RESUMEN
Males and females exhibit profound differences in immune responses and disease susceptibility. However, the factors responsible for sex differences in tissue immunity remain poorly understood. Here, we uncovered a dominant role for type 2 innate lymphoid cells (ILC2s) in shaping sexual immune dimorphism within the skin. Mechanistically, negative regulation of ILC2s by androgens leads to a reduction in dendritic cell accumulation and activation in males, along with reduced tissue immunity. Collectively, our results reveal a role for the androgen-ILC2-dendritic cell axis in controlling sexual immune dimorphism. Moreover, this work proposes that tissue immune set points are defined by the dual action of sex hormones and the microbiota, with sex hormones controlling the strength of local immunity and microbiota calibrating its tone.
Asunto(s)
Andrógenos , Células Dendríticas , Inmunidad Innata , Linfocitos , Caracteres Sexuales , Piel , Femenino , Masculino , Andrógenos/metabolismo , Células Dendríticas/inmunología , Hormonas Esteroides Gonadales/metabolismo , Linfocitos/inmunología , Piel/inmunología , Animales , Ratones , Ratones Endogámicos C57BL , MicrobiotaRESUMEN
Males and females differ in their susceptibility to develop autoimmunity and allergy but also in their capacity to cope with infections and cancers. Cellular targets and molecular pathways underlying sexual dimorphism in immunity have started to emerge and appeared multifactorial. It became increasingly clear that sex-linked biological factors have important impact on the development, tissue maintenance and effector function acquisition of distinct immune cell populations, thereby regulating multiple layers of innate or adaptive immunity through distinct mechanisms. This review discusses the recent development in our understanding of the cell-intrinsic actions of biological factors linked to sex, sex hormones and sex chromosome complement, on immune cells, which may account for the sex differences in susceptibility to autoimmune diseases and allergies, and the sex-biased responses in natural immunity and cancer.
Asunto(s)
Enfermedades Autoinmunes , Hipersensibilidad , Femenino , Masculino , Humanos , Cromosoma X , Hormonas Esteroides Gonadales/genética , Enfermedades Autoinmunes/genética , Inmunidad AdaptativaRESUMEN
BACKGROUND: Despite the wide development of 90Y-loaded microspheres, 188Re-labeled lipiodol is still being used for radioembolization of hepatocellular carcinoma (HCC). However, the use of this latter compound is limited by in vivo instability. This study sought to evaluate the safety, bio-distribution, and response to 188Re-SSS lipiodol, a new and more stable compound. METHOD: Lip-Re-01 was an activity-escalation Phase 1 study involving HCC patients progressing after sorafenib. The primary endpoint was safety based on Common Terminology Criteria for Adverse Events (AEs) of Grade ≥3 within 2 months. Secondary endpoints included bio-distribution assessed by scintigraphy quantification from 1 to 72 h, tumor to non-tumor uptake ratio (T/NT), as well as blood, urine and feces collection over 72 h, dosimetry, and response evaluation (mRECIST). RESULTS: Overall, 14 heavily pre-treated HCC patients were treated using a whole liver approach. The mean injected activity was 1.5 ± 0.4 GBq for activity Level 1 (n = 6), 3.6 ± 0.3 GBq for Level 2 (n = 6), and 5.0 ± 0.4 GBq for Level 3 (n = 2). Safety was acceptable with only 1/6 of Level 1 and 1/6 of Level 2 patients experiencing limiting toxicity (one liver failure; one lung disease). The study was prematurely discontinued unrelated to clinical outcomes. Uptake occurred in the tumor, liver, and lungs, and only sometimes in the bladder. The T/NT ratio was high with a mean of 24.9 ± 23.4. Cumulative urinary elimination and fecal eliminations at 72 h were very low, 4.8 ± 3.2% and 0.7 ± 0.8%, respectively. Partial response occurred in 21% of patients (0% in the first activity level; 37.5% in the others). CONCLUSION: The high in vivo stability of 188Re-SSS lipiodol was confirmed, resulting in encouraging responses for a Phase 1 study. As the 3.6 GBq activity proved to be safe, it will be used in a future Phase 2 study.
RESUMEN
BACKGROUND: Type I interferon (IFN-I) production by plasmacytoid dendritic cells (pDCs) occurs during viral infection, in response to Toll-like receptor 7 (TLR7) stimulation and is more vigorous in females than in males. Whether this sex bias persists in ageing people is currently unknown. In this study, we investigated the effect of sex and aging on IFN-α production induced by PRR agonist ligands. METHODS: In a large cohort of individuals from 19 to 97 years old, we measured the production of IFN-α and inflammatory cytokines in whole-blood upon stimulation with either R-848, ODN M362 CpG-C, or cGAMP, which activate the TLR7/8, TLR9 or STING pathways, respectively. We further characterized the cellular sources of IFN-α. FINDINGS: We observed a female predominance in IFN-α production by pDCs in response to TLR7 or TLR9 ligands. The higher TLR7-driven IFN-α production in females was robustly maintained across ages, including the elderly. The sex-bias in TLR9-driven interferon production was lost after age 60, which correlated with the decline in circulating pDCs. By contrast, STING-driven IFN-α production was similar in both sexes, preserved with aging, and correlated with circulating monocyte numbers. Indeed, monocytes were the primary cellular source of IFN-α in response to cGAMP. INTERPRETATION: We show that the sex bias in the TLR7-induced IFN-I production is strongly maintained through ages, and identify monocytes as the main source of IFN-I production via STING pathway. FUNDING: This work was supported by grants from Région Occitanie/Pyrénées-Méditerranée (#12052910, Inspire Program #1901175), University Paul Sabatier, and the European Regional Development Fund (MP0022856).
