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1.
Nat Immunol ; 13(12): 1145-54, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-23160217

RESUMEN

Dendritic cells (DCs) are essential mediators of innate and adaptive immune responses. Study of these critical cells has been complicated by their similarity to other hematopoietic lineages, particularly monocytes and macrophages. Progress has been made in three critical areas of DC biology: the characterization of lineage-restricted progenitors in the bone marrow, the identification of cytokines and transcription factors required during differentiation, and the development of genetic tools for the visualization and depletion of DCs in vivo. Collectively, these advances have clarified the nature of the DC lineage and have provided novel insights into their function during health and disease.


Asunto(s)
Diferenciación Celular , Linaje de la Célula , Células Dendríticas/inmunología , Células de la Médula Ósea/citología , Células de la Médula Ósea/inmunología , Citocinas/metabolismo , Células Dendríticas/citología , Células Dendríticas/metabolismo , Humanos , Macrófagos/inmunología , Monocitos/inmunología , Células Madre/citología , Células Madre/metabolismo , Factores de Transcripción/metabolismo
2.
Eur J Nucl Med Mol Imaging ; 51(5): 1361-1370, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38114616

RESUMEN

PURPOSE: The emergence of chimeric antigen receptor (CAR) T-cell therapy fundamentally changed the management of individuals with relapsed and refractory large B-cell lymphoma (LBCL). However, real-world data have shown divergent outcomes for the approved products. The present study therefore set out to evaluate potential risk factors in a larger cohort. METHODS: Our analysis set included 88 patients, treated in four German university hospitals and one Italian center, who had undergone 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography (PET) before CAR T-cell therapy with tisagenlecleucel or axicabtagene ciloleucel. We first determined the predictive value of conventional risk factors, treatment lines, and response to bridging therapy for progression-free survival (PFS) through forward selection based on Cox regression. In a second step, the additive potential of two common PET parameters was assessed. Their optimal dichotomizing thresholds were calculated individually for each CAR T-cell product. RESULTS: Extra-nodal involvement emerged as the most relevant of the conventional tumor and patient characteristics. Moreover, we found that inclusion of metabolic tumor volume (MTV) further improves outcome prediction. The hazard ratio for a PFS event was 1.68 per unit increase of our proposed risk score (95% confidence interval [1.20, 2.35], P = 0.003), which comprised both extra-nodal disease and lymphoma burden. While the most suitable MTV cut-off among patients receiving tisagenlecleucel was 11 mL, a markedly higher threshold of 259 mL showed optimal predictive performance in those undergoing axicabtagene ciloleucel treatment. CONCLUSION: Our analysis demonstrates that the presence of more than one extra-nodal lesion and higher MTV in LBCL are associated with inferior outcome after CAR T-cell treatment. Based on an assessment tool including these two factors, patients can be assigned to one of three risk groups. Importantly, as shown by our study, metabolic tumor burden might facilitate CAR T-cell product selection and reflect the individual need for bridging therapy.


Asunto(s)
Inmunoterapia Adoptiva , Linfoma de Células B Grandes Difuso , Humanos , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Linfoma de Células B Grandes Difuso/diagnóstico por imagen , Linfoma de Células B Grandes Difuso/terapia , Pronóstico , Tomografía de Emisión de Positrones , Medición de Riesgo
3.
Nat Immunol ; 9(6): 603-12, 2008 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-18438409

RESUMEN

Calcineurin is required for B cell receptor (BCR)-induced proliferation of mature B cells. Paradoxically, loss of NFAT transcription factors, themselves calcineurin targets, induces hyperactivity, which suggests that calcineurin targets other than NFAT are required for BCR-induced proliferation. Here we demonstrate a function for the calcineurin-regulated transcription factor Mef2c in B cells. BCR-induced calcium mobilization was intact after Mef2c deletion, but loss of Mef2c caused defects in B cell proliferation and survival after BCR stimulation in vitro and lower T cell-dependent antibody responses and germinal center formation in vivo. Mef2c activity was specific to BCR stimulation, as Toll-like receptor and CD40 signaling induced normal responses in Mef2c-deficient B cells. Mef2c-dependent targets included the genes encoding cyclin D2 and the prosurvival factor Bcl-x(L). Our results emphasize an unrecognized but critical function for Mef2c in BCR signaling.


