RESUMEN
Parent-Child Interaction Therapy (PCIT) is one of the strongest evidence-based treatments available for young children and their families. Research has supported the use of PCIT for children with a history of trauma; however, the treatment does not directly address trauma in the child. PCIT is a dyadic treatment; yet, the impact of the carer's trauma on the carer-child relationship is not assessed or incorporated into treatment. For these reasons, therapists, families, agencies, and funders tend to view PCIT as a trauma treatment with skepticism. PCIT therapists who currently address trauma within the intervention do so without a standardized approach. Trauma-Directed Interaction (TDI) is an adaptation developed to directly address these concerns. TDI maintains the key elements and theoretical underpinnings of PCIT while adding sessions to cover psychoeducation about trauma, carer response to a child's trauma reactions (SAFE skills), and coping skills to aid both the child and the carer to manage trauma activators (COPE skills). The TDI module creates a consistent strategy for PCIT therapists to address trauma, thus allowing research and replication which will advance the dual fields of PCIT and family trauma. The theoretical conceptualization of TDI is presented along with next steps in its evaluation.
Asunto(s)
Cuidadores , Relaciones Padres-Hijo , Preescolar , HumanosRESUMEN
The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) regulates target gene expression upon ligand binding. Apart from its effects on metabolism, PPARγ activity can inhibit the production of pro-inflammatory cytokines by several immune cells, including dendritic cells and macrophages. In chronic inflammatory disease models, PPARγ activation delays the onset and ameliorates disease severity. Here, we investigated the effect of PPARγ activation by the agonist Pioglitazone on the function of hepatic immune cells and its effect in a murine model of immune-mediated hepatitis. Cytokine production by both liver sinusoidal endothelial cells (IL-6) and in T cells ex vivo (IFNγ) was decreased in cells from Pioglitazone-treated mice. However, PPARγ activation did not decrease pro-inflammatory tumor necrosis factor alpha TNFα production by Kupffer cells after Toll-like receptor (TLR) stimulation ex vivo. Most interestingly, although PPARγ activation was shown to ameliorate chronic inflammatory diseases, it did not improve hepatic injury in a model of immune-mediated hepatitis. In contrast, Pioglitazone-induced PPARγ activation exacerbated D-galactosamine (GalN)/lipopolysaccharide (LPS) hepatitis associated with an increased production of TNFα by Kupffer cells and increased sensitivity of hepatocytes towards TNFα after in vivo Pioglitazone administration. These results unravel liver-specific effects of Pioglitazone that fail to attenuate liver inflammation but rather exacerbate liver injury in an experimental hepatitis model.
Asunto(s)
Hepatitis Autoinmune/inmunología , PPAR gamma/agonistas , Pioglitazona/farmacología , Animales , Células Cultivadas , Interferón gamma/metabolismo , Macrófagos del Hígado/efectos de los fármacos , Macrófagos del Hígado/inmunología , Activación de Linfocitos , Activación de Macrófagos , Ratones , Ratones Endogámicos C57BL , PPAR gamma/metabolismo , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Receptores Toll-Like/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
FAH domain containing protein 1 (FAHD1) is a mammalian mitochondrial protein, displaying bifunctionality as acylpyruvate hydrolase (ApH) and oxaloacetate decarboxylase (ODx) activity. We report the crystal structure of mouse FAHD1 and structural mapping of the active site of mouse FAHD1. Despite high structural similarity with human FAHD1, a rabbit monoclonal antibody (RabMab) could be produced that is able to recognize mouse FAHD1, but not the human form, whereas a polyclonal antibody recognized both proteins. Epitope mapping in combination with our deposited crystal structures revealed that the epitope overlaps with a reported SIRT3 deacetylation site in mouse FAHD1.