Asunto(s)
Interferón-alfa , Monocitos , Receptor Toll-Like 7 , Adulto , Anciano , Anciano de 80 o más Años , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Femenino , Humanos , Interferón-alfa/biosíntesis , Interferón-alfa/sangre , Interferón-alfa/inmunología , Ligandos , Masculino , Proteínas de la Membrana/sangre , Proteínas de la Membrana/inmunología , Persona de Mediana Edad , Monocitos/inmunología , Monocitos/metabolismo , Receptor Toll-Like 9/metabolismo , Adulto JovenRESUMEN
BACKGROUND: Allergic asthma is more severe and frequent in women than in men. In male mice, androgens negatively control group 2 innate lymphoid cell (ILC2) development and function by yet unknown mechanisms. OBJECTIVES: We sought to investigate the impact of androgen on ILC2 homeostasis and IL-33-mediated inflammation in female lungs. We evaluated the role of androgen receptor (AR) signaling and the contribution of the putative inhibitory receptor killer cell lectin-like receptor G1 (KLRG1). METHODS: Subcutaneous pellets mimicking physiological levels of androgen were used to treat female mice together with mice expressing a reporter enzyme under the control of androgen response elements and mixed bone marrow chimeras to assess the cell-intrinsic role of AR activation within ILC2s. We generated KLRG1-deficient mice. RESULTS: We established that lung ILC2s express a functionally active AR that can be in vivo targeted with exogenous androgens to negatively control ILC2 homeostasis, proliferation, and function. Androgen signaling upregulated KLRG1 on ILC2s, which inhibited their proliferation on E-cadherin interaction. Despite evidence that KLRG1 impaired the competitive fitness of lung ILC2s during inflammation, KLRG1 deficiency neither alters in vivo ILC2 numbers and functions, nor did it lead to hyperactive ILC2s in either sexes. CONCLUSIONS: AR agonists can be used in vivo to inhibit ILC2 homeostatic numbers and ILC2-dependent lung inflammation through cell-intrinsic AR activation. Although androgen signals in ILC2s to upregulate KLRG1, we demonstrate that KLRG1 is dispensable for androgen-mediated inhibition of pulmonary ILC2s.
Asunto(s)
Andrógenos/farmacología , Lectinas Tipo C/inmunología , Linfocitos/inmunología , Neumonía/inmunología , Receptores Inmunológicos/inmunología , Testosterona/farmacología , Animales , Femenino , Interleucina-33/inmunología , Pulmón/inmunología , Pulmón/patología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Neumonía/patología , Caracteres Sexuales , Transducción de SeñalRESUMEN
Innate lymphoid cell (ILC) subsets at barrier surfaces contribute to maintain tissue homeostasis and appropriate responses to infection. ILCs respond to environmental factors produced by non-hematopoietic cells within tissues, but also circulating cytokines or dietary compounds which allow them to adapt to organ milieu. Among these extrinsic signals, evidence is emerging that sex steroid hormones may act in a cell-intrinsic manner to regulate the development, maintenance in tissues and effector functions of specific subsets of ILCs. Understanding the nature and molecular mechanisms of sex steroid hormone actions on ILCs is important to unravel the cause of sexual disparity in human diseases and could lead to new drug development for the treatment of chronic inflammatory diseases or cancers. This review discusses the recent development in our understanding of the cell-intrinsic actions of sex steroid hormones on ILCs and their consequences on tissue-specific immunity with a particular focus on group 2 innate lymphoid cells and NK cells.