Asunto(s)
Linfocitos B/fisiología , Calcineurina/metabolismo , Supervivencia Celular/fisiología , Factores Reguladores Miogénicos/fisiología , Receptores de Antígenos de Linfocitos B/fisiología , Animales , Ciclo Celular/fisiología , Factores de Transcripción MEF2 , Ratones , Factores de Transcripción/fisiología
4.
Nature ; 507(7491): 243-7, 2014 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-24509714

RESUMEN

The transcription factors c-Myc and N-Myc--encoded by Myc and Mycn, respectively--regulate cellular growth and are required for embryonic development. A third paralogue, Mycl1, is dispensable for normal embryonic development but its biological function has remained unclear. To examine the in vivo function of Mycl1 in mice, we generated an inactivating Mycl1(gfp) allele that also reports Mycl1 expression. We find that Mycl1 is selectively expressed in dendritic cells (DCs) of the immune system and controlled by IRF8, and that during DC development, Mycl1 expression is initiated in the common DC progenitor concurrent with reduction in c-Myc expression. Mature DCs lack expression of c-Myc and N-Myc but maintain L-Myc expression even in the presence of inflammatory signals such as granulocyte-macrophage colony-stimulating factor. All DC subsets develop in Mycl1-deficient mice, but some subsets such as migratory CD103(+) conventional DCs in the lung and liver are greatly reduced at steady state. Importantly, loss of L-Myc by DCs causes a significant decrease in in vivo T-cell priming during infection by Listeria monocytogenes and vesicular stomatitis virus. The replacement of c-Myc by L-Myc in immature DCs may provide for Myc transcriptional activity in the setting of inflammation that is required for optimal T-cell priming.


Asunto(s)
Reactividad Cruzada/inmunología , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Regulación de la Expresión Génica , Proteínas Proto-Oncogénicas c-myc/metabolismo , Linfocitos T/inmunología , Animales , Antígenos CD/metabolismo , División Celular , Células Dendríticas/citología , Femenino , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Inflamación/inmunología , Inflamación/metabolismo , Cadenas alfa de Integrinas/metabolismo , Factores Reguladores del Interferón/metabolismo , Listeria monocytogenes/inmunología , Hígado/citología , Hígado/inmunología , Pulmón/citología , Pulmón/inmunología , Masculino , Ratones , Proteínas Proto-Oncogénicas c-myc/deficiencia , Transcripción Genética , Vesiculovirus/inmunología
5.
Nature ; 490(7421): 502-7, 2012 Oct 25.
Artículo en Inglés | MEDLINE | ID: mdl-22992524

RESUMEN

The AP1 transcription factor Batf3 is required for homeostatic development of CD8α(+) classical dendritic cells that prime CD8 T-cell responses against intracellular pathogens. Here we identify an alternative, Batf3-independent pathway in mice for CD8α(+) dendritic cell development operating during infection with intracellular pathogens and mediated by the cytokines interleukin (IL)-12 and interferon-γ. This alternative pathway results from molecular compensation for Batf3 provided by the related AP1 factors Batf, which also functions in T and B cells, and Batf2 induced by cytokines in response to infection. Reciprocally, physiological compensation between Batf and Batf3 also occurs in T cells for expression of IL-10 and CTLA4. Compensation among BATF factors is based on the shared capacity of their leucine zipper domains to interact with non-AP1 factors such as IRF4 and IRF8 to mediate cooperative gene activation. Conceivably, manipulating this alternative pathway of dendritic cell development could be of value in augmenting immune responses to vaccines.


