RESUMEN
NK cells play a major role in protection against tumor recurrence and infection after allogeneic hematopoietic stem cell transplantation (HSCT). It has been shown that NK cell function after HSCT is impaired, but underlying molecular mechanisms are not well-known. In this report we show that the level of T-bet and Eomesodermin (Eomes), two T-box transcription factors regulating lymphocyte effector functions, is strongly reduced in NK cells from HSCT recipients compared with healthy control subjects. Reduction of T-bet and Eomes expression appeared early and persisted for years after HSCT, affecting all peripheral blood NK cells independently of their differentiation status. Reduced T-bet levels in NK cells from allogeneic HSCT recipients significantly correlated with reduced perforin expression. Acute, but not chronic, graft-versus-host disease, as well as CMV reactivation, was associated with further downregulation of T-bet expression in NK cells. Lower levels of T-bet expression in NK cells were associated with less favorable outcome after HSCT as a result of increased nonrelapse mortality. Collectively, our results provide a possible molecular explanation for the previously reported functional exhaustion of NK cells after allogeneic HSCT and suggest an impact of the NK transcriptional machinery status on HSCT outcome.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Proteínas de Dominio T Box/metabolismo , Adolescente , Adulto , Anciano , Antígeno CD56/biosíntesis , Femenino , Enfermedad Injerto contra Huésped/inmunología , Humanos , Masculino , Persona de Mediana Edad , Perforina/biosíntesis , Proteínas de Dominio T Box/biosíntesis , Transcripción Genética , Trasplante Homólogo , Adulto JovenRESUMEN
CD56(bright) NK cells express receptors for IL-2, IL-7, IL-15, and SCF. We found that human peripheral blood CD56(bright) NK cells responded to IL-2, IL-7, IL-15 by phosphorylating STAT-5, ERK, and Akt but did not respond to SCF. However, CD56(bright) NK cells in culture upregulated c-kit transcription three to fourfold, which led to a steady increase in c-kit and a concomitant acquisition of responsiveness to SCF. After 44 h, CD56(bright) NK cells had upregulated c-kit approximately 20-fold and phosphorylated ERK and Akt in response to SCF concentrations well below levels present in plasma. CD56(bright) NK cells cultured in IL-15 maintained c-kit transcription/expression at ex vivo levels and did not become responsive to SCF. Furthermore, SCF-responsive, CD56(bright) c-kit(high) NK cells swiftly downregulated c-kit and stopped responding to SCF after IL-15 stimulation. However, commitment of CD56(bright) NK cells to a c-kit-negative, SCF-unresponsive state did not occur, as after 5 days of culture, withdrawal of IL-15 restored c-kit to maximal levels and reestablished SCF-responsiveness. CD56(bright) NK cells that had upregulated c-kit firmly adhered to COS cells transfected with the membrane form of SCF. Furthermore, SCF signaling significantly increased the capacity of CD56(bright) NK cells to degranulate. Collectively, our data suggest that c-kit on human CD56(bright) NK cells is a functional receptor that is downregulated in peripheral blood, possibly to render CD56(bright) NK cells unresponsive to the SCF therein.
