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1.
Blood ; 128(6): 794-804, 2016 08 11.
Artículo en Inglés | MEDLINE | ID: mdl-27338097

RESUMEN

Chronic graft-versus-host disease (cGVHD) is a major cause of late mortality following allogeneic bone marrow transplantation (BMT) and is characterized by tissue fibrosis manifesting as scleroderma and bronchiolitis obliterans. The development of acute GVHD (aGVHD) is a powerful clinical predictor of subsequent cGVHD, suggesting that aGVHD may invoke the immunologic pathways responsible for cGVHD. In preclinical models in which sclerodermatous cGVHD develops after a preceding period of mild aGVHD, we show that antigen presentation within major histocompatibility complex (MHC) class II of donor dendritic cells (DCs) is markedly impaired early after BMT. This is associated with a failure of regulatory T-cell (Treg) homeostasis and cGVHD. Donor DC-restricted deletion of MHC class II phenocopied this Treg deficiency and cGVHD. Moreover, specific depletion of donor Tregs after BMT also induced cGVHD, whereas adoptive transfer of Tregs ameliorated it. These data demonstrate that the defect in Treg homeostasis seen in cGVHD is a causative lesion and is downstream of defective antigen presentation within MHC class II that is induced by aGVHD.


Asunto(s)
Presentación de Antígeno , Trasplante de Médula Ósea/efectos adversos , Células Dendríticas/patología , Enfermedad Injerto contra Huésped/patología , Linfocitos T Reguladores/patología , Enfermedad Aguda , Traslado Adoptivo , Animales , Enfermedad Crónica , Células Dendríticas/inmunología , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/terapia , Antígenos de Histocompatibilidad Clase II/inmunología , Recuento de Linfocitos , Ratones , Ratones Endogámicos BALB C , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/trasplante
2.
Blood ; 125(19): 2933-6, 2015 May 07.
Artículo en Inglés | MEDLINE | ID: mdl-25788702

RESUMEN

Granulocyte colony-stimulating factor (G-CSF) is widely used clinically to prevent neutropenia after cytotoxic chemotherapy and to mobilize hematopoietic stem cells (HSCs) for transplantation. Autophagy, a process of cytoplasmic component recycling, maintains cellular homeostasis and protects the cell during periods of metabolic stress or nutrient deprivation. We have observed that G-CSF activates autophagy in neutrophils and HSCs from both mouse and human donors. Furthermore, G-CSF-induced neutrophil and HSC mobilization is impaired in the absence of autophagy. In contrast, autophagy is dispensable for direct HSC mobilization in response to the CXCR4 antagonist AMD3100. Altogether, these data demonstrate an important role for G-CSF in invoking autophagy within hematopoietic and myeloid cells and suggest that this pathway is critical for ensuring cell survival in response to clinically relevant cytokine-induced stress. These findings have direct relevance to HSC transplantation and the increasing clinical use of agents that modulate autophagy.


Asunto(s)
Autofagia , Factor Estimulante de Colonias de Granulocitos/farmacología , Movilización de Célula Madre Hematopoyética , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas/efectos de los fármacos , Animales , Fármacos Anti-VIH/farmacología , Antígenos CD34/genética , Antígenos CD34/metabolismo , Proteína 5 Relacionada con la Autofagia , Bencilaminas , Western Blotting , Células Cultivadas , Ciclamas , Citometría de Flujo , Células Madre Hematopoyéticas/patología , Compuestos Heterocíclicos/farmacología , Humanos , Ratones , Ratones Noqueados , Proteínas Asociadas a Microtúbulos/fisiología , Neutrófilos/efectos de los fármacos , Neutrófilos/patología , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores CXCR4/antagonistas & inhibidores , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Trasplante Autólogo
3.
Blood Adv ; 8(8): 2032-2043, 2024 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-38295282

RESUMEN

ABSTRACT: Autophagy is an intracellular survival process that has established roles in the long-term survival and function of hematopoietic stem cells (HSC). We investigated the contribution of autophagy to HSC fitness during allogeneic transplantation and graft-versus-host disease (GVHD). We demonstrate in vitro that both tumor necrosis factor and IL-1ß, major components of GVHD cytokine storm, synergistically promote autophagy in both HSC and their more mature hematopoietic progenitor cells (HPC). In vivo we demonstrate that autophagy is increased in donor HSC and HPC during GVHD. Competitive transplant experiments demonstrated that autophagy-deficient cells display reduced capacity to reconstitute the hematopoietic system compared to wild-type counterparts. In a major histocompatibility complex-mismatched model of GVHD and associated cytokine dysregulation, we demonstrate that autophagy-deficient HSC and progenitors fail to establish durable hematopoiesis, leading to primary graft failure and universal transplant related mortality. Using several different models, we confirm that autophagy activity is increased in early progenitor and HSC populations in the presence of T-cell-derived inflammatory cytokines and that these HSC populations require autophagy to survive. Thus, autophagy serves as a key survival mechanism in HSC and progenitor populations after allogeneic stem cell transplant and may represent a therapeutic target to prevent graft failure during GVHD.


