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1.
Am J Transplant ; 21(3): 1027-1038, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-32865886

RESUMEN

Islet transplantation is an effective therapy for life-threatening hypoglycemia, but graft function gradually declines over time in many recipients. We characterized islet-specific T cells in recipients within an islet transplant program favoring alemtuzumab (ATZ) lymphodepleting induction and examined associations with graft function. Fifty-eight recipients were studied: 23 pretransplant and 40 posttransplant (including 5 with pretransplant phenotyping). The proportion with islet-specific T cell responses was not significantly different over time (pre-Tx: 59%; 1-6 m posttransplant: 38%; 7-12 m: 44%; 13-24 m: 47%; and >24 m: 45%). However, phenotype shifted significantly, with IFN-γ-dominated response in the pretransplant group replaced by IL-10-dominated response in the 1-6 m posttransplant group, reverting to predominantly IFN-γ-oriented response in the >24 m group. Clustering analysis of posttransplant responses revealed two main agglomerations, characterized by IFN-γ and IL-10 phenotypes, respectively. IL-10-oriented posttransplant response was associated with relatively low graft function. Recipients within the IL-10+ cluster had a significant decline in C-peptide levels in the period preceding the IL-10 response, but stable graft function following the response. In contrast, an IFN-γ response was associated with subsequently decreased C-peptide. Islet transplantation favoring ATZ induction is associated with an initial altered islet-specific T cell phenotype but reversion toward pretransplant profiles over time. Posttransplant autoreactive T cell phenotype may be a predictor of subsequent graft function.


Asunto(s)
Diabetes Mellitus Tipo 1 , Trasplante de Células Madre Hematopoyéticas , Trasplante de Islotes Pancreáticos , Alemtuzumab/uso terapéutico , Supervivencia de Injerto , Humanos , Fenotipo , Linfocitos T
2.
Immunology ; 150(1): 55-63, 2017 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-27608289

RESUMEN

Vitamin D is widely reported to inhibit innate immune signalling and dendritic cell (DC) maturation as a potential immunoregulatory mechanism. It is not known whether vitamin D has global or gene-specific effects on transcriptional responses downstream of innate immune stimulation, or whether vitamin D inhibition of innate immune signalling is common to different cells. We confirmed vitamin D inhibition of nuclear factor-κB (NF-κB) and p38 mitogen-activated protein kinase (MAPK) signalling in monocyte-derived DC (MDDC) stimulated with lipopolysaccharide (LPS). This was associated with global but modest attenuation of LPS-induced transcriptional changes at genome-wide level. Surprisingly, vitamin D did not inhibit innate immune NF-κB activation in monocyte-derived macrophages. Consistent with our findings in MDDC, ex vivo vitamin D treatment of primary peripheral blood myeloid DC also led to significant inhibition of LPS-inducible NF-κB activation. Unexpectedly, in the same samples, vitamin D enhanced activation of both NF-κB and MAPK signalling in primary peripheral blood monocytes. In a cross-sectional clinical cohort, we found no relationship between peripheral blood vitamin D levels and LPS-inducible activation of NF-κB and MAPK pathways in monocytes of myeloid DC. Remarkably, however, in vivo supplementation of people with vitamin D deficiency in this clinical cohort also enhanced LPS-inducible MAPK signalling in peripheral blood monocytes. Therefore, we report that vitamin D differentially modulates the molecular response to innate immune stimulation in monocytes, macrophages and dendritic cells. These results are of importance in the design of studies on vitamin D supplementation in infectious and immunological diseases.


Asunto(s)
Células Dendríticas/efectos de los fármacos , Inmunidad Innata/efectos de los fármacos , Macrófagos/efectos de los fármacos , Monocitos/efectos de los fármacos , Especificidad de Órganos , Deficiencia de Vitamina D/tratamiento farmacológico , Vitamina D/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Células Cultivadas , Estudios de Cohortes , Células Dendríticas/inmunología , Humanos , Lipopolisacáridos/inmunología , Macrófagos/inmunología , Persona de Mediana Edad , Monocitos/inmunología , FN-kappa B/metabolismo , Transducción de Señal/efectos de los fármacos , Deficiencia de Vitamina D/inmunología , Adulto Joven , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
3.
Eur J Immunol ; 44(6): 1781-90, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24643654