Asunto(s)
Inmunidad Innata , Linfocitos , Citocinas , Hormonas Esteroides Gonadales , Homeostasis , HumanosRESUMEN
BACKGROUND: All randomised phase 3 studies of selective internal radiation therapy for advanced hepatocellular carcinoma published to date have reported negative results. However, these studies did not use personalised dosimetry. We aimed to compare the efficacy of a personalised versus standard dosimetry approach of selective internal radiation therapy with yttrium-90-loaded glass microspheres in patients with hepatocellular carcinoma. METHODS: DOSISPHERE-01 was a randomised, multicentre, open-label phase 2 trial done at four health-care centres in France. Patients were eligible if they were aged 18 years or older and had unresectable locally advanced hepatocellular carcinoma, at least one measurable lesion 7 cm or more in size, a hepatic reserve of at least 30% after selective internal radiation therapy, no extrahepatic spread (other than to the lymph nodes of the hilum, with a lesion <2 cm in size), and no contraindications to selective internal radiation therapy, as assessed by use of a technetium-99m macro-aggregated albumin scan. Patients were randomly assigned (1:1) by use of a permutated block method, with block sizes of four and without stratification, to receive either standard dosimetry (120â±â20 Gy) targeted to the perfused lobe; standard dosimetry group) or personalised dosimetry (≥205 Gy targeted to the index lesion; personalised dosimetry group). Investigators, patients, and study staff were not masked to treatment. The primary endpoint was the investigator-assessed objective response rate in the index lesion, according to European Association for the Study of the Liver criteria, at 3 months after selective internal radiation therapy in the modified intention-to-treat population. Safety was assessed in all patients who received at least one selective internal radiation therapy injection, and analysed on the basis of the treatment actually received (defined by central dosimetry assessment). The trial is registered with ClinicalTrials.gov, NCT02582034, and has been completed. FINDINGS: Between Dec 5, 2015, and Jan 4, 2018, 93 patients were assessed for eligibility. Of these patients, 60 were randomly assigned: 31 to the personalised dosimetry group and 29 to the standard dosimetry group (intention-to-treat population). 56 (93%) patients (28 in each group) were treated (modified intention-to-treat population). In the modified intention-to-treat population, 20 (71% [95% CI 51-87]) of 28 patients in the personalised dosimetry group and ten (36% [19-56]) of 28 patients in the standard dosimetry group had an objective response (p=0·0074). In the safety analysis population, a least one serious adverse event was reported in seven (20%) of the 35 patients who received personalised dosimetry, and in seven (33%) of the 21 patients who received standard dosimetry. The most frequent (ie, occurring in >5% of patients) grade 3 or higher adverse events were ascites (one [3%] patient who received personalised dosimetry vs two [10%] patients who received standard dosimetry), hepatic failure (two [6%] vs none), lymphopenia (12 [34%] vs nine [43%]), increased aspartate aminotransferase concentrations (three [9%] vs two [10%]), increased alanine aminotransferase concentrations (three [9%] vs none), anaemia (two [6%] vs one [5%]), gastrointestinal haemorrhage (none vs two [10%]), and icterus (none vs two [10%]). One treatment-related death occurred in each group. INTERPRETATION: Compared with standard dosimetry, personalised dosimetry significantly improved the objective response rate in patients with locally advanced hepatocellular carcinoma. The results of this study suggest that personalised dosimetry is likely to improve outcomes in clinical practice and should be used in future trials of selective internal radiation therapy. FUNDING: Biocompatibles UK, a Boston Scientific Group company.
Asunto(s)
Carcinoma Hepatocelular/radioterapia , Relación Dosis-Respuesta en la Radiación , Neoplasias Hepáticas/radioterapia , Dosificación Radioterapéutica , Radioterapia Conformacional/métodos , Radioisótopos de Itrio/uso terapéutico , Angiografía/métodos , Carcinoma Hepatocelular/irrigación sanguínea , Carcinoma Hepatocelular/patología , Arteria Hepática/diagnóstico por imagen , Humanos , Neoplasias Hepáticas/irrigación sanguínea , Neoplasias Hepáticas/patología , Microesferas , Supervivencia sin Progresión , Radioisótopos/uso terapéutico , Resultado del TratamientoRESUMEN
Type I IFN (IFN-I) production by plasmacytoid DCs (pDCs) occurs during acute HIV-1 infection in response to TLR7 stimulation, but the role of pDC-derived IFN-I in controlling or promoting HIV-1 infection is ambiguous. We report here a sex-biased interferogenic phenotype for a frequent single-nucleotide polymorphism of human TLR7, rs179008, displaying an impact on key parameters of acute HIV-1 infection. We show allele rs179008 T to determine lower TLR7 protein abundance in cells from women, specifically - likely by diminishing TLR7 mRNA translation efficiency through codon usage. The hypomorphic TLR7 phenotype is mirrored by decreased TLR7-driven IFN-I production by female pDCs. Among women from the French ANRS PRIMO cohort of acute HIV-1 patients, carriage of allele rs179008 T associated with lower viremia, cell-associated HIV-1 DNA, and CXCL10 (IP-10) plasma concentrations. RNA viral load was decreased by 0.85 log10 (95% CI, -1.51 to -0.18) among T/T homozygotes, who also exhibited a lower frequency of acute symptoms. TLR7 emerges as an important control locus for acute HIV-1 viremia, and the clinical phenotype for allele rs179008 T, carried by 30%-50% of European women, supports a beneficial effect of toning down TLR7-driven IFN-I production by pDCs during acute HIV-1 infection.