Asunto(s)
Antígeno CD56/metabolismo , Células Asesinas Naturales/metabolismo , Proteínas Proto-Oncogénicas c-kit/metabolismo , Factor de Células Madre/metabolismo , Regulación hacia Arriba/genética , Animales , Antígeno CD56/genética , Células COS , Células Cultivadas , Chlorocebus aethiops , Regulación hacia Abajo/genética , Humanos , Interleucina-15/genética , Interleucina-15/metabolismo , Sistema de Señalización de MAP Quinasas/genética , Fosforilación/genética , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-kit/genética , Transducción de Señal/genética , Factor de Células Madre/genética , Transcripción Genética/genéticaRESUMEN
Identification of pretransplantation risk factors is important in evaluating patient outcomes after hematopoietic stem cell transplantation. Current scoring schemes, such as the European Group for Blood and Marrow Transplantation risk score or the Hematopoietic Cell Transplantation-Specific Comorbidity Index, may under-rate disease and disease status at the time of transplantation. The recently published Disease Risk Index (DRI) specifically investigates these aspects by defining 4 risk groups (low, intermediate, high, very high) with significant differences in overall survival (OS). We retrospectively investigated whether the DRI could be applied at the transplantation center of Geneva's University Hospitals (Geneva, Switzerland), where 64% of patients are underwent transplantation with T cell-depleted grafts (TDEP). We analyzed 409 patients with various hematological malignancies who underwent transplantation between January 1998 and October 2012. Using the DRI, the 4-year OS for the low, intermediate, high, and very high groups was 82%, 53%, 27%, and 31%, respectively (P < .0001). For TDEP patients, the 4-year OS for low, intermediate, and high overall risk groups was 86%, 53%, and 33%, respectively (P < .0001). As patients in the very high overall risk group are usually not eligible for TDEP, our group comprised too few patients (n = 3) for meaningful analysis. For non-TDEP patients, the 4-year OS for low, intermediate, high, and very high overall risk groups was 63%, 54%, 22%, and 18%, respectively (P < .0001). Our results confirm the prognostic value of the DRI in a cohort with a majority of TDEP patients.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Acondicionamiento Pretrasplante/métodos , Trasplante Homólogo/métodos , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Humanos , Depleción Linfocítica , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Análisis de Supervivencia , Resultado del Tratamiento , Estudios de Validación como Asunto , Adulto JovenRESUMEN
BACKGROUND: Quantification of titers of ubiquitous viruses such as Torque teno virus (TTV) that do not cause clinical symptoms might be helpful in assessing the immune status of an individual. We hereby describe the validation of a SYBR Green-based TTV quantification method for plasma samples. METHODS: Plasmids with TTV specific inserts were used for preparing standards and absolute quantification of TTV was performed using SYBR Green methodology. The method was assessed for its accuracy and precision (intra and inter-day) on four non-consecutive days. TTV was also quantified from plasma samples of 20 healthy volunteers and from 30 hematopoietic stem cell transplant (HSCT) recipients. RESULTS: The assay was specific and showed satisfactory efficiency (82.2%, R2=0.99) with the limit of quantification defined as 100 copies per reaction. The assay had good precision (inter and intra-day coefficient of variation in cycle threshold (CT) < 4%) and accuracy (100 ± 10%) in the range of 100 to 1010 copies/reaction. We found TTV loads ranging from 2.5 - 4.07 log copies/mL of plasma with CT (mean ± SD) of 33.8 ± 1.77 in healthy individuals and 2.06 - 8.49 log copies/mL of plasma with CT (mean ± SD) of 24.3 ± 1.04 in HSCT recipients. CONCLUSION: SYBR Green-based q-PCR assay combines simplicity with satisfactory sensitivity and may be suitable for monitoring the immune status of transplant recipients, where TTV loads over time may serve as a marker for immune reconstitution in human plasma samples.
Asunto(s)
Infecciones por Virus ADN/virología , Compuestos Orgánicos/metabolismo , Plasma/virología , Coloración y Etiquetado/métodos , Torque teno virus/aislamiento & purificación , Carga Viral/métodos , Adulto , Benzotiazoles , Diaminas , Humanos , Quinolinas , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Viremia/virologíaRESUMEN
BACKGROUND AIMS: Umbilical cord blood (UCB) is a source of hematopoietic stem cells that initially was used exclusively for the hematopoietic reconstitution of pediatric patients. It is now suggested for use for adults as well, a fact that increases the pressure to obtain units with high cellularity. Therefore, the optimization of UCB processing is a priority. METHODS: The present study focused on parameters influencing total nucleated cell (TNC), mononucleated cell (MNC) and CD34+ cell (CD34C) recovery after routine volume reduction of 1553 UCB units using hydroxyethyl starch-induced sedimentation with an automated device, under routine laboratory conditions. RESULTS: We show that the unit volume rather than the TNC count significantly affects TNC, MNC and CD34C processing efficiency (PEf), and this in a non-linear fashion: when units were sampled according to the collection volume, including pre-loaded anticoagulant (gross volume), PEf increased up to a unit volume of 110-150 mL and decreased thereafter. Thus units with initial gross volumes < 90 mL and > 170 mL similarly exhibited a poor PEf. CONCLUSIONS: These data identify unit gross volume as a major parameter influencing PEf and suggest that fractionation of large units should be contemplated only when the resulting volume of split units is > 90 mL.