Asunto(s)
Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Células Dendríticas/citología , Células Dendríticas/metabolismo , Factores Reguladores del Interferón/metabolismo , Animales , Presentación de Antígeno , Antígenos CD/metabolismo , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/química , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/deficiencia , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/inmunología , Antígenos CD8/inmunología , Antígenos CD8/metabolismo , Antígeno CTLA-4/metabolismo , Diferenciación Celular , Línea Celular Tumoral , Linaje de la Célula , Células Dendríticas/inmunología , Femenino , Fibrosarcoma/inmunología , Fibrosarcoma/metabolismo , Fibrosarcoma/patología , Regulación de la Expresión Génica , Cadenas alfa de Integrinas/metabolismo , Factores Reguladores del Interferón/deficiencia , Factores Reguladores del Interferón/genética , Interleucina-10/metabolismo , Interleucina-12/inmunología , Interleucina-12/metabolismo , Leucina Zippers , Masculino , Ratones , Ratones Endogámicos C57BL , Trasplante de Neoplasias , Proteína Oncogénica p65(gag-jun)/metabolismo , Unión Proteica , Estructura Terciaria de Proteína , Proteínas Represoras/deficiencia , Proteínas Represoras/genética , Linfocitos T Colaboradores-Inductores/citología , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/metabolismo , Toxoplasma/inmunología
6.
Blood ; 120(2): 335-46, 2012 Jul 12.
Artículo en Inglés | MEDLINE | ID: mdl-22665933

RESUMEN

Myeloid ecotropic viral integration site 1 (Meis1) forms a heterodimer with Pbx1 that augments Hox-dependent gene expression and is associated with leukemogenesis and HSC self-renewal. Here we identified 2 independent actions of Meis1 in hematopoietic development: one regulating cellular proliferation and the other involved in megakaryocyte lineage development. First, we found that endogenous Mesp1 indirectly induces Meis1 and Meis2 in endothelial cells derived from embryonic stem cells. Overexpression of Meis1 and Meis2 greatly enhanced the formation of hematopoietic colonies from embryonic stem cells, with the exception of erythroid colonies, by maintaining hematopoietic progenitor cells in a state of proliferation. Second, overexpression of Meis1 repressed the development of early erythroid progenitors, acting in vivo at the megakaryocyte-erythroid progenitor stage to skew development away from erythroid generation and toward megakaryocyte development. This previously unrecognized action of Meis1 may explain the embryonic lethality observed in Meis1(-/-) mice that arises from failure of lymphatic-venous separation and can result as a consequence of defective platelet generation. These results show that Meis1 exerts 2 independent functions, with its role in proliferation of hematopoietic progenitors acting earlier in development from its influence on the fate choice at the megakaryocyte-erythroid progenitor between megakaryocytic and erythroid development.


Asunto(s)
Células Precursoras Eritroides/citología , Células Precursoras Eritroides/fisiología , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/fisiología , Proteínas de Homeodominio/fisiología , Proteínas de Neoplasias/fisiología , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/fisiología , Línea Celular , Linaje de la Célula/genética , Linaje de la Célula/fisiología , Proliferación Celular , Ensayo de Unidades Formadoras de Colonias , Eritropoyesis/genética , Eritropoyesis/fisiología , Regulación del Desarrollo de la Expresión Génica , Hematopoyesis/genética , Hematopoyesis/fisiología , Proteínas de Homeodominio/genética , Megacariocitos/citología , Megacariocitos/fisiología , Ratones , Ratones Noqueados , Proteína 1 del Sitio de Integración Viral Ecotrópica Mieloide , Proteínas de Neoplasias/deficiencia , Proteínas de Neoplasias/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/fisiología , Transducción de Señal
7.
Blood Adv ; 8(8): 1934-1945, 2024 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-38197968

RESUMEN

ABSTRACT: Antibody-based immunotherapies have revolutionized leukemia and lymphoma treatment, with animal studies being crucial in evaluating effectiveness and side effects. By targeting the evolutionary conserved Slamf7 immune receptor, which is naturally expressed by the murine multiple myeloma cell line MPC-11, we have developed a syngeneic mouse model for direct comparison of 3 immunotherapies: monoclonal antibodies (mAb), bispecific T-cell engagers (BiTE), and chimeric antigen receptor (CAR) T cells (CART), all targeting Slamf7. Slamf7-BiTE is a bispecific single-chain antibody consisting of α-Slamf7 and α-CD3 Fv fragments joined through a Gly-Ser linker, and Slamf7-CART comprises the α-Slamf7 Fv fragment fused to the msCD8α transmembrane and msCD28, 4-1BB, and CD3ζ intracellular signaling domains. Slamf7-BiTE and Slamf7-CART effectively killed MPC-11 cells in vitro, independently of Slamf7-mediated inhibitory signaling by self-ligation. After chimerizing the constant region of the rat-anti-mouse Slamf7 antibody to mouse Fc-immunoglobulin G2a for enhanced effector functions, Slamf7-mAb triggered antigen-specific antibody-dependent cellular cytotoxicity by binding to Fcγ receptor IV. In vivo, all 3 immunotherapies showed antitumor effects against Slamf7-expressing targets. Unlike Slamf7-mAb, Slamf7-BiTE led to considerable side effects in test animals, including weight loss and general malaise, which were also observed to a lesser extent after Slamf7-CART infusion. In allogeneic transplant, Slamf7-BiTE and Slamf7-CART maintained activity compared with the nontransplant setting, whereas Slamf7-mAb displayed enhanced antimyeloma activity. In summary, our model faithfully replicates treatment efficacy and side effects detected after human immunotherapy. It aids in developing and improving immunotherapies and may help devise novel approaches to mitigate undesired effects in steady state and allogeneic stem cell transplantation.