Asunto(s)
Infecciones por VIH/tratamiento farmacológico , VIH-1/patogenicidad , Interferón-alfa/metabolismo , Receptor Toll-Like 7/metabolismo , Viremia/virología , Adulto , Linfocitos T CD4-Positivos/metabolismo , Células Dendríticas/metabolismo , Células Dendríticas/virología , Femenino , Infecciones por VIH/inmunología , VIH-1/metabolismo , Humanos , Persona de Mediana Edad , Receptor Toll-Like 7/efectos de los fármacosRESUMEN
Plasmacytoid dendritic cells (pDCs) are found in the CNS during neuroinflammation and have been reported to exert regulatory functions in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). However, the mechanisms of entry of pDCs into the CNS as well as their phenotype and innate functional properties, once recruited into the CNS, have not been thoroughly examined. Herein, we show that pDCs rapidly accumulate into the brain and spinal cord during the acute phase of EAE, and maintain the expression of numerous phenotypic markers typical of peripheral pDCs. Functionally, CNS-pDCs constitutively expressed IRF7 and were able to rapidly produce type I IFNs and IL-12p40 upon ex vivo TLR-9 stimulation. Using adoptive transfer experiments, we provide evidence that CNS-pDC are recruited from the blood and accumulate into the CNS during the acute phase of EAE. Accumulation of pDCs into the CNS was strongly inhibited in the absence of CD29, but not CD18, suggesting a major role for ß1 but not ß2 integrins. Indeed, blocking the CD49d α4-integrins during acute EAE drastically diminished CNS-pDC numbers. Together, our results demonstrate that circulating pDCs are actively recruited into the CNS during acute EAE through a mechanism largely dependent on CD49d/CD29-integrins.
Asunto(s)
Encéfalo/inmunología , Células Dendríticas/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Integrina alfa4/inmunología , Integrina beta1/inmunología , Médula Espinal/inmunología , Traslado Adoptivo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/patología , Movimiento Celular/inmunología , Células Dendríticas/efectos de los fármacos , Células Dendríticas/patología , Células Dendríticas/trasplante , Encefalomielitis Autoinmune Experimental/inducido químicamente , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/patología , Femenino , Regulación de la Expresión Génica , Inmunidad Innata , Integrina alfa4/genética , Integrina beta1/genética , Factor 7 Regulador del Interferón/genética , Factor 7 Regulador del Interferón/inmunología , Interferón Tipo I/genética , Interferón Tipo I/inmunología , Subunidad p40 de la Interleucina-12/genética , Subunidad p40 de la Interleucina-12/inmunología , Ratones , Ratones Endogámicos C57BL , Glicoproteína Mielina-Oligodendrócito/administración & dosificación , Fragmentos de Péptidos/administración & dosificación , Toxina del Pertussis/administración & dosificación , Transducción de Señal , Médula Espinal/efectos de los fármacos , Médula Espinal/patología , Receptor Toll-Like 9/genética , Receptor Toll-Like 9/inmunologíaRESUMEN
Men and women differ in their susceptibility to develop autoimmunity and allergy but also in their capacity to cope with infections. Mechanisms responsible for this sexual dimorphism are still poorly documented and probably multifactorial. This review discusses the recent development in our understanding of the cell-intrinsic actions of biological factors linked to sex, sex hormones and sex chromosome complement, on immune cells, which may account for the sex differences in the enhanced susceptibility of women to develop immunological disorders, such as allergic asthma or systemic lupus erythematosus (SLE). We choose to more specifically discuss the impact of sex hormones on the development and function of immune cell populations directly involved in type-2 immunity, and the role of the X-linked Toll like receptor 7 (TLR7) in anti-viral immunity and in SLE. We will also elaborate on the recent evidence demonstrating that TLR7 escapes from X chromosome inactivation in the immune cells of women, and how this may contribute to endow woman immune system with enhanced responsiveness to RNA-virus and susceptibility to SLE.
Asunto(s)
Asma/etiología , Asma/inmunología , Autoinmunidad , Hormonas Esteroides Gonadales/fisiología , Hipersensibilidad/etiología , Caracteres Sexuales , Animales , Asma/genética , Asma/metabolismo , Femenino , Hormonas Esteroides Gonadales/genética , Hormonas Esteroides Gonadales/metabolismo , Humanos , Hipersensibilidad/genética , Inmunidad Innata/genética , Lupus Eritematoso Sistémico/etiología , Masculino , Microbiota/inmunología , Infecciones por Virus ARN/inmunología , Receptores de Esteroides/fisiología , Receptor Toll-Like 7/fisiología , Cromosoma XRESUMEN
Biphenotypic sinonasal sarcoma (BSNS) is a locally aggressive tumor occurring in the sinonasal region. It harbors both myogenic and neural differentiation and is characterized by PAX3 rearrangement with MAML3 as the most frequent fusion partner, but the partner of PAX3 remains unidentified in a subset of cases. About 70 cases have been reported so far. In this study, we report a series of 41 cases with clinical, pathologic, and molecular description. Twenty-five (61%) patients were female individuals, and the median age was 49 years. Tumors arose predominantly in the nasal cavity and ethmoidal sinuses. Local recurrences occurred in 8 cases of the 25 (32%). Histologic features were characteristic of BSNS, with 5 cases showing focal rhabdomyoblastic differentiation. Immunohistochemistry showed a constant positivity of S100 protein and PAX3 and negativity of SOX10. MyoD1 was focally positive in 91% of cases, whereas only 20% were positive for myogenin. Molecular analysis showed a PAX3-MAML3 transcript in 37 cases (90%). RNA sequencing was performed in the 4 negative cases for PAX3-MAML3 fusion, and it showed that 1 case harbored a PAX3-FOXO1 fusion, as previously described in the literature, and 2 novel fusions: PAX3-WWTR1 fusion in 2 cases and PAX3-NCOA2 fusion in 1 case. RNA sequencing results were confirmed by fluorescence in situ hybridization, reverse transcription-polymerase chain reaction, and Sanger sequencing. The PAX3-NCOA2-positive case showed focal rhabdomyoblastic differentiation. In conclusion, we report 2 novel fusions (PAX3-WWTR1 and PAX3-NCOA2) in BSNS and show that MyoD1 is more sensitive than myogenin for demonstrating myogenic differentiation in this tumor.
