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1.
Proc Natl Acad Sci U S A ; 116(22): 10917-10926, 2019 05 28.
Artículo en Inglés | MEDLINE | ID: mdl-31088972

RESUMEN

T cell cytokines contribute to immunity against Staphylococcus aureus, but the predominant T cell subsets involved are unclear. In an S. aureus skin infection mouse model, we found that the IL-17 response was mediated by γδ T cells, which trafficked from lymph nodes to the infected skin to induce neutrophil recruitment, proinflammatory cytokines IL-1α, IL-1ß, and TNF, and host defense peptides. RNA-seq for TRG and TRD sequences in lymph nodes and skin revealed a single clonotypic expansion of the encoded complementarity-determining region 3 amino acid sequence, which could be generated by canonical nucleotide sequences of TRGV5 or TRGV6 and TRDV4 However, only TRGV6 and TRDV4 but not TRGV5 sequences expanded. Finally, Vγ6+ T cells were a predominant γδ T cell subset that produced IL-17A as well as IL-22, TNF, and IFNγ, indicating a broad and substantial role for clonal Vγ6+Vδ4+ T cells in immunity against S. aureus skin infections.


Asunto(s)
Interleucina-17/fisiología , Infecciones Estafilocócicas/inmunología , Staphylococcus aureus/patogenicidad , Subgrupos de Linfocitos T/inmunología , Linfocitos T/inmunología , Animales , Modelos Animales de Enfermedad , Humanos , Ganglios Linfáticos/inmunología , Ratones , Infecciones Estafilocócicas/microbiología
2.
J Neurooncol ; 149(2): 243-252, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32914293

RESUMEN

INTRODUCTION: Glioblastoma multiforme (GBM) is the most common primary intracranial malignancy; survival can be improved by maximizing the extent-of-resection. METHODS: A near-infrared fluorophore (Indocyanine-Green, ICG) was combined with a photosensitizer (Chlorin-e6, Ce6) on the surface of superparamagnetic-iron-oxide-nanoparticles (SPIONs), all FDA-approved for clinical use, yielding a nanocluster (ICS) using a microemulsion. The physical-chemical properties of the ICS were systematically evaluated. Efficacy of photodynamic therapy (PDT) was evaluated in vitro with GL261 cells and in vivo in a subtotal resection trial using a syngeneic flank tumor model. NIR imaging properties of ICS were evaluated in both a flank and an intracranial GBM model. RESULTS: ICS demonstrated high ICG and Ce6 encapsulation efficiency, high payload capacity, and chemical stability in physiologic conditions. In vitro cell studies demonstrated significant PDT-induced cytotoxicity using ICS. Preclinical animal studies demonstrated that the nanoclusters can be detected through NIR imaging in both flank and intracranial GBM tumors (ex: 745 nm, em: 800 nm; mean signal-to-background 8.5 ± 0.6). In the flank residual tumor PDT trial, subjects treated with PDT demonstrated significantly enhanced local control of recurrent neoplasm starting on postoperative day 8 (23.1 mm3 vs 150.5 mm3, p = 0.045), and the treatment effect amplified to final mean volumes of 220.4 mm3 vs 806.1 mm3 on day 23 (p = 0.0055). CONCLUSION: A multimodal theragnostic agent comprised solely of FDA-approved components was developed to couple optical imaging and PDT. The findings demonstrated evidence for the potential theragnostic benefit of ICS in surgical oncology that is conducive to clinical integration.