Asunto(s)
Anticuerpos Biespecíficos , Mieloma Múltiple , Ratones , Ratas , Humanos , Animales , Mieloma Múltiple/tratamiento farmacológico , Línea Celular Tumoral , Modelos Animales de Enfermedad , Anticuerpos Monoclonales/uso terapéutico , Inmunoterapia , Anticuerpos Biespecíficos/uso terapéutico
8.
Hemasphere ; 7(1): e817, 2023 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-36698613

RESUMEN

The introduction of chimeric antigen receptor (CAR) T-cell therapy has led to a fundamental shift in the management of relapsed and refractory large B-cell lymphoma. However, our understanding of risk factors associated with non-response is still insufficient and the search for predictive biomarkers continues. Some parameters measurable on 18F-fluorodeoxyglucose positron emission tomography (PET) may be of additional value in this context. A total of 47 individuals from three German university centers who underwent re-staging with PET prior to CAR T-cell therapy were enrolled into the present study. After multivariable analysis considering tumor characteristics and patient factors that might affect progression-free survival (PFS), we investigated whether metabolic tumor volume (MTV) or maximum standardized uptake value (SUVmax) further improve risk stratification. Their most suitable cut-offs were determined by Cox and logistic regression. Forward selection identified extra-nodal disease as the most predictive factor of those routinely available, and we found it to be associated with significantly inferior overall survival after CAR T-cell treatment (P = 0.012). Furthermore, patients with MTV and SUVmax higher than the optimal threshold of 11 mL and 16.7, respectively, experienced shorter PFS (P = 0.016 and 0.002, respectively). Hence, these risk factors might be useful for selection of individuals likely to benefit from CAR T-cell therapy and their management.

9.
J Clin Oncol ; 41(10): 1876-1887, 2023 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-36608310

RESUMEN

PURPOSE: To present primary and final analyses from the randomized, double-blind, placebo-controlled, phase III iNTEGRATE study, which evaluated the safety and efficacy of ibrutinib with prednisone in previously untreated patients with chronic graft-versus-host disease (cGVHD). METHODS: Patients (age ≥ 12 years) with newly diagnosed moderate or severe cGVHD, requiring systemic corticosteroid therapy, and with no prior systemic treatment for cGVHD were randomly assigned 1:1 to receive ibrutinib 420 mg once daily plus prednisone, starting at 1 mg/kg once daily or placebo plus prednisone. The primary end point was response rate at 48 weeks according to 2014 National Institutes of Health Consensus Development Project Criteria. Other end points included event-free survival, duration of response, time to withdrawal of immunosuppressants, improvement in Lee cGVHD Symptom Scale score, overall survival (OS), and safety. RESULTS: Ninety-five and 98 patients enrolled in the ibrutinib-prednisone and placebo-prednisone arms, respectively. At 48 weeks, response rates were 41% (ibrutinib-prednisone) and 37% (placebo-prednisone; P = .54). At 33 months of follow-up, median duration of response was 19 months (ibrutinib-prednisone) and 10 months (placebo-prednisone; P = .10). Median event-free survival was 15 months (ibrutinib-prednisone) and 8 months (placebo-prednisone; hazard ratio, 0.76; 95% CI, 0.54 to 1.1; P = .11). Improvement in overall Lee cGVHD Symptom Scale was 43% (ibrutinib-prednisone) and 31% (placebo-ibrutinib; P = .07). Median OS was not reached in either arm. The 24-month Kaplan-Meier OS estimates were 80% for both arms (hazard ratio, 1.06; 95% CI, 0.59 to 1.90). Grade ≥ 3 serious adverse events occurred in 49% (ibrutinib-prednisone) and 47% (placebo-prednisone) of patients. CONCLUSION: There was no statistical difference observed in the primary and secondary end points with ibrutinib-prednisone treatment. No new safety signals were observed with ibrutinib treatment in previously untreated patients with cGVHD. The primary end point of iNTEGRATE was not met.