Asunto(s)
Biomarcadores de Tumor , Cavidad Nasal , Neoplasias de los Senos Paranasales , Senos Paranasales , Sarcoma , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Diferenciación Celular , Femenino , Fusión Génica , Predisposición Genética a la Enfermedad , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Proteína MioD/análisis , Cavidad Nasal/química , Cavidad Nasal/patología , Coactivador 2 del Receptor Nuclear/genética , Proteínas de Fusión Oncogénica/genética , Factor de Transcripción PAX3/genética , Factores de Transcripción Paired Box/genética , Neoplasias de los Senos Paranasales/química , Neoplasias de los Senos Paranasales/genética , Neoplasias de los Senos Paranasales/patología , Neoplasias de los Senos Paranasales/terapia , Senos Paranasales/química , Senos Paranasales/patología , Fenotipo , Estudios Prospectivos , Estudios Retrospectivos , Sarcoma/química , Sarcoma/genética , Sarcoma/patología , Sarcoma/terapia , Transactivadores/genética , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZRESUMEN
PURPOSE: This study sought to provide preliminary results on the biodistribution and dosimetry following intra-arterial liver injection of 188Re-SSS Lipiodol on hepatocellular carcinoma patients included in the Phase I Lip-Re 1 study. METHODS: Results of the first six patients included are reported. Analysis of the 188Re-SSS Lipiodol biodistribution was based on planar scintigraphic and tomoscintigraphic (SPECT) studies performed at 1, 6, 24, 48, and 72 h post-administration. Quantification in blood, urine, and stool samples was performed. Determination of the tumour to non-tumour uptake ratio (T/NT) was calculated. Absorbed doses to target organs and tumours were evaluated using the MIRD formalism. RESULTS: The mean injected activity of 188Re-SSS Lipiodol was 1645 ± 361 MBq. Uptakes were seen in the liver (tumour and healthy liver) and the lungs only. All these uptakes were stable over time. A mean 1.4 ± 0.7% of 188Re-SSS Lipiodol administered was detected in serum samples at 6 h, declining rapidly thereafter. On average, 1.5 ± 1.6% of administered activity was eliminated in urine and feces over 72 h. Overall, 90.7 ± 1.6% of detected activity on SPECT studies was found in the liver (74.9 ± 1.8% in tumours and 19.1 ± 1.7% in the healthy liver) and 9.3 ± 1.6% in the lungs (5.7 ± 1.1% in right and 3.7 ± 0.5% in left lungs). Mean doses absorbed were 7.9 ± 3.7Gy to the whole liver, 42.7 ± 34.0Gy to the tumours, 10.2 ± 3.7Gy to the healthy liver, and 1.5 ± 1.2Gy to the lungs. Four patients had stable disease on CT scans at 2 months. The first patient with rapidly progressive disease died at 1 month, most probably of massive tumour progression. Due to this early death and using a conservative approach, the trial independent evaluation committee decided to consider this event as a treatment-related toxicity. CONCLUSION: 188Re-SSS Lipiodol has a favorable biodistribution profile concerning radioembolization, with the highest in-vivo stability among all radiolabeled Lipiodol compounds reported to date. These preliminary results must be further confirmed while completing this Phase I Lip Re1 study.
Asunto(s)
Carcinoma Hepatocelular/diagnóstico por imagen , Carcinoma Hepatocelular/terapia , Embolización Terapéutica/métodos , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/terapia , Hígado/diagnóstico por imagen , Anciano , Progresión de la Enfermedad , Combinación de Medicamentos , Femenino , Humanos , Inyecciones Intraarteriales , Aceite Yodado , Pulmón/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Compuestos Organometálicos , Estudios Prospectivos , Radiometría , Radiofármacos/uso terapéutico , Distribución Tisular , Tomografía Computarizada de Emisión de Fotón Único , Tomografía Computarizada por Rayos XRESUMEN
17ß-Estradiol (E2) suppresses the development of experimental autoimmune encephalomyelitis (EAE) through estrogen receptor (ER) α, yet the cellular targets remain elusive. We have used an adoptive transfer model of myelin oligodendrocyte glycoprotein-specific CD4+ T cells from 2D2 TCR transgenic mice. We show that in the recipient mice, ERα expression in bystander CD4+ T cells, rather than in cognate 2D2 T cells, is required for the inhibition of Th17 cell differentiation by E2. Coadministration of estrogen-primed WT, but not ERα-deficient CD4+ T cells, with naive 2D2 T cells lacking ERα inhibited the development of Th17 cell-mediated EAE. Suppression of Th17 cells and protection from EAE were maintained when ERα was deleted in Foxp3+ regulatory T cells. We showed that in vivo PD-L1 blockade alleviated the anti-inflammatory action of E2 and that PD-1 expression on cognate but not bystander T cells was required for the E2-dependent inhibition of Th17 differentiation. In cotransfer experiments, we found that only WT but not PD-1KO 2D2 T cells were amenable to E2-dependent inhibition of Th17 differentiation. These results support the conclusion that the restriction of Th17 cell development by E2-primed bystander CD4+ T cells requires cell-intrinsic PD-1 signaling within cognate T cells rather than induction of regulatory 2D2 T cells through PD-1 engagement. Altogether, our results indicate that pregnancy-level concentrations of estrogen signal in conventional Foxp3neg CD4+ T cells to limit the differentiation of cognate Th17 cells through a trans-acting mechanism of suppression that requires a functional PD-1/PD-L1 regulatory axis.
