeos , Humanos , Interferon gama/biossíntese , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Células T Matadoras Naturais/imunologia , Baço/imunologia , Células Th1 , Adulto JovemRESUMO
A rational monoclonal antibody (mAb)-based antitumor therapy approach has previously been shown to eradicate various established experimental and carcinogen-induced tumors in a majority of mice. This therapy comprised an agonistic mAb reactive with tumor necrosis factor-related apoptosis-inducing ligand receptor (DR5), expressed by tumor cells, an agonistic anti-CD40 mAb to mature dendritic cells, and an agonistic anti-4-1BB mAb to costimulate CD8(+) T cells. Because agonists of CD40 have been toxic in patients, we were interested in substituting anti-CD40 mAb with other dendritic cell-maturing agents, such as glycolipid ligands recognized by invariant natural killer T (iNKT) cells. Here, we show that CD1d-restricted glycolipid ligands for iNKT cells effectively substitute for anti-CD40 mAb and reject established experimental mouse breast and renal tumors when used in combination with anti-DR5 and anti-4-1BB mAbs (termed "NKTMab" therapy). NKTMab therapy-induced tumor rejection was dependent on CD4(+) and CD8(+) T cells, NKT cells, and the cytokine IFN-gamma. NKTMab therapy containing either alpha-galactosylceramide (alpha-GC) or alpha-C-galactosylceramide (alpha-c-GC) at high concentrations induced similar rates of tumor rejection in mice; however, toxicity was observed at the highest doses of alpha-GC (>250 ng/injection), limiting the use of this glycolipid. By contrast, even very low doses of alpha-c-GC (25 ng/injection) retained considerable antitumor activity when used in combination with anti-DR5/anti-4-1BB, and thus, alpha-c-GC showed a considerably greater therapeutic index. In summary, sequential tumor cell apoptosis and amplification of dendritic cell function by NKT cell agonists represents an exciting and novel approach for cancer treatment.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Carcinoma de Células Renais/terapia , Galactosilceramidas/imunologia , Imunoterapia , Células Matadoras Naturais/imunologia , Neoplasias Mamárias Experimentais/terapia , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/imunologia , Animais , Anticorpos Monoclonais/imunologia , Apoptose , Linfócitos T CD8-Positivos , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Terapia Combinada , Neoplasias Renais/imunologia , Neoplasias Renais/patologia , Neoplasias Renais/terapia , Fígado/imunologia , Ativação Linfocitária , Neoplasias Mamárias Experimentais/imunologia , Neoplasias Mamárias Experimentais/patologia , Glicoproteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Taxa de Sobrevida , Ligante Indutor de Apoptose Relacionado a TNF , Transaminases/sangueRESUMO
In this report the concept of converting carbohydrate to non-carbohydrate asymmetric molecules has been successfully exploited. The mixed acetal segment of glyceroplasmalopsychosine, a novel glycolipid has been synthesized in a stereo-specific manner using two simple sugar units. The glycosidation reaction between these two monosaccharides ensured the correct acetal stereocenter of the target molecule. Either olefin metathesis or heterogeneous Wittig reactions were used for constructing the long aliphatic chain of glyceroplasmalopsychosine.
RESUMO
The identification of immunoactive agents for clinical and mechanistic applications is a very active area of research. In this vein, analogues of the potent immunostimulant KRN 7000 with diverse cytokine profiles have attracted considerable attention. These compounds have been shown to activate iNKT cells via presentation by CD1d. Herein, we report on the synthesis and activity for four new C-glycosides of KRN 7000, 11-phenylundecanoyl and 11-p-fluorophenylundecanoyl derivatives of C-KRN 7000, 2,3-bis-epi-C-KRN 7000 and the reverse amide of C-KRN 7000. In mice, compared to C-KRN 7000, 2,3-bis-epi-C-KRN 7000 stimulated higher release of the anti-inflammatory cytokine IL-4 and lower release of the inflammatory cytokines IFN-γ and IL-12. The phenyl terminated alkanoyl and reverse amide analogues were inactive. These data suggest that structure activity effects for KRN 7000 are not necessarily additive and their use in the design of new analogues will require an improved understanding of how subtle structural changes impact on cytokine activity.