Asunto(s)
Síndrome de Bronquiolitis Obliterante , Humanos , Niño , Prednisona/efectos adversos , Supervivencia sin Progresión , Piperidinas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Método Doble Ciego
10.
Bone Marrow Transplant ; 55(7): 1410-1420, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32001801

RESUMEN

Relapse after allogeneic haematopoietic stem cell transplantation (SCT) is a major cause of death in patients with acute lymphoblastic leukaemia (ALL). Here, we retrospectively analysed the contributions of lineage-sorted donor cell chimerism (sDCC) and quantitative PCR (qPCR) targeting disease-specific genetic rearrangements to detect minimal residual/relapsing disease (MRD) and predict impending relapse in 94 adult ALL patients after SCT. With a median follow-up of surviving patients (n = 61) of 3.3 years, qPCR and/or sDCC measurements turned positive in 38 patients (40%). Of these, 22 patients relapsed and 16 remained in complete remission. At 3 years, qPCR and/or sDCC positive patients showed an increased incidence of relapse (50% vs. 4%, p < 0.0001), decreased relapse-free survival (RFS, 40% vs. 85%, p < 0.0001), and decreased overall survival (OS, 47% vs. 87%, p 0.004). Both, qPCR and sDCC pre-detected 11 of 21 relapses occurring within the first two years after SCT and, overall, complemented for each other method in four of the relapsing and four of the non-relapsing cases. Patients receiving pre-emptive MRD-driven interventions (n = 11) or not (n = 10) showed comparable median times until relapse, RFS, and OS. In our single centre cohort, qPCR and sDCC were similarly effective and complementary helpful to indicate haematological relapse of ALL after SCT.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Humanos , Recurrencia Local de Neoplasia , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Recurrencia , Estudios Retrospectivos , Trasplante de Células Madre
11.
Bone Marrow Transplant ; 53(7): 807-819, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29362503

RESUMEN

Durable remissions of hematological malignancies regularly observed following allogeneic hematopoietic stem cell transplantation (aHSCT) are due to the conditioning regimen, as well as an immunological phenomenon called graft-versus-leukemia (GVL) or graft-versus-tumor (GVT) effect. The development of GVL is closely linked to graft-versus-host disease (GVHD), the main side effect associated with aHSCT. Both, GVHD and GVL are mediated by donor T cells that are initially activated by antigen-presenting cells that present recipient-derived alloantigens in the context of either matched or mismatched MHC class I molecules. Using murine models of aHSCT we show that ubiquitously expressed minor histocompatibility alloantigens (mHAg) are no relevant target for GVT effects. Interestingly, certain ubiquitously expressed MHC alloantigens augmented GVT effects early after transplantation, while others did not. The magnitude of GVT effects correlated with tumor infiltration by CD8+ cytotoxic T cells and tumor cell apoptosis. Furthermore, the immune response underlying GVHD and GVT was oligoclonal, highlighting that immunodominance is an important factor during alloimmune responses. These results emphasize that alloantigen expression on non-hematopoietic tissues can influence GVT effects in a previously unrecognized fashion. These findings bear significance for harnessing optimal GVL effects in patients receiving aHSCT.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Isoantígenos/metabolismo , Acondicionamiento Pretrasplante/métodos , Trasplante Homólogo/métodos , Animales , Modelos Animales de Enfermedad , Humanos , Ratones
12.
J Exp Med ; 213(12): 2553-2565, 2016 11 14.
Artículo en Inglés | MEDLINE | ID: mdl-27810926