Asunto(s)
Hidrolasas/genética , Acetoacetatos/metabolismo , Animales , Carboxiliasas/metabolismo , Dominio Catalítico , Cristalografía por Rayos X , Mapeo Epitopo/métodos , Humanos , Hidrolasas/química , Hidrolasas/metabolismo , Ratones , Mitocondrias/metabolismo , Proteínas Mitocondriales/metabolismo , Relación Estructura-ActividadRESUMEN
This study examined the efficacy of the Child-Directed Interaction Training (CDIT) phase of Parent-Child Interaction Therapy for children with an Autism Spectrum Disorder (ASD). Thirty mother-child dyads with children ages 3-7 years with a diagnosis of ASD participated in this randomized controlled study. Following manualized CDIT, statistically significant and meaningful improvements in child disruptive behavior and social awareness as well as maternal distress associated with child disruptive behavior occurred. Across 8 sessions, mothers learned to provide positive attention to their children's appropriate social and play behaviors. Both child and parent changes were maintained at 6-week follow-up. A relatively brief, time-limited, and accessible intervention may be efficacious for improving child and parent behaviors in families of young children with ASD. By decreasing child disruptive behaviors, CDIT may also help to prepare children to benefit further from future interventions.
Asunto(s)
Trastorno del Espectro Autista/rehabilitación , Educación en Salud/métodos , Relaciones Padres-Hijo , Padres/educación , Adaptación Psicológica , Trastorno del Espectro Autista/psicología , Niño , Preescolar , Femenino , Humanos , Masculino , Madres/psicología , Padres/psicologíaRESUMEN
CD11b+Gr1+ myeloid derived suppressor cells (MDSC) are known to be very potent suppressors of T cell immunity and can be further stratified into granulocytic MDSC and monocytic MDSC in mice based on expression of Ly6G or Ly6C, respectively. Here, using these markers and functional assays, we aimed to identify whether MDSC are induced during chronic inflammation leading to fibrosis in both kidney and liver and whether additional markers could more specifically identify these MDSC subsets. In an adenine-induced model of kidney inflammation/fibrosis suppressive Ly6Gpos MDSC were induced. The suppressive function within the Ly6G+ MDSC population was exclusively present in IFNγRß expressing cells. In contrast, in chronic inflammation in the liver induced by bile duct ligation, suppressive capacity was exclusively present in the Ly6Cpos MDSC subset. Gene expression analyses confirmed the differential origins and regulation of those MDSC subsets. Additionally, depletion of MDSC in either kidney or liver fibrosis enhanced fibrosis markers, indicating a protective role for MDSC in organ fibrosis. Thus, our data demonstrate that during liver inflammation and kidney fibrosis MDSC with similar function arise bearing a distinct marker profile and arising from different cell populations.
Asunto(s)
Antígenos Ly/metabolismo , Cirrosis Hepática/inmunología , Células Mieloides/inmunología , Células Mieloides/metabolismo , Insuficiencia Renal Crónica/inmunología , Animales , Biomarcadores/metabolismo , Progresión de la Enfermedad , Granulocitos/inmunología , Granulocitos/metabolismo , Inflamación/inmunología , Ratones , FenotipoRESUMEN
Fumarylacetoacetate hydrolase (FAH) domain-containing proteins occur in both prokaryotes and eukaryotes, where they carry out diverse enzymatic reactions, probably related to structural differences in their respective FAH domains; however, the precise relationship between structure of the FAH domain and the associated enzyme function remains elusive. In mammals, three FAH domain-containing proteins, FAHD1, FAHD2A, and FAHD2B, are known; however, their enzymatic function, if any, remains to be demonstrated. In bacteria, oxaloacetate is subject to enzymatic decarboxylation; however, oxaloacetate decarboxylases (ODx) were so far not identified in eukaryotes. Based on molecular modeling and subsequent biochemical investigations, we identified FAHD1 as a eukaryotic ODx enzyme. The results presented here indicate that dedicated oxaloacetate decarboxylases exist in eukaryotes.