Asunto(s)
Técnicas de Cultivo de Célula/métodos , Sangre Fetal/citología , Células Madre Hematopoyéticas/citología , Leucocitos Mononucleares/citología , Antígenos CD34/inmunología , Sedimentación Sanguínea , Humanos , Derivados de Hidroxietil Almidón/química , Linfocitos T/citología , Linfocitos T/inmunologíaAsunto(s)
Refuerzo Inmunológico de Injertos , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Depleción Linfocítica , Mutación , Tirosina Quinasa 3 Similar a fms/genética , Adulto , Anciano , Aloinjertos , Supervivencia sin Enfermedad , Femenino , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
The bone marrow constitutes a favorable environment for long-lived antibody-secreting plasma cells, providing blood-circulating antibody. Plasma cells are also present in mucosa-associated lymphoid tissue (MALT) to mediate local frontline immunity, but how plasma cell survival there is regulated is not known. Here we report that a proliferation-inducing ligand (APRIL) promoted survival of human upper and lower MALT plasma cells by upregulating expression of the antiapoptotic proteins bcl-2, bcl-xL, and mcl-1. The in situ localization of APRIL was consistent with such a prosurvival role in MALT. In upper MALT, tonsillar epithelium produced APRIL. Upon infection, APRIL production increased considerably when APRIL-secreting neutrophils recruited from the blood infiltrated the crypt epithelium. Heparan sulfate proteoglycans (HSPGs) retained secreted APRIL in the subepithelium of the infected zone to create APRIL-rich niches, wherein IgG-producing plasma cells accumulated. In lower MALT, neutrophils were the unique source of APRIL, giving rise to similar niches for IgA-producing plasmocytes in villi of lamina propria. Furthermore, we found that mucosal humoral immunity in APRIL-deficient mice is less persistent than in WT mice. Hence, production of APRIL by inflammation-recruited neutrophils may create plasma cell niches in MALT to sustain a local antibody production.
Asunto(s)
Proteoglicanos de Heparán Sulfato/metabolismo , Membrana Mucosa/inmunología , Neutrófilos/metabolismo , Células Plasmáticas/inmunología , Miembro 13 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/metabolismo , Línea Celular , Humanos , Riñón/citología , Miembro 13 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/genéticaRESUMEN
Ligands of the aryl hydrocarbon receptor (AHR), a transcription factor mediating the effects of dioxin, favor Th17 differentiation and exacerbate autoimmunity in mice. We investigated how AHR ligands affected human T-cell polarization. We found that the high affinity and stable AHR-ligand dioxin as well as the natural AHR-ligand 6-formylinolo[3,2-b] carbazole induced the downstream AHR-target cytochrome P450A1, and without affecting IFN-gamma, they enhanced IL-22 while simultaneously decreasing IL-17A production by CD4(+) T cells. The specific AHR-inhibitor CH-223191 abolished these effects. Furthermore, blockade of IL-23 and IL-1, important for Th17 expansion, profoundly decreased IL-17A but not IL-22 production. AHR agonists reduced the expression of the Th17 master transcription factor retinoic acid-related orphan receptor C (RORC), without affecting T-bet, GATA-3 and Foxp3. They also decreased the expression of the IL-23 receptor. Importantly, AHR-ligation did not only decrease the number of Th17 cells but also primed naïve CD4(+) T cells to produce IL-22 without IL-17 and IFN-gamma. Furthermore, IL-22 single producers did not express CD161, which distinguished them from the CD161(+) Th17 cells. Hence, our data provide compelling evidence that AHR activation participates in shaping human CD4(+) T-cell polarization favoring the emergence of a distinct subset of IL-22-producing cells that are independent from the Th17 lineage.