Assuntos
Adjuvantes Imunológicos/síntese química , Adjuvantes Imunológicos/farmacologia , Ceramidas/química , Galactosilceramidas/síntese química , Galactosilceramidas/farmacologia , Monossacarídeos/química , Adjuvantes Imunológicos/química , Animais , Técnicas de Química Sintética , Citocinas/biossíntese , Galactosilceramidas/química , Glicosídeos , CamundongosRESUMO
The discovery of the Ramberg-Bäcklund procedure for preparing exo-glycals from S-glycoside dioxides, developed independently in (Old) York and New York, is reviewed. The methodology is successful with glucose, galactose, mannose, xylose, fucose, ribose, altrose, 2-deoxy-arabino-hexose (2-deoxy-glucose) and daunosamine derivatives, and has been used to prepare di-, tri- and tetra-substituted exo-glycals. More recent developments, such as one-pot variants, and protecting group-free procedures, are also covered. Synthetic applications of the exo-glycals, for example, to prepare beta-glycosidase inhibitors, spirocyclic glucose derivatives, beta-C-glycosides, C-glycosyl porphyrin glycoconjugates and C-glycosyl amino acids, are also discussed. Finally, applications of the Ramberg-Bäcklund process for the synthesis of known and novel C-glycosides, and in natural product synthesis, are reviewed.
Assuntos
Alcenos/síntese química , Dissacarídeos/síntese química , Glicosídeos/síntese química , Aminoácidos/síntese química , Glicerídeos/síntese química , Sulfonas/químicaRESUMO
[reaction: see text] The cycloaddition of Weinreb amide functionalized nitrile oxide/nitrones with a range of dipolarophiles has been explored.
Assuntos
Compostos Heterocíclicos com 1 Anel/síntese química , Nitrilas/síntese química , Óxidos de Nitrogênio/síntese química , Alcinos/química , Ciclização , Compostos Heterocíclicos com 1 Anel/química , Estrutura Molecular , Nitrilas/química , Óxidos de Nitrogênio/química , EstereoisomerismoRESUMO
[reaction: see text] Olefin cross-metathesis has been used to prepare alpha-C-galactosylceramide derivatives. The metathesis process merged vinyl and propenyl glycosides with vinyl derivatives of phytosphingosine. The use of ethylene enhanced the yield of the methathesis step.
Assuntos
Adjuvantes Imunológicos/síntese química , Alcenos/química , Etilenos/química , Galactosilceramidas/síntese química , Adjuvantes Imunológicos/farmacologia , Galactosilceramidas/farmacologia , Glicosídeos/química , Estrutura Molecular , Esfingosina/análogos & derivados , Compostos de Vinila/químicaRESUMO
Infection with influenza A virus represents a major public health threat worldwide, particularly in patients with asthma. However, immunity induced by influenza A virus may have beneficial effects, particularly in young children, that might protect against the later development of asthma, as suggested by the hygiene hypothesis. Herein, we show that infection of suckling mice with influenza A virus protected the mice as adults against allergen-induced airway hyperreactivity (AHR), a cardinal feature of asthma. The protective effect was associated with the preferential expansion of CD4-CD8-, but not CD4+, NKT cells and required T-bet and TLR7. Adoptive transfer of this cell population into allergen-sensitized adult mice suppressed the development of allergen-induced AHR, an effect associated with expansion of the allergen-specific forkhead box p3+ (Foxp3+) Treg cell population. Influenza-induced protection was mimicked by treating suckling mice with a glycolipid derived from Helicobacter pylori (a bacterium associated with protection against asthma) that activated NKT cells in a CD1d-restricted fashion. These findings suggest what we believe to be a novel pathway that can regulate AHR, and a new therapeutic strategy (treatment with glycolipid activators of this NKT cell population) for asthma.