Asunto(s)
Carboxiliasas/metabolismo , Hidrolasas/metabolismo , Secuencia de Aminoácidos , Animales , Carboxiliasas/química , Carboxiliasas/genética , Cristalografía por Rayos X , Metabolismo Energético , Femenino , Regulación de la Expresión Génica , Humanos , Hidrolasas/química , Hidrolasas/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Moleculares , Datos de Secuencia Molecular , Conformación Proteica , Estructura Terciaria de Proteína , Ácido Pirúvico/metabolismo , Alineación de SecuenciaRESUMEN
The initiation of adaptive immunity requires cell-to-cell contact between T cells and antigen-presenting cells. Together with immediate TCR signal transduction, the formation of an immune synapse (IS) is one of the earliest events detected during T cell activation. Here, we show that interaction of liver sinusoidal endothelial cells (LSEC) with naive CD8 T cells, which induces CD8 T cells without immediate effector function, is characterized by a multi-focal type IS. The co-inhibitory molecule B7H1, which is pivotal for the development of non-responsive LSEC-primed T cells, did not alter IS structure or TCRß/CD11a cluster size or density, indicating that IS form does not determine the outcome of LSEC-mediated T cell activation. Instead, PD-1 signaling during CD8 T cell priming by LSEC repressed IL-2 production as well as sustained CD25 expression. When acting during the first 24 h of LSEC/CD8 T cell interaction, CD28 co-stimulation inhibited the induction of non-responsive LSEC-primed T cells. However, after more than 36 h of PD-1 signaling, CD28 co-stimulation failed to rescue effector function in LSEC-primed T cells. Together, these data show that during LSEC-mediated T cell priming, integration of co-inhibitory PD-1 signaling over time turns on a program for CD8 T cell development, that cannot be overturned by co-stimulatory signals.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Reactividad Cruzada/inmunología , Células Endoteliales/metabolismo , Hígado/citología , Transducción de Señal/inmunología , Animales , Células Presentadoras de Antígenos/inmunología , Antígeno CD11a/metabolismo , Antígenos CD28/metabolismo , Linfocitos T CD8-positivos/citología , Comunicación Celular , Recuento de Células , Tamaño de la Célula , Sinapsis Inmunológicas/metabolismo , Interleucina-2/biosíntesis , Ratones Endogámicos C57BL , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Factores de TiempoRESUMEN
UNLABELLED: Immunity against cancer is impeded by local mechanisms promoting development of tumor-specific T cell tolerance, such as regulatory T cells, myeloid-derived suppressor cells, or immunosuppressive factors in the tumor microenvironment. The release of soluble antigens, such as carcinoembryonic antigen (CEA) from colorectal carcinoma (CRC) cells, has been investigated for diagnostic purposes, but not for its immunological consequences. Here, we address the question of whether soluble CEA influences tumor-specific immunity. Mice were injected with soluble CEA protein, and CEA-specific CD8 T cells were analyzed for their phenotype and functionality by means of restimulation ex vivo or antitumor efficacy in vivo. We furthermore characterized the CD8 T cell population in peripheral blood mononuclear cell (PBMCs) from healthy donors and colorectal carcinoma patients. In mice, circulating CEA was preferentially taken up in a mannose receptor-dependent manner and cross-presented by liver sinusoidal endothelial cells, but not dendritic cells, to CD8 T cells. Such systemically circulating CEA promoted tolerization of CEA-specific CD8 T cells in the endogenous T cell repertoire through the coinhibitory molecule B7H1. These CD8 T cells were not deleted but were rendered nonresponsive to antigen-specific stimulation and failed to control growth of CEA-expressing tumor cells. These nonresponsive CD8 T cells were phenotypically similar to central memory T cells being CD44(high) CD62L(high) CD25(neg) . We found T cells with a similar phenotype in PBMCs of healthy donors and at increased frequency also in patients with colorectal carcinoma. CONCLUSION: Our results provide evidence for the existence of an unrecognized tumor immune escape involving cross-presentation of systemically circulating tumor antigens that may influence immunotherapy of cancer.