Asunto(s)
Interleucina-17/metabolismo , Interleucinas/metabolismo , Receptores de Hidrocarburo de Aril/metabolismo , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Colaboradores-Inductores/metabolismo , Compuestos Azo/farmacología , Antígenos CD4/biosíntesis , Carbazoles/farmacología , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Citocromo P-450 CYP1A1/metabolismo , Dioxinas/farmacología , Humanos , Interferón gamma/inmunología , Interferón gamma/metabolismo , Interleucina-17/genética , Interleucina-17/inmunología , Interleucinas/genética , Interleucinas/inmunología , Activación de Linfocitos/efectos de los fármacos , Subfamilia B de Receptores Similares a Lectina de Células NK/biosíntesis , Pirazoles/farmacología , Receptores de Hidrocarburo de Aril/inmunología , Subgrupos de Linfocitos T/efectos de los fármacos , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/patología , Linfocitos T Colaboradores-Inductores/efectos de los fármacos , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/patología , Factores de Transcripción/genética , Factores de Transcripción/inmunología , Factores de Transcripción/metabolismo , Regulación hacia Arriba , Interleucina-22RESUMEN
We studied early NK-cell recovery in 29 allografted patients undergoing different lymphoreductive regimens. Already at 2 wk after graft take, the number of NK cells had reached (supra)normal levels but NK-cell subsets were skewed. The number of CD56(dim) CD16(bright) NK cells was low and correlated strongly with the level of hematopoiesis, whereas the number of the more abundant NK cells expressing high levels of CD56 did not. Post-transplant CD56(bright) NK cells (ptCD56(bright)) differed from CD56(bright) NK cells in normal controls (CD56(bright)) in being HLA-DR- and perforin-positive, CCR7(-), CD27(-), CD127(-) and mostly c-kit(-). CD56(bright) from normal controls stimulated by IL-15 in vitro (NK(IL-15)) acquired all the characteristics distinguishing CD56(bright) from ptCD56(bright). IL-2 exerted similar effects. Moreover, when cultured without cytokines, ptCD56(bright), CD56(bright) and NK(IL-15) responded similarly by upregulating CD127 and c-kit but not CCR7. IL-12 stimulated IFN-γ production in ptCD56(bright), whereas CD56(bright) responded only to IL-12 plus IL-15. Hence, ptCD56(bright) have all the features of cytokine-stimulated CD56(bright). Because only patients with low numbers of T cells had high numbers of ptCD56(bright), we conclude that ptCD56(bright) are activated CD56(bright) that expand while competing with T cells for the elevated post-transplant level of IL-15.
Asunto(s)
Antígeno CD56 , Hematopoyesis/inmunología , Trasplante de Células Madre Hematopoyéticas , Células Asesinas Naturales/inmunología , Activación de Linfocitos/inmunología , Linfocitos T/inmunología , Antígenos de Diferenciación/biosíntesis , Antígenos de Diferenciación/inmunología , Citocinas/inmunología , Citocinas/metabolismo , Femenino , Neoplasias Hematológicas/sangre , Neoplasias Hematológicas/inmunología , Neoplasias Hematológicas/terapia , Humanos , Células Asesinas Naturales/metabolismo , Recuento de Linfocitos , Masculino , Linfocitos T/metabolismo , Trasplante Homólogo , Regulación hacia Arriba/inmunologíaRESUMEN
BACKGROUND: Responses to influenza vaccines are poorly characterized in immunocompromised patients. The goal of this study was to assess the efficacy of the AS03-adjuvanted influenza H1N1/A/09 vaccine in allogeneic hematopoietic stem cell transplant recipients. DESIGN AND METHODS: We enrolled 65 patients and 138 controls in an open prospective study. Controls received one dose and patients 2 doses of the AS03-adjuvanted influenza H1N1/A/09 vaccine at a 3-week interval. Geometric mean titers and seroprotection/seroconversion rates were determined by hemagglutination inhibition before and four weeks after the last immunization. Clinical and biological markers, including immunoglobulins, CD3+, CD4+, CD8+ and naïve CD4+ T-cell counts were assessed in all patients. RESULTS: Baseline seroprotection rates were low in patients (6.6%) and controls (14.8%). After 2 doses, patients (n=57, 92.3%) achieved similar seroprotection rates (84% vs. 87%, P=0.65) and antibody titers (305 vs. 340, P=0.88) as controls (n=131, 93.9%) after one dose. In univariate analysis, transplant-to-vaccination interval less than 12 months, active graft-versus-host disease, immunosuppressive drugs, hemoglobin less than 12 g/L, lymphopenia less than 1 G/L, IgG less than 4 g/L, IgA less than 0.5 g/L, IgM less than 0.5 g/L and naive CD4+ T cells less than 150/µL were significantly associated with weaker responses. Multivariate analysis identified transplant-to-vaccination interval and active graft-versus-host disease as the most powerful negative predictors of antibody responses (P=0.04 and P=0.002, respectively). Vaccination was well tolerated in both cohorts. CONCLUSIONS: In allogeneic hematopoietic stem cell transplant recipients, 2 doses of an adjuvanted influenza vaccine elicited comparable responses to a single dose in healthy individuals. However, vaccine responses remained poor in patients with ongoing graft-versus-host disease, supporting the need for additional strategies in this high-risk patient population. (ClinicalTrials.gov Identifier: NCT01022905).