Asunto(s)
Efecto Espectador , Sistema Nervioso Central/inmunología , Estrógenos/metabolismo , Linfocitos T Reguladores/inmunología , Células Th17/inmunología , Traslado Adoptivo , Animales , Anticuerpos Monoclonales/administración & dosificación , Autoinmunidad , Antígeno B7-H1/inmunología , Antígenos CD4/metabolismo , Diferenciación Celular , Modelos Animales de Enfermedad , Receptor alfa de Estrógeno/genética , Femenino , Factores de Transcripción Forkhead/metabolismo , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Glicoproteína Mielina-Oligodendrócito/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Transducción de SeñalRESUMEN
PURPOSE: Selective internal radiation therapy (SIRT) appears to be an interesting treatment possibility for locally-advanced intrahepatic cholangiocarcinoma (ICC), yet the appropriate dosimetry has never been evaluated in this context. METHODS: We retrospectively studied data from 40 patients treated at our institution with 90Y-loaded glass microsphere SIRT combined with chemotherapy for inoperable ICC as first-line treatment. Macroaggregated albumin (MAA)-based single-photon emission computed tomography (SPECT)/computed tomography (CT) quantitative analysis was used to calculate the tumor dose (TD), healthy-injected liver dose (HILD), and injected liver dose (ILD). Response was evaluated at 3 months using the European Association for the Study of the Liver criteria. Factors associated with response and toxicity were analyzed using univariate analysis. RESULTS: We assessed a total of 35 patients (five excluded) receiving 55 injections. Mean TD was 322 ± 165Gy and mean HILD was 74 ± 24Gy for a mean ILD of 128 ± 28Gy. All but two lesions responded, with a minimal TD for responding lesions of 158Gy. Six Grade 3-4 permanent liver toxicities were observed. Mean HILD was not associated with liver toxicity (73.2 ± 25.8Gy for patients with liver toxicity and 77.8 ± 16.9Gy for patients without, ns). Only underlying Child-Pugh status (p = 0.0014) and underlying cirrhosis (p = 0.0021) were associated with liver toxicity. Median progression-free survival was 12.7 months and median overall survival (OS) was 28.6 months. Median OS was 52.7 months for patients with Child-Pugh A5 status. CONCLUSIONS: When combined with chemotherapy, SIRT is highly effective, with a TD > 158Gy. Tolerance was good except for the few patients with cirrhosis or Child-Pugh status ≥A6, who exhibited some liver toxicity. Prospective studies are warranted to confirm.
Asunto(s)
Albúminas/uso terapéutico , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Neoplasias de los Conductos Biliares/radioterapia , Colangiocarcinoma/tratamiento farmacológico , Colangiocarcinoma/radioterapia , Vidrio/química , Microesferas , Albúminas/efectos adversos , Neoplasias de los Conductos Biliares/patología , Colangiocarcinoma/patología , Terapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Radiometría , Estudios Retrospectivos , Análisis de SupervivenciaRESUMEN
Allergic asthma is a chronic pulmonary inflammatory disease initiated by exposure to normally harmless allergens and marked by bronchial hyperreactivity. It affects more than 300 million people worldwide. Asthma often starts in childhood. Epidemiological studies show that there are sexual disparities in the prevalence and severity of asthma. Before the age of 10, the disease is more common in boys. This tendency reverses at puberty suggesting a regulating role of the sex hormones. In this synthesis, we summarize current knowledge on the role of sex hormones in allergic inflammation, with a particular focus on the impact of androgens on the development and function of recently introduced group 2 innate lymphoid cell subsets (ILC2) as critical actors in the initiation of allergic responses.â¢.
