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1.
Elife ; 102021 04 30.
Artículo en Inglés | MEDLINE | ID: mdl-33929324

RESUMEN

Self-specific CD8+T cells can escape clonal deletion, but the properties and capabilities of such cells in a physiological setting are unclear. We characterized polyclonal CD8+ T cells specific for the melanocyte antigen tyrosinase-related protein 2 (Trp2) in mice expressing or lacking this enzyme (due to deficiency in Dct, which encodes Trp2). Phenotypic and gene expression profiles of pre-immune Trp2/Kb-specific cells were similar; the size of this population was only slightly reduced in wild-type (WT) compared to Dct-deficient (Dct-/-) mice. Despite comparable initial responses to Trp2 immunization, WT Trp2/Kb-specific cells showed blunted expansion and less readily differentiated into a CD25+proliferative population. Functional self-tolerance clearly emerged when assessing immunopathology: adoptively transferred WT Trp2/Kb-specific cells mediated vitiligo much less efficiently. Hence, CD8+ T cell self-specificity is poorly predicted by precursor frequency, phenotype, or even initial responsiveness, while deficient activation-induced CD25 expression and other gene expression characteristics may help to identify functionally tolerant cells.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Autotolerancia , Animales , Linfocitos T CD8-positivos/citología , Diferenciación Celular , Femenino , Subunidad alfa del Receptor de Interleucina-2/genética , Subunidad alfa del Receptor de Interleucina-2/inmunología , Oxidorreductasas Intramoleculares/genética , Oxidorreductasas Intramoleculares/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Vitíligo/inmunología
2.
Nat Commun ; 12(1): 3391, 2021 06 07.
Artículo en Inglés | MEDLINE | ID: mdl-34099646

RESUMEN

Increased risk of premature cardiovascular disease (CVD) is well recognized in systemic lupus erythematosus (SLE). Aberrant type I-Interferon (IFN)-neutrophil interactions contribute to this enhanced CVD risk. In lupus animal models, the Janus kinase (JAK) inhibitor tofacitinib improves clinical features, immune dysregulation and vascular dysfunction. We conducted a randomized, double-blind, placebo-controlled clinical trial of tofacitinib in SLE subjects (ClinicalTrials.gov NCT02535689). In this study, 30 subjects are randomized to tofacitinib (5 mg twice daily) or placebo in 2:1 block. The primary outcome of this study is safety and tolerability of tofacitinib. The secondary outcomes include clinical response and mechanistic studies. The tofacitinib is found to be safe in SLE meeting study's primary endpoint. We also show that tofacitinib improves cardiometabolic and immunologic parameters associated with the premature atherosclerosis in SLE. Tofacitinib improves high-density lipoprotein cholesterol levels (p = 0.0006, CI 95%: 4.12, 13.32) and particle number (p = 0.0008, CI 95%: 1.58, 5.33); lecithin: cholesterol acyltransferase concentration (p = 0.024, CI 95%: 1.1, -26.5), cholesterol efflux capacity (p = 0.08, CI 95%: -0.01, 0.24), improvements in arterial stiffness and endothelium-dependent vasorelaxation and decrease in type I IFN gene signature, low-density granulocytes and circulating NETs. Some of these improvements are more robust in subjects with STAT4 risk allele.


Asunto(s)
Aterosclerosis/prevención & control , Inhibidores de las Cinasas Janus/administración & dosificación , Lupus Eritematoso Sistémico/tratamiento farmacológico , Piperidinas/administración & dosificación , Pirimidinas/administración & dosificación , Adulto , Anciano , Animales , Aterosclerosis/sangre , Aterosclerosis/genética , Aterosclerosis/inmunología , HDL-Colesterol/sangre , Método Doble Ciego , Femenino , Predisposición Genética a la Enfermedad , Factores de Riesgo de Enfermedad Cardiaca , Humanos , Inhibidores de las Cinasas Janus/efectos adversos , Lupus Eritematoso Sistémico/sangre , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/inmunología , Masculino , Persona de Mediana Edad , Piperidinas/efectos adversos , Pirimidinas/efectos adversos , Factor de Transcripción STAT4/genética , Resultado del Tratamiento , Rigidez Vascular/efectos de los fármacos , Vasodilatación/efectos de los fármacos , Adulto Joven
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