Asunto(s)
Enfermedad Injerto contra Huésped/inmunología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Inmunidad Humoral/inmunología , Vacunas contra la Influenza/inmunología , Adulto , Anciano , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Formación de Anticuerpos/inmunología , Femenino , Humanos , Inmunización , Huésped Inmunocomprometido , Vacunas contra la Influenza/efectos adversos , Masculino , Persona de Mediana Edad , Trasplante Homólogo/inmunología , Adulto JovenRESUMEN
OBJECTIVES: The aim of this retrospective study was to assess the incidence of late complications occurring ≥2 years after allogeneic hematopoietic stem cell transplantation (HSCT) for malignant diseases using a T-cell depletion strategy. METHODS: Between 1984 and 2004, 142 patients were eligible for the study. Total body irradiation (TBI) was carried out in 85% of the patients and T-cell depletion in 84%. RESULTS: Non-relapse mortality (NRM) was 3% (95% CI 0-11) at 10 years, and serious late events affected a substantial number of patients. The cumulative incidence (CI) of chronic graft-versus-host disease (cGvHD) was 30% (95% CI 23-40), and that of infectious complications was 17% (95% CI 11-23). Multivariate analysis showed a higher risk for late complications in patients with cGvHD (HR 1.9, 95% CI 1.2-3.2, P=0.011) and patients receiving methylprednisolone during conditioning (HR 1.9, 95% CI 1.1-3.3, P=0.019 1), patients with cGvHD also having a higher risk for NRM (HR 13.2, 95% CI 1.2-143, P=0.03), as well as those receiving steroids for >3 months (HR 40.3, 95% CI 2.3-718, P=0.02) and those receiving antithymocyte globulin (HR 9.6, 95% CI 0.8-68, P=0.024). CONCLUSIONS: A significant proportion of long-term survivors of HSCT had late complications. cGvHD remained an important risk factor for late complications despite T-cell depletion resulting in immunosuppression and infectious complications.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/efectos adversos , Adolescente , Adulto , Suero Antilinfocítico/efectos adversos , Niño , Preescolar , Oftalmopatías/etiología , Femenino , Enfermedad Injerto contra Huésped/etiología , Humanos , Hipotiroidismo/etiología , Terapia de Inmunosupresión/efectos adversos , Infecciones/etiología , Depleción Linfocítica , Masculino , Metilprednisolona/efectos adversos , Persona de Mediana Edad , Análisis Multivariante , Neoplasias Primarias Secundarias/etiología , Enfermedades del Sistema Nervioso/etiología , Estudios Retrospectivos , Factores de Riesgo , Linfocitos T/inmunología , Factores de Tiempo , Acondicionamiento Pretrasplante/efectos adversos , Trasplante Homólogo , Resultado del Tratamiento , Adulto JovenRESUMEN
Impaired immune reconstitution after allogeneic hematopoietic stem cell transplantation (HSCT) contributes to increased risk of cancer relapse and infection resulting in significant morbidity and mortality. Unfortunately, effective strategies to functionally assess the quality of immune reconstitution are still missing. Quantification of in vivo replication of the ubiquitous, non-pathogenic virus Torque Teno Virus (TTV) has been reported in small series as a test to functionally evaluate the quality of post-transplant immune reconstitution. In the present study, we analyzed by quantitative PCR TTV titers in plasma samples from a large cohort of 168 allogeneic HSCT recipients. Our analysis confirms that TTV titers peaked at 100 days post-transplant, followed by progressive normalization thereafter. Negative correlation of TTV titers with T cell absolute numbers during the first year post-transplant points to the restoration of an active anti-TTV immunity. Univariable and multivariable linear regression analysis demonstrated that donor CMV positive serostatus, donor type and immune suppression resulting from GVHD treatment affected the restoration of anti-TTV immunity. Importantly, higher TTV titers at 100 days after transplantation were associated with worse overall survival and higher risk of acute GVHD and infections. Our results provide new insights into the factors affecting the dynamics of TTV replication and indicate that TTV is a potentially useful biomarker to assess immune reconstitution and to predict complications and outcomes of allogeneic HSCT.