Asunto(s)
Andrógenos/fisiología , Asma/epidemiología , Hipersensibilidad/epidemiología , Inmunidad Innata/fisiología , Linfocitos/fisiología , Animales , Asma/etiología , Femenino , Humanos , Hipersensibilidad/complicaciones , Hipersensibilidad/etiología , Masculino , Prevalencia , Distribución por SexoRESUMEN
BACKGROUND: Endogenous opioids, including enkephalins, are fundamental regulators of pain. In inflammatory conditions, the local release of opioids by leukocytes at the inflammatory site inhibits nociceptor firing, thereby inducing analgesia. Accordingly, in chronic intestinal Th1/Th17-associated inflammation, enkephalins released by colitogenic CD4+ T lymphocytes relieve inflammation-induced visceral pain. The present study aims to investigate whether mucosal T-cell-derived enkephalins also exhibit a potent anti-inflammatory activity as described for exogenous opioid drugs in Th1/Th17-associated colitis. METHODS: The anti-inflammatory effects of endogenous opioids were investigated in both Th1/Th17-associated (transfer of CD4+CD45RBhigh T lymphocytes) and Th2-associated (oxazolone) colitis models in mice. Inflammation-induced colonic damage and CD4+ T cell subsets were compared in mice treated or not treated with naloxone methiodide, a peripheral antagonist of opioid receptors. The anti-inflammatory activity of T-cell-derived enkephalins was further estimated by comparison of colitis severity in immunodeficient mice into which naïve CD4+CD45RBhigh T lymphocytes originating from wild-type or enkephalin-knockout mice had been transferred. RESULTS: Peripheral opioid receptor blockade increases the severity of Th1/Th17-induced colitis and attenuates Th2 oxazolone colitis. The opposite effects of naloxone methiodide treatment in these two models of intestinal inflammation are dependent on the potency of endogenous opioids to promote a Th2-type immune response. Accordingly, the transfer of enkephalin-deficient CD4+CD45RBhigh T lymphocytes into immunodeficient mice exacerbates inflammation-induced colonic injury. CONCLUSIONS: Endogenous opioids, including T-cell-derived enkephalins, promote a Th2-type immune response, which, depending on the context, may either attenuate (Th1/Th17-associated) or aggravate (Th2-associated) intestinal inflammation.
Asunto(s)
Colitis/inmunología , Encefalinas/inmunología , Células TH1/inmunología , Células Th17/inmunología , Animales , Linfocitos T CD4-Positivos/trasplante , Colitis/tratamiento farmacológico , Inmunidad Mucosa , Transfusión de Linfocitos , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Naloxona/uso terapéutico , Subgrupos de Linfocitos T/inmunología , Dolor Visceral/inmunologíaRESUMEN
PURPOSE: This study aimed at identifying prior therapy dosimetric parameters using 99mTc-labeled macro-aggregates of albumin (MAA) that are associated with contralateral hepatic hypertrophy occurring after unilobar radioembolization of hepatocellular carcinoma (HCC) performed with 90Y-loaded glass microspheres. METHODS: The dosimetry data of 73 HCC patients were collected prior to the treatment with 90Y-loaded microspheres for unilateral disease. The injected liver dose (ILD), the tumor dose (TD) and healthy injected liver dose (HILD) were calculated based on MAA quantification. Following treatment, the maximal hypertrophy (MHT) of an untreated lobe was calculated. RESULTS: Mean MHT was 35.4 ± 40.4%. When using continuous variables, the MHT was not correlated with any tested variable, i.e., injected activity, ILD, HILD or TD except with a percentage of future remnant liver (FRL) following the 90Y-microspheres injection (r = -0.56). MHT ≥ 10% was significantly more frequent for patients with HILD ≥ 88 Gy, (52% of the cases), i.e., in 92.2% versus 65.7% for HILD < 88 Gy (p = 0.032). MHT ≥ 10% was also significantly more frequent for patients with a TD ≥ 205 Gy and a tumor volume (VT) ≥ 100 cm3 in patients with initial FRL < 50%. MHT ≥10% was seen in 83.9% for patients with either an HILD ≥ 88 Gy or a TD ≥ 205 Gy for tumors larger than 100cm3 (85% of the cases), versus only 54.5% (p = 0.0265) for patients with none of those parameters. MHT ≥10% was also associated with FRL and the Child-Pugh score. Using multivariate analysis, the Child-Pugh score (p < 0.0001), FRL (p = 0.0023) and HILD (p = 0.0029) were still significantly associated with MHT ≥10%. CONCLUSION: This study demonstrates for the first time that HILD is significantly associated with liver hypertrophy. There is also an impact of high tumor doses in large lesions in one subgroup of patients. Larger prospective studies evaluating the MAA dosimetric parameters have to be conducted to confirm these promising results.