RESUMEN

Current systems for conditional gene deletion within mouse macrophage lineages are limited by ectopic activity or low efficiency. In this study, we generated a Mafb-driven Cre strain to determine whether any dendritic cells (DCs) identified by Zbtb46-GFP expression originate from a Mafb-expressing population. Lineage tracing distinguished macrophages from classical DCs, neutrophils, and B cells in all organs examined. At steady state, Langerhans cells (LCs) were lineage traced but also expressed Zbtb46-GFP, a phenotype not observed in any other population. After exposure to house dust mite antigen, Zbtb46-negative CD64+ inflammatory cells infiltrating the lung were substantially lineage traced, but Zbtb46-positive CD64- cells were not. These results provide new evidence for the unique identity of LCs and challenge the notion that some inflammatory cells are a population of monocyte-derived DCs.


Asunto(s)
Linaje de la Célula/inmunología , Células de Langerhans/citología , Células de Langerhans/metabolismo , Macrófagos/citología , Factor de Transcripción MafB/metabolismo , Animales , Antígenos Ly/metabolismo , Técnicas de Sustitución del Gen , Marcación de Gen , Hematopoyesis , Integrasas/metabolismo , Pulmón/patología , Ratones Endogámicos C57BL , Modelos Biológicos , Monocitos/citología , Monocitos/metabolismo , Especificidad de Órganos , Neumonía/patología , Factores de Transcripción/metabolismo
13.
J Exp Med ; 209(6): 1135-52, 2012 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-22615127

RESUMEN

Distinguishing dendritic cells (DCs) from other cells of the mononuclear phagocyte system is complicated by the shared expression of cell surface markers such as CD11c. In this study, we identified Zbtb46 (BTBD4) as a transcription factor selectively expressed by classical DCs (cDCs) and their committed progenitors but not by plasmacytoid DCs (pDCs), monocytes, macrophages, or other lymphoid or myeloid lineages. Using homologous recombination, we replaced the first coding exon of Zbtb46 with GFP to inactivate the locus while allowing detection of Zbtb46 expression. GFP expression in Zbtb46(gfp/+) mice recapitulated the cDC-specific expression of the native locus, being restricted to cDC precursors (pre-cDCs) and lymphoid organ- and tissue-resident cDCs. GFP(+) pre-cDCs had restricted developmental potential, generating cDCs but not pDCs, monocytes, or macrophages. Outside the immune system, Zbtb46 was expressed in committed erythroid progenitors and endothelial cell populations. Zbtb46 overexpression in bone marrow progenitor cells inhibited granulocyte potential and promoted cDC development, and although cDCs developed in Zbtb46(gfp/gfp) (Zbtb46 deficient) mice, they maintained expression of granulocyte colony-stimulating factor and leukemia inhibitory factor receptors, which are normally down-regulated in cDCs. Thus, Zbtb46 may help enforce cDC identity by restricting responsiveness to non-DC growth factors and may serve as a useful marker to identify rare cDC progenitors and distinguish between cDCs and other mononuclear phagocyte lineages.


Asunto(s)
Linaje de la Célula/inmunología , Células Dendríticas/inmunología , Factores de Transcripción/genética , Factores de Transcripción/inmunología , Animales , Secuencia de Bases , Células de la Médula Ósea/citología , Células de la Médula Ósea/metabolismo , Diferenciación Celular/inmunología , Células Dendríticas/citología , Células Endoteliales/metabolismo , Regulación de la Expresión Génica , Factor Estimulante de Colonias de Granulocitos , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Recombinación Homóloga , Tejido Linfoide/citología , Tejido Linfoide/inmunología , Tejido Linfoide/metabolismo , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Datos de Secuencia Molecular , Células Mieloides/metabolismo , Receptores OSM-LIF , Células Madre/fisiología , Factores de Transcripción/metabolismo
14.
J Exp Med ; 207(12): 2551-9, 2010 Nov 22.
Artículo en Inglés | MEDLINE | ID: mdl-21078889