Asunto(s)
Infecciones por Virus ADN/virología , Trasplante de Células Madre Hematopoyéticas , Huésped Inmunocomprometido , Torque teno virus/crecimiento & desarrollo , Replicación Viral , Adulto , Infecciones por Virus ADN/sangre , Infecciones por Virus ADN/diagnóstico , Infecciones por Virus ADN/inmunología , Femenino , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Cinética , Masculino , Persona de Mediana Edad , Monitorización Inmunológica , Reacción en Cadena de la Polimerasa , Valor Predictivo de las Pruebas , Estudios Prospectivos , Medición de Riesgo , Factores de Riesgo , Torque teno virus/inmunología , Trasplante Homólogo , Resultado del Tratamiento , Carga ViralRESUMEN
Immune exhaustion contributes to treatment failure after allogeneic hematopoietic stem cell transplantation (HSCT) for hematological malignancies. Immune checkpoint blockade, including programmed cell death protein-1 (PD-1) blockade, is a promising strategy to improve the antitumor effect of allogeneic HSCT with high rates of response reported in patients treated for disease relapse. However, severe and sometimes fatal Graft- vs.-Host-Disease (GvHD) has been reported as a complication. Little is known about the dynamics of PD-1 expression on immune effector cells after allogeneic HSCT. In the present study, we analyzed PD-1 expression on T cell subpopulations isolated from 105 allogeneic HSCT recipients. Our analysis revealed a significant increase in proportions of PD-1-expressing CD4 and CD8 T cells early after allogeneic HSCT followed by a progressive normalization of PD-1 expression at CD8 but not CD4 T cell surface. Analysis of co-expression of two other exhaustion markers, 2B4 and CD160, revealed a preferential expansion of PD-1-single positive cells. Moreover, the analysis of granzyme B and perforin expression in PD-1+ and PD-1- CD8 T cells from HSCT recipients did not reveal any impairment in cytotoxic molecules production by PD-1-expressing CD8 T cells. Analyzing the association between clinical factors and the expression of PD-1 on T cells, we identified the use of in vivo and/or ex vivo T-cell depletion as the factor most strongly associated with elevated PD-1 levels on T cells. Our results extend our knowledge of the regulation of PD-1 expression at T cell surface after allogeneic HSCT, a crucial information for the optimization of post-transplantation PD-1 blocking therapies.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Trasplante de Células Madre Hematopoyéticas , Receptor de Muerte Celular Programada 1/análisis , Adolescente , Adulto , Anciano , Antígeno B7-H1/antagonistas & inhibidores , Femenino , Enfermedad Injerto contra Huésped/inmunología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Estudios Prospectivos , Trasplante Homólogo , Adulto JovenAsunto(s)
Infecciones por Citomegalovirus/diagnóstico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Células Asesinas Naturales/inmunología , Neumonía/diagnóstico , Esclerodermia Sistémica/cirugía , Adulto , Infecciones por Citomegalovirus/etiología , Femenino , Supervivencia de Injerto , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Células Asesinas Naturales/patología , Neumonía/etiología , Medición de Riesgo , Esclerodermia Sistémica/diagnóstico , Trasplante Autólogo/efectos adversosRESUMEN
Graft-versus-host disease (GvHD)-free, relapse-free survival (GRFS) is a recently reported composite endpoint that allows to simultaneously estimate risk of death, relapse and GvHD after allogeneic hematopoietic stem cell transplantation (HSCT). In this retrospective study comprising 333 patients transplanted for hematologic malignancies, we compared GRFS in patients receiving partial T-cell-depleted (pTCD) grafts with patients receiving T-cell-replete grafts (No-TCD). pTCD was associated with a significantly improved GRFS. The beneficial effect of pTCD on GRFS remained highly significant in multivariable analysis taking into account clinical factors differing between patient groups. We observed no effect of pTCD on overall survival, progression-free survival, and relapse cumulative incidence, while non-relapse mortality cumulative incidence was significantly lower in patients receiving pTCD. The results of our retrospective analysis suggest that pTCD could improve GRFS in allogeneic HSCT recipients without significantly affecting OS and PFS, thus improving patients' quality of life without impairing the curative potential of allogeneic HSCT.
