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Artigo em Inglês | MEDLINE | ID: mdl-31980915


BACKGROUND: The chemokine MIP-3α (CCL20) binds to CCR6 on immature dendritic cells. DNA vaccines fusing MIP-3α to melanoma-associated antigens have shown improved efficacy and immunogenicity in the B16F10 mouse melanoma model. Here, we report that the combination of type-I interferon therapy (IFNα) with 5-Aza-2'-deoxycitidine (5Aza) profoundly enhanced the therapeutic efficacy of a MIP-3α-Gp100-Trp2 DNA vaccine. METHODS: Beginning on day 5 post-transplantation of B16F10 melanoma, vaccine was administered intramuscularly (i.m.) by electroporation. CpG adjuvant was given 2 days later. 5Aza was given intraperitoneally at 1 mg/kg and IFNα therapy either intratumorally or i.m. as noted. Tumor sizes, tumor growth, and mouse survival were assessed. Tumor lysate gene expression levels and tumor-infiltrating lymphocytes (TILs) were assessed by qRT-PCR and flow cytometry, respectively. RESULTS: Adding IFNα and 5Aza treatments to mice vaccinated with MIP-3α-Gp100-Trp2 leads to reduced tumor burden and increased median survival (39% over vaccine and 95% over controls). Tumor lysate expression of CCL19 and CCR7 were upregulated ten and fivefold over vaccine, respectively. Vaccine-specific and overall CD8+ TILs were increased over vaccine (sevenfold and fourfold, respectively), as well as the proportion of TILs that were CD8+ (twofold). CONCLUSIONS: Efficient targeting of antigen to immature dendritic cells with a chemokine-fusion vaccine offers an alternative to classic and dendritic cell vaccines. Combining this approach with IFNα and 5Aza treatment significantly improved vaccine efficacy. This improved efficacy correlated with changes in chemokine gene expression and CD8+ TIL infiltration and was dependent on the presence of all therapeutic components.

J Allergy Clin Immunol ; 133(5): 1400-9, 1409.e1-5, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24589341


BACKGROUND: Identifying genetic syndromes that lead to significant atopic disease can open new pathways for investigation and intervention in allergy. OBJECTIVE: We sought to define a genetic syndrome of severe atopy, increased serum IgE levels, immune deficiency, autoimmunity, and motor and neurocognitive impairment. METHODS: Eight patients from 2 families with similar syndromic features were studied. Thorough clinical evaluations, including brain magnetic resonance imaging and sensory evoked potentials, were performed. Peripheral lymphocyte flow cytometry, antibody responses, and T-cell cytokine production were measured. Whole-exome sequencing was performed to identify disease-causing mutations. Immunoblotting, quantitative RT-PCR, enzymatic assays, nucleotide sugar, and sugar phosphate analyses, along with matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry of glycans, were used to determine the molecular consequences of the mutations. RESULTS: Marked atopy and autoimmunity were associated with increased T(H)2 and T(H)17 cytokine production by CD4(+) T cells. Bacterial and viral infection susceptibility were noted along with T-cell lymphopenia, particularly of CD8(+) T cells, and reduced memory B-cell numbers. Apparent brain hypomyelination resulted in markedly delayed evoked potentials and likely contributed to neurologic abnormalities. Disease segregated with novel autosomal recessive mutations in a single gene, phosphoglucomutase 3 (PGM3). Although PGM3 protein expression was variably diminished, impaired function was demonstrated by decreased enzyme activity and reduced uridine diphosphate-N-acetyl-D-glucosamine, along with decreased O- and N-linked protein glycosylation in patients' cells. These results define a new congenital disorder of glycosylation. CONCLUSIONS: Autosomal recessive hypomorphic PGM3 mutations underlie a disorder of severe atopy, immune deficiency, autoimmunity, intellectual disability, and hypomyelination.

Doenças Autoimunes/genética , Transtornos Cognitivos/genética , Imunodeficiência de Variável Comum/genética , Doenças Genéticas Inatas/genética , Hipersensibilidade/genética , Mutação , Fosfoglucomutase/genética , Doenças Autoimunes/enzimologia , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Linfócitos B/enzimologia , Linfócitos B/imunologia , Linfócitos B/patologia , Linfócitos T CD8-Positivos/enzimologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Criança , Pré-Escolar , Transtornos Cognitivos/enzimologia , Transtornos Cognitivos/imunologia , Transtornos Cognitivos/patologia , Imunodeficiência de Variável Comum/enzimologia , Imunodeficiência de Variável Comum/imunologia , Imunodeficiência de Variável Comum/patologia , Família , Feminino , Doenças Genéticas Inatas/enzimologia , Doenças Genéticas Inatas/imunologia , Doenças Genéticas Inatas/patologia , Humanos , Hipersensibilidade/enzimologia , Hipersensibilidade/imunologia , Hipersensibilidade/patologia , Imunoglobulina E/genética , Imunoglobulina E/imunologia , Masculino , Linhagem , Fosfoglucomutase/imunologia , Fosfoglucomutase/metabolismo , Células Th17/enzimologia , Células Th17/imunologia , Células Th17/patologia , Células Th2/enzimologia , Células Th2/imunologia , Células Th2/patologia , Adulto Jovem