RESUMEN

Graft-versus-host disease (GVHD) causes significant morbidity and mortality in allogeneic hematopoietic stem cell transplantation (aHSCT), preventing its broader application to non-life-threatening diseases. We show that a single administration of a nondepleting monoclonal antibody specific for the coinhibitory immunoglobulin receptor, B and T lymphocyte associated (BTLA), permanently prevented GVHD when administered at the time of aHSCT. Once GVHD was established, anti-BTLA treatment was unable to reverse disease, suggesting that its mechanism occurs early after aHSCT. Anti-BTLA treatment prevented GVHD independently of its ligand, the costimulatory tumor necrosis factor receptor herpesvirus entry mediator (HVEM), and required BTLA expression by donor-derived T cells. Furthermore, anti-BTLA treatment led to the relative inhibition of CD4(+) forkhead box P3(-) (Foxp3(-)) effector T cell (T eff cell) expansion compared with precommitted naturally occurring donor-derived CD4(+) Foxp3(+) regulatory T cell (T reg cell) and allowed for graft-versus-tumor (GVT) effects as well as robust responses to pathogens. These results suggest that BTLA agonism rebalances T cell expansion in lymphopenic hosts after aHSCT, thereby preventing GVHD without global immunosuppression. Thus, targeting BTLA with a monoclonal antibody at the initiation of aHSCT therapy might reduce limitations imposed by histocompatibility and allow broader application to treatment of non-life-threatening diseases.


Asunto(s)
Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas , Terapia de Inmunosupresión , Receptores Inmunológicos/fisiología , Animales , Anticuerpos Monoclonales/uso terapéutico , Línea Celular Tumoral , Listeriosis/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Receptores Inmunológicos/antagonistas & inhibidores , Miembro 14 de Receptores del Factor de Necrosis Tumoral/fisiología , Linfocitos T Reguladores/inmunología
15.
J Exp Med ; 207(4): 823-36, 2010 Apr 12.
Artículo en Inglés | MEDLINE | ID: mdl-20351058

RESUMEN

Although CD103-expressing dendritic cells (DCs) are widely present in nonlymphoid tissues, the transcription factors controlling their development and their relationship to other DC subsets remain unclear. Mice lacking the transcription factor Batf3 have a defect in the development of CD8alpha+ conventional DCs (cDCs) within lymphoid tissues. We demonstrate that Batf3(-/-) mice also lack CD103+CD11b- DCs in the lung, intestine, mesenteric lymph nodes (MLNs), dermis, and skin-draining lymph nodes. Notably, Batf3(-/-) mice displayed reduced priming of CD8 T cells after pulmonary Sendai virus infection, with increased pulmonary inflammation. In the MLNs and intestine, Batf3 deficiency resulted in the specific lack of CD103+CD11b- DCs, with the population of CD103+CD11b+ DCs remaining intact. Batf3(-/-) mice showed no evidence of spontaneous gastrointestinal inflammation and had a normal contact hypersensitivity (CHS) response, despite previous suggestions that CD103+ DCs were required for immune homeostasis in the gut and CHS. The relationship between CD8alpha+ cDCs and nonlymphoid CD103+ DCs implied by their shared dependence on Batf3 was further supported by similar patterns of gene expression and their shared developmental dependence on the transcription factor Irf8. These data provide evidence for a developmental relationship between lymphoid organ-resident CD8alpha+ cDCs and nonlymphoid CD103+ DCs.


Asunto(s)
Antígenos CD/metabolismo , Antígenos CD8/metabolismo , Células Dendríticas/citología , Células Dendríticas/metabolismo , Cadenas alfa de Integrinas/metabolismo , Animales , Antígenos de Superficie/genética , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Células Dendríticas/inmunología , Dermatitis por Contacto/inmunología , Dermatitis por Contacto/patología , Dinitrofluorobenceno/inmunología , Femenino , Expresión Génica/genética , Expresión Génica/inmunología , Factores Reguladores del Interferón/genética , Mucosa Intestinal/citología , Mucosa Intestinal/inmunología , Pulmón/citología , Pulmón/inmunología , Ganglios Linfáticos/citología , Ganglios Linfáticos/inmunología , Masculino , Mesenterio/citología , Mesenterio/inmunología , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Mutantes , Análisis de Secuencia por Matrices de Oligonucleótidos , Receptor de Factor Estimulante de Colonias de Macrófagos/genética , Proteínas Represoras/genética , Infecciones por Respirovirus/inmunología , Virus Sendai/inmunología , Piel/citología , Piel/inmunología , Linfocitos T/inmunología , Factores de Transcripción/genética , Tirosina Quinasa 3 Similar a fms/genética
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