Asunto(s)
Enfermedad Injerto contra Huésped/mortalidad , Enfermedad Injerto contra Huésped/prevención & control , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Depleción Linfocítica/mortalidad , Linfocitos T/inmunología , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Estudios de Seguimiento , Enfermedad Injerto contra Huésped/etiología , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Trasplante Homólogo , Adulto JovenRESUMEN
BACKGROUND: Non-HLA immunogenetic polymorphisms may influence outcome of hematopoietic stem cell transplantation (HSCT). In this study, we have determined the role of TNFa, TNFd, IL-10, IL-1, IL-1Ra, and IL-4R polymorphisms in patients transplanted with HSC of an unrelated donor. METHODS: The allelic variants of four SNPs (IL-10-1082, IL-1beta-511, IL-4R-3223, IL-4R-1902) and four microsatellites (TNFa, TNFd, IL-10-1064, IL-1Ra) were determined in 131 unrelated patient/donor pairs typed for HLA-A/B/C/DR/DQ (four digits). RESULTS: The allelic distribution of the polymorphisms was similar to that previously reported in Caucasoid populations. Patient and donor TNFd and patient IL-10-1064 polymorphisms correlated with mortality in univariate analysis. Patients with TNFd1/d2/d3 genotypes had 3-year survival rates of 65%. A gradual decrease in survival rates was observed for patients with TNFd3/d3 genotypes (50%, p=n.s.), TNFd4 (46%, P=0.08), and TNFd5 (33%, P=0.03). A multivariate analysis of 10/10 matched patients revealed that the following patient genotypes correlated with lower survival: TNFd3/d3 (RR 4.08, P=0.026) TNFd4 (RR 3.78, P=0.032) and TNFd5 (RR 6.69, P=0.021) all compared to TNFd1/d2/d3 genotypes. Patient IL-10 (12, 14, 15) microsatellite alleles correlated with lower 3-year survival (28%) when compared to IL-10 (<12) (56%, P=0.052) and to Il-10 (13) alleles (60%, P=0.0023). In multivariate analysis this correlation remained significant only in recipients of HSCT of 10/10 HLA matched donors (RR=2.96, P=0.038). CONCLUSION: The data demonstrate a significant correlation of the TNFd and IL-10-1064 microsatellite polymorphisms with mortality after unrelated HSCT. They support the hypothesis that simple genomic tests, in addition to precise HLA matching, may contribute to determine prognosis in patients undergoing unrelated HSCT.
Asunto(s)
Variación Genética , Interleucina-10/genética , Polimorfismo Genético , Trasplante de Células Madre/mortalidad , Factor de Necrosis Tumoral alfa/genética , Adolescente , Adulto , Secuencia de Bases , Niño , Preescolar , Cartilla de ADN , Femenino , Genotipo , Prueba de Histocompatibilidad , Humanos , Lactante , Masculino , Persona de Mediana Edad , Probabilidad , Tasa de SupervivenciaRESUMEN
Peroxisome proliferator-activated receptors (PPARs) are essential in glucose and lipid metabolism and are implicated in metabolic disorders predisposing to atherosclerosis, such as diabetes and dyslipidemia. Conversely, antidiabetic glitazones and hypolipidemic fibrate drugs, known as PPARgamma and PPARalpha ligands, respectively, reduce the process of atherosclerotic lesion formation, which involves chronic immunoinflammatory processes. Major histocompatibility complex class II (MHC-II) molecules, expressed on the surface of specialized cells, are directly involved in the activation of T lymphocytes and in the control of the immune response. Interestingly, expression of MHC-II has recently been observed in atherosclerotic plaques, and it can be induced by the proinflammatory cytokine interferon-gamma (IFN-gamma) in vascular cells. To explore a possible role for PPAR ligands in the regulation of the immune response, we investigated whether PPAR activation affects MHC-II expression in atheroma-associated cells. In the present study, we demonstrate that PPARgamma but not PPARalpha ligands act as inhibitors of IFN-gamma-induced MHC-II expression and thus as repressors of MHC-II-mediated T-cell activation. All different types of PPARgamma ligands tested inhibit MHC-II. This effect of PPARgamma ligands is due to a specific inhibition of promoter IV of CIITA and does not concern constitutive expression of MHC-II. Thus, the beneficial effects of antidiabetic PPARgamma activators on atherosclerotic plaque development may be partly explained by their repression of MHC-II expression and subsequent inhibition of T-lymphocyte activation.