Asunto(s)
Carbocianinas/química , Glioblastoma/terapia , Nanopartículas/administración & dosificación , Procedimientos Neuroquirúrgicos/métodos , Fotoquimioterapia/métodos , Porfirinas/química , Cirugía Asistida por Computador/métodos , Animales , Apoptosis , Proliferación Celular , Colorantes , Terapia Combinada , Femenino , Fluorescencia , Glioblastoma/metabolismo , Glioblastoma/patología , Humanos , Ratones , Ratones Endogámicos C57BL , Nanopartículas/química , Nanomedicina Teranóstica , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
3.
J Allergy Clin Immunol ; 143(4): 1426-1443.e6, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30240702

RESUMEN

BACKGROUND: Atopic dermatitis (AD) is associated with epidermal barrier defects, dysbiosis, and skin injury caused by scratching. In particular, the barrier-defective epidermis in patients with AD with loss-of-function filaggrin mutations has increased IL-1α and IL-1ß levels, but the mechanisms by which IL-1α, IL-1ß, or both are induced and whether they contribute to the aberrant skin inflammation in patients with AD is unknown. OBJECTIVE: We sought to determine the mechanisms through which skin injury, dysbiosis, and increased epidermal IL-1α and IL-1ß levels contribute to development of skin inflammation in a mouse model of injury-induced skin inflammation in filaggrin-deficient mice without the matted mutation (ft/ft mice). METHODS: Skin injury of wild-type, ft/ft, and myeloid differentiation primary response gene-88-deficient ft/ft mice was performed, and ensuing skin inflammation was evaluated by using digital photography, histologic analysis, and flow cytometry. IL-1α and IL-1ß protein expression was measured by means of ELISA and visualized by using immunofluorescence and immunoelectron microscopy. Composition of the skin microbiome was determined by using 16S rDNA sequencing. RESULTS: Skin injury of ft/ft mice induced chronic skin inflammation involving dysbiosis-driven intracellular IL-1α release from keratinocytes. IL-1α was necessary and sufficient for skin inflammation in vivo and secreted from keratinocytes by various stimuli in vitro. Topical antibiotics or cohousing of ft/ft mice with unaffected wild-type mice to alter or intermix skin microbiota, respectively, resolved the skin inflammation and restored keratinocyte intracellular IL-1α localization. CONCLUSIONS: Taken together, skin injury, dysbiosis, and filaggrin deficiency triggered keratinocyte intracellular IL-1α release that was sufficient to drive chronic skin inflammation, which has implications for AD pathogenesis and potential therapeutic targets.


Asunto(s)
Dermatitis Atópica/metabolismo , Inflamación/metabolismo , Interleucina-1alfa/metabolismo , Proteínas de Filamentos Intermediarios/deficiencia , Queratinocitos/metabolismo , Animales , Dermatitis Atópica/inmunología , Dermatitis Atópica/microbiología , Disbiosis/inmunología , Disbiosis/metabolismo , Proteínas Filagrina , Inflamación/inmunología , Inflamación/microbiología , Interleucina-1alfa/inmunología , Queratinocitos/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados
4.
Adv Drug Deliv Rev ; 176: 113884, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34302897

RESUMEN

Design of micro- or nanocarriers for drug delivery has primarily been focused on properties such as hydrophobicity, biodegradability, size, shape, surface charge, and toxicity, so that they can achieve optimal delivery with respect to drug loading, release kinetics, biodistribution, cellular uptake, and biocompatibility. Incorporation of stimulus-sensitive moieties into the carriers would lead to "smart" delivery systems. A further evolution would be to endow the carrier with a therapeutic function such that it no longer serves as a mere passive entity to release the drug at the target tissue but can be viewed as a therapeutic agent in itself. In this review, we will discuss recent and ongoing efforts over the past decade to design therapeutic drug carriers that confer a biological benefit, including ROS scavenging or generating, pro- or anti-inflammatory, and immuno-evasive properties, to enhance the overall therapeutic efficacy of the delivery systems.