RESUMEN

The active vitamin D metabolite 1α,25-dihydroxyvitamin D (1,25[OH]2 D) potently inhibits DC priming of T-cell activation, suggesting that it mediates a homeostatic role in this context. Therefore, careful regulation of 1,25[OH]2 D levels is necessary to avoid inappropriate inhibition of T-cell activation. Cell-autonomous control of vitamin D activity can be modulated by the action of the vitamin D-activating and -inactivating hydroxylases, CYP27B1, and CYP24A1, respectively. We show that in comparison to macrophages, human monocyte-derived DCs exhibit significantly less activation of 25-dihydroxyvitamin D to 1,25[OH]2 D, and that DCs predominantly express a truncated CYP27B1 transcript that may contribute to the deficiency in activation of vitamin D. Furthermore, in response to stimulation with 1,25[OH]2 D, upregulation of the inactivating enzyme CYP24A1 curtailed the functional effects of vitamin D in DCs, but not macrophages. Production of 1,25[OH]2 D by macrophages was adequate to induce expression of vitamin D-responsive genes by DCs, inhibit DC maturation in response to innate immune stimulation and DC-dependent T-cell responses. Our data suggest that in comparison to macrophages, differential regulation of hydroxylases limits autocrine vitamin D activity in DCs, and that paracrine activation of vitamin D exerts a more potent mechanism for homeostatic control of DC function.


Asunto(s)
25-Hidroxivitamina D3 1-alfa-Hidroxilasa/inmunología , Calcitriol/inmunología , Células Dendríticas/inmunología , Activación de Linfocitos/fisiología , Esteroide Hidroxilasas/inmunología , Linfocitos T/inmunología , Células Dendríticas/citología , Femenino , Homeostasis/fisiología , Humanos , Macrófagos/citología , Macrófagos/inmunología , Masculino , Monocitos/citología , Monocitos/inmunología , Linfocitos T/citología , Vitamina D3 24-Hidroxilasa
4.
PLoS One ; 13(6): e0199323, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29924875

RESUMEN

Coxsackie B Virus (CBV) infection has been linked to the aetiology of type 1 diabetes (T1D) and vaccination has been proposed as prophylaxis for disease prevention. Serum neutralising antibodies and the presence of viral protein and RNA in tissues have been common tools to examine this potential disease relationship, whilst the role of anti-CBV cytotoxic T cell responses and their targets have not been studied. To address this knowledge gap, we augmented conventional HLA-binding predictive algorithm-based epitope discovery by cross-referencing epitopes with sites of positive natural selection within the CBV3 viral genome, identified using mixed effects models of evolution. Eight epitopes for the common MHC class I allele HLA-A*0201 occur at sites that appear to be positively selected. Furthermore, such epitopes span the viral genome, indicating that effective anti-viral responses may not be restricted to the capsid region. To assess the spectrum of IFNy responses in non-diabetic subjects and recently diagnosed type 1 diabetes (T1D) patients, we stimulated PBMC ex vivo with pools of synthetic peptides based on component-restricted sequences identified in silico. We found responders were more likely to recognize multiple rather than a single CBV peptide pool, indicating that the natural course of infection results in multiple targets for effector memory responses, rather than immunodominant epitopes or viral components. The finding that anti-CBV CD8 T cell immunity is broadly targeted has implications for vaccination strategies and studies on the pathogenesis of CBV-linked diseases.


Asunto(s)
Cápside/metabolismo , Simulación por Computador , Enterovirus Humano B/metabolismo , Sistema Inmunológico/virología , Secuencia de Aminoácidos , Secuencia de Bases , Estudios de Casos y Controles , Diabetes Mellitus/virología , Enterovirus Humano B/genética , Epítopos/química , Epítopos/inmunología , Evolución Molecular , Genoma Viral , Antígenos de Histocompatibilidad Clase I/metabolismo , Humanos , Interferón gamma/metabolismo , Péptidos/química , Péptidos/metabolismo , Filogenia , Selección Genética , Serotipificación
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