Asunto(s)
Carcinoma Hepatocelular/radioterapia , Embolización Terapéutica/efectos adversos , Neoplasias Hepáticas/radioterapia , Hígado/patología , Hígado/efectos de la radiación , Radioisótopos de Itrio/efectos adversos , Radioisótopos de Itrio/uso terapéutico , Anciano , Femenino , Humanos , Hipertrofia/etiología , Masculino , Radiometría , Estudios Retrospectivos , Agregado de Albúmina Marcado con Tecnecio Tc 99m/efectos adversos , Agregado de Albúmina Marcado con Tecnecio Tc 99m/uso terapéuticoRESUMEN
Infectious diseases, autoimmune diseases, and also allergy differentially affect women and men. In general, women develop strongest immune responses and thus the proportion of infected individuals and the severity of many viral, bacterial, or parasitic infections are increased in men. However, heightened immunity in women makes them more susceptible than men to autoimmunity and allergy. While sex differences in immunity are well documented, little is known about the cellular and molecular mechanisms underlying these immunological differences, particularly in allergic asthma. Asthma is a chronic inflammation of the airways mediated by exacerbated type 2 immune responses. Sex differences have been reported in the incidence, prevalence, and severity of asthma. While during childhood, males are more susceptible to asthma than females, there is a switch at the onset of puberty as for many other allergic diseases. This decrease of asthma incidence around puberty in males suggests that hormonal mediators could play a protective role in the susceptibility to allergic responses in male. Group 2 innate lymphoid cells (ILC2s) have recently emerged as critical players in the initiation of allergic responses, but also in the resolution of parasitic infection, through their capacity to rapidly and potently produce type 2 cytokines. This review will cover the current understanding of the impact of sex-linked factors in allergic inflammation, with a particular focus on the role of sex hormones on the development and function of tissue-resident ILC2s.
RESUMEN
Prevalence of asthma is higher in women than in men, but the mechanisms underlying this sex bias are unknown. Group 2 innate lymphoid cells (ILC2s) are key regulators of type 2 inflammatory responses. Here, we show that ILC2 development is greatly influenced by male sex hormones. Male mice have reduced numbers of ILC2 progenitors (ILC2Ps) and mature ILC2s in peripheral tissues compared with females. In consequence, males exhibit reduced susceptibility to allergic airway inflammation in response to environmental allergens and less severe IL-33-driven lung inflammation, correlating with an impaired expansion of lung ILC2s. Importantly, orchiectomy, but not ovariectomy, abolishes the sex differences in ILC2 development and restores IL-33-mediated lung inflammation. ILC2Ps express the androgen receptor (AR), and AR signaling inhibits their differentiation into mature ILC2s. Finally, we show that hematopoietic AR expression limits IL-33-driven lung inflammation through a cell-intrinsic inhibition of ILC2 expansion. Thus, androgens play a crucial protective role in type 2 airway inflammation by negatively regulating ILC2 homeostasis, thereby limiting their capacity to expand locally in response to IL-33.
Asunto(s)
Andrógenos/metabolismo , Inmunidad Innata/inmunología , Linfocitos/inmunología , Transducción de Señal , Andrógenos/farmacología , Animales , Asma/complicaciones , Asma/inmunología , Asma/patología , Castración , Proliferación Celular/efectos de los fármacos , Susceptibilidad a Enfermedades , Femenino , Hipersensibilidad/complicaciones , Hipersensibilidad/inmunología , Hipersensibilidad/patología , Interleucina-33/metabolismo , Pulmón/inmunología , Pulmón/patología , Recuento de Linfocitos , Masculino , Ratones Endogámicos C57BL , Neumonía/complicaciones , Neumonía/inmunología , Neumonía/patología , Pyroglyphidae/inmunología , Receptores Androgénicos/metabolismo , SexismoRESUMEN
Autoimmunity, infectious diseases and cancer affect women and men differently. Because they tend to develop more vigorous adaptive immune responses than men, women are less susceptible to some infectious diseases but also at higher risk of autoimmunity. The regulation of immune responses by sex-dependent factors probably involves several non-redundant mechanisms. A privileged area of study, however, concerns the role of sex steroid hormones in the biology of innate immune cells, especially dendritic cells (DCs). In recent years, our understanding of the lineage origin of DC populations has expanded, and the lineage-committing transcription factors shaping peripheral DC subsets have been identified. Both progenitor cells and mature DC subsets express estrogen receptors (ERs), which are ligand-dependent transcription factors. This suggests that estrogens may contribute to the reported sex differences in immunity by regulating DC biology. Here, we review the recent literature and highlight evidence that estrogen-dependent activation of ERα regulates the development or the functional responses of particular DC subsets. The in vitro model of GM-CSF-induced DC differentiation shows that CD11c+ CD11bint Ly6cneg cells depend on ERα activation by estrogen for their development, and for the acquisition of competence to activate naive CD4+ T lymphocytes and mount a robust pro-inflammatory cytokine response to CD40 stimulation. In this model, estrogen signaling in conjunction with GM-CSF is necessary to promote early interferon regulatory factor (Irf)-4 expression in macrophage-DC progenitors and their subsequent differentiation into IRF-4hi CD11c+ CD11bint Ly6cneg cells, closely related to the cDC2 subset. The Flt3L-induced model of DC differentiation in turn shows that ERα signaling promotes the development of conventional DC (cDC) and plasmacytoid DC (pDC) with higher capability of pro-inflammatory cytokine production in response to TLR stimulation. Likewise, cell-intrinsic ER signaling positively regulates the TLR-driven production of type I interferons (IFNs) in mouse pDCs in vivo. This effect of estrogens likely contributes to the greater proficiency of women's pDCs than men's as regards the production of type I IFNs elicited by TLR7 ligands. In summary, evidence is emerging in support of the notion that estrogen signaling regulates important aspects of cDC and pDC development and/or effector functions, in both mice and humans.