Asunto(s)
Arteriosclerosis/metabolismo , Regulación de la Expresión Génica/fisiología , Antígenos de Histocompatibilidad Clase II/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Factores de Transcripción/metabolismo , Arteriosclerosis/inmunología , Arteriosclerosis/patología , Células Cultivadas , Relación Dosis-Respuesta a Droga , Endotelio Vascular/citología , Endotelio Vascular/metabolismo , Citometría de Flujo , Regulación de la Expresión Génica/efectos de los fármacos , Genes Reporteros , Antígenos de Histocompatibilidad Clase II/genética , Humanos , Hipoglucemiantes/farmacología , Interferón gamma/farmacología , Ligandos , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , Prueba de Cultivo Mixto de Linfocitos , Monocitos/citología , Monocitos/efectos de los fármacos , Monocitos/inmunología , Prostaglandina D2/análogos & derivados , Prostaglandina D2/farmacología , ARN Mensajero/metabolismo , Receptores Citoplasmáticos y Nucleares/genética , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Factores de Transcripción/genéticaRESUMEN
Recent reports give insights into the role of the T-box transcription factors, T-bet and Eomesodermin (Eomes), in NK cell biology. In this mini-review, we recapitulate the initial reports that delineate T-bet and Eomes as master regulators of NK cell development, maturation, and function. We discuss how T-bet and Eomes expression is regulated during NK cell development and peripheral maturation. Furthermore, we summarize the current literature on the role of T-bet and Eomes in the transcriptional regulation of NK cell function and review possible effects of T-box transcription factor anomalies during aging, infection, cancer, and after hematopoietic stem cell transplantation. We discuss how the current data argue in favor of a model of T-bet and Eomes synergy in transcriptional regulation of NK cell function and identify T-box transcription factors as potential targets for therapeutic interventions.
RESUMEN
Peripheral natural killer (NK) cells upregulate T-bet and downregulate Eomes, the key transcription factors regulating NK cell maturation and function during the last maturation steps toward terminally differentiated effector cells. During this process, NK cells acquire killer immunoglobulin-like receptors (KIR) and effector functions, such as cytotoxicity and target cell-induced cytokine production. Inhibitory KIR are pivotal in the control of effector functions, but whether they also modulate T-bet/Eomes expression is unknown. We have measured T-bet/Eomes levels, KIR expression, and effector functions of maturing CD94(neg)CD56(dim)NK cells using CD57 as surface marker for maturation. Our cohort consisted of 23 healthy blood donors (HBD) homozygous for the KIR A haplotype that contains only inhibitory KIR2DL1 (ligand HLA-C2), KIR2DL3 (ligand HLA-C1), and KIR3DL1 (ligand HLA-Bw4). We confirm that during maturation of NK cells, the number of KIR increases, levels of T-bet/Eomes are modulated, and that cells acquire effector functions, such as cytotoxicity (CD107) and target cell-induced cytokine production (TNF-α). Because maturation was associated with the increase of the number of KIR as well as with the modulation of T-bet/Eomes, the number of KIR correlated with the extent of T-bet/Eomes modulation. However, whether the KIR were triggered by their cognate HLA ligands or not had no impact on T-bet and Eomes expression, indicating that modulation of T-box transcription factors during NK cell maturation does not depend on signals conveyed by KIR. We discuss the relevance of this finding in the context of models of NK cell maturation while cautioning that results obtained in a perhaps quite heterogeneous cohort of HBD are not necessarily conclusive.