Asunto(s)
Sistemas de Liberación de Medicamentos , Animales , Humanos , Especies Reactivas de Oxígeno
5.
J Clin Invest ; 128(3): 1026-1042, 2018 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-29400698

RESUMEN

The mechanisms that mediate durable protection against Staphylococcus aureus skin reinfections are unclear, as recurrences are common despite high antibody titers and memory T cells. Here, we developed a mouse model of S. aureus skin reinfection to investigate protective memory responses. In contrast with WT mice, IL-1ß-deficient mice exhibited poor neutrophil recruitment and bacterial clearance during primary infection that was rescued during secondary S. aureus challenge. The γδ T cells from skin-draining LNs utilized compensatory T cell-intrinsic TLR2/MyD88 signaling to mediate rescue by trafficking and producing TNF and IFN-γ, which restored neutrophil recruitment and promoted bacterial clearance. RNA-sequencing (RNA-seq) of the LNs revealed a clonotypic S. aureus-induced γδ T cell expansion with a complementarity-determining region 3 (CDR3) aa sequence identical to that of invariant Vγ5+ dendritic epidermal T cells. However, this T cell receptor γ (TRG) aa sequence of the dominant CDR3 sequence was generated from multiple gene rearrangements of TRGV5 and TRGV6, indicating clonotypic expansion. TNF- and IFN-γ-producing γδ T cells were also expanded in peripheral blood of IRAK4-deficient humans no longer predisposed to S. aureus skin infections. Thus, clonally expanded γδ T cells represent a mechanism for long-lasting immunity against recurrent S. aureus skin infections.


Asunto(s)
Linfocitos Intraepiteliales/inmunología , Enfermedades Cutáneas Bacterianas/inmunología , Infecciones Estafilocócicas/inmunología , Animales , Femenino , Reordenamiento Génico , Interferón gamma/inmunología , Interleucina-17/inmunología , Interleucina-1beta/inmunología , Interleucinas/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Infiltración Neutrófila , Neutrófilos/citología , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Análisis de Secuencia de ARN , Transducción de Señal , Staphylococcus aureus , Factor de Necrosis Tumoral alfa/inmunología , Interleucina-22
6.
Cell Host Microbe ; 22(5): 653-666.e5, 2017 Nov 08.
Artículo en Inglés | MEDLINE | ID: mdl-29120743

RESUMEN

Staphylococcus aureus colonization contributes to skin inflammation in diseases such as atopic dermatitis, but the signaling pathways involved are unclear. Herein, epicutaneous S. aureus exposure to mouse skin promoted MyD88-dependent skin inflammation initiated by IL-36, but not IL-1α/ß, IL-18, or IL-33. By contrast, an intradermal S. aureus challenge promoted MyD88-dependent host defense initiated by IL-1ß rather than IL-36, suggesting that different IL-1 cytokines trigger MyD88 signaling depending on the anatomical depth of S. aureus cutaneous exposure. The bacterial virulence factor PSMα, but not α-toxin or δ-toxin, contributed to the skin inflammation, which was driven by IL-17-producing γδ and CD4+ T cells via direct IL-36R signaling in the T cells. Finally, adoptive transfer of IL-36R-expressing T cells to IL-36R-deficient mice was sufficient for mediating S. aureus-induced skin inflammation. Together, this study defines a previously unknown pathway by which S. aureus epicutaneous exposure promotes skin inflammation involving IL-36R/MyD88-dependent IL-17 T cell responses.


Asunto(s)
Dermatitis Atópica/inmunología , Inflamación/inmunología , Interleucina-1/inmunología , Piel/inmunología , Infecciones Estafilocócicas/inmunología , Staphylococcus aureus/patogenicidad , Linfocitos T/inmunología , Animales , Toxinas Bacterianas/inmunología , Linfocitos T CD4-Positivos/inmunología , Citocinas/metabolismo , Dermatitis Atópica/microbiología , Dermatitis Atópica/patología , Modelos Animales de Enfermedad , Femenino , Proteínas Hemolisinas/inmunología , Interacciones Huésped-Parásitos/inmunología , Inflamación/patología , Interleucina-17 , Interleucina-18/metabolismo , Interleucina-1alfa/metabolismo , Interleucina-1beta/metabolismo , Interleucina-33/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Factor 88 de Diferenciación Mieloide/metabolismo , Receptores de Interleucina-1/metabolismo , Piel/microbiología , Piel/patología , Infecciones Estafilocócicas/patología , Linfocitos T/microbiología , Factores de Virulencia/inmunología
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