Asunto(s)
Autofagia , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Animales , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Ratones , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/citología , Modelos Animales de Enfermedad , Trasplante Homólogo , Rechazo de Injerto , Citocinas/metabolismo
4.
J Immunother Cancer ; 11(1)2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36634920

RESUMEN

BACKGROUND: Pixatimod is a unique activator of the Toll-like Receptor 9 pathway. This phase I trial evaluated safety, efficacy and pharmacodynamics of pixatimod and PD-1 inhibitor nivolumab in immunologically cold cancers. METHODS: 3+3 dose escalation with microsatellite stable metastatic colorectal cancer (MSS mCRC) and metastatic pancreatic ductal adenocarcinoma (mPDAC) expansion cohorts. Participants received pixatimod once weekly as a 1-hour intravenous infusion plus nivolumab every 2 weeks. Objectives included assessment of safety, antitumor activity, pharmacodynamics, and pharmacokinetic profile. RESULTS: Fifty-eight participants started treatment. The maximum tolerated dose of pixatimod was 25 mg in combination with 240 mg nivolumab, which was used in the expansion phases of the study. Twenty-one grade 3-5 treatment-related adverse events were reported in 12 participants (21%); one participant receiving 50 mg pixatimod/nivolumab had a treatment-related grade 5 AE. The grade 3/4 rate in the MSS mCRC cohort (n=33) was 12%. There were no responders in the mPDAC cohort (n=18). In the MSS mCRC cohort, 25 participants were evaluable (initial postbaseline assessment scans >6 weeks); of these, three participants had confirmed partial responses (PR) and eight had stable disease (SD) for at least 9 weeks. Clinical benefit (PR+SD) was associated with lower Pan-Immune-Inflammation Value and plasma IL-6 but increased IP-10 and IP-10/IL-8 ratio. In an MSS mCRC participant with PR as best response, increased infiltration of T cells, dendritic cells, and to a lesser extent NK cells, were evident 5 weeks post-treatment. CONCLUSIONS: Pixatimod is well tolerated at 25 mg in combination with nivolumab. The efficacy signal and pharmacodynamic changes in MSS mCRC warrants further investigation. TRIAL REGISTRATION NUMBER: NCT05061017.


Asunto(s)
Adenocarcinoma , Neoplasias Colorrectales , Humanos , Nivolumab/farmacología , Nivolumab/uso terapéutico , Receptor Toll-Like 9 , Quimiocina CXCL10 , Adenocarcinoma/patología , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Inhibidores de la Angiogénesis/uso terapéutico , Repeticiones de Microsatélite , Neoplasias Pancreáticas
6.
JCI Insight ; 1(15): e86850, 2016 09 22.
Artículo en Inglés | MEDLINE | ID: mdl-27699243

RESUMEN

Regulatory T cells (Tregs) play a crucial role in the maintenance of peripheral tolerance. Quantitative and/or qualitative defects in Tregs result in diseases such as autoimmunity, allergy, malignancy, and graft-versus-host disease (GVHD), a serious complication of allogeneic stem cell transplantation (SCT). We recently reported increased expression of autophagy-related genes (Atg) in association with enhanced survival of Tregs after SCT. Autophagy is a self-degradative process for cytosolic components that promotes cell homeostasis and survival. Here, we demonstrate that the disruption of autophagy within FoxP3+ Tregs (B6.Atg7fl/fl-FoxP3cre+ ) resulted in a profound loss of Tregs, particularly within the bone marrow (BM). This resulted in dysregulated effector T cell activation and expansion, and the development of enterocolitis and scleroderma in aged mice. We show that the BM compartment is highly enriched in TIGIT+ Tregs and that this subset is differentially depleted in the absence of autophagy. Moreover, following allogeneic SCT, recipients of grafts from B6.Atg7fl/fl-FoxP3cre+ donors exhibited reduced Treg reconstitution, exacerbated GVHD, and reduced survival compared with recipients of B6.WT-FoxP3cre+ grafts. Collectively, these data indicate that autophagy-dependent Tregs are critical for the maintenance of tolerance after SCT and that the promotion of autophagy represents an attractive immune-restorative therapeutic strategy after allogeneic SCT.


Asunto(s)
Autofagia , Enfermedad Injerto contra Huésped/inmunología , Linfocitos T Reguladores/inmunología , Animales , Médula Ósea/fisiopatología , Femenino , Trasplante de Células Madre Hematopoyéticas , Tolerancia Inmunológica , Activación de Linfocitos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL
7.
J Exp Med ; 212(8): 1303-21, 2015 Jul 27.
Artículo en Inglés | MEDLINE | ID: mdl-26169940

RESUMEN

The primacy of the gastrointestinal (GI) tract in dictating the outcome of graft-versus-host disease (GVHD) is broadly accepted; however, the mechanisms controlling this effect are poorly understood. Here, we demonstrate that GVHD markedly enhances alloantigen presentation within the mesenteric lymph nodes (mLNs), mediated by donor CD103(+)CD11b(-) dendritic cells (DCs) that migrate from the colon under the influence of CCR7. Expansion and differentiation of donor T cells specifically within the mLNs is driven by profound levels of alloantigen, IL-12, and IL-6 promoted by Toll-like receptor (TLR) and receptor for advanced glycation end products (RAGE) signals. Critically, alloantigen presentation in the mLNs imprints gut-homing integrin signatures on donor T cells, leading to their emigration into the GI tract where they mediate fulminant disease. These data identify a critical, anatomically distinct, donor DC subset that amplifies GVHD. We thus highlight multiple therapeutic targets and the ability of GVHD, once initiated by recipient antigen-presenting cells, to generate a profound, localized, and lethal feed-forward cascade of donor DC-mediated indirect alloantigen presentation and cytokine secretion within the GI tract.


Asunto(s)
Antígenos CD/metabolismo , Movimiento Celular/inmunología , Colon/citología , Células Dendríticas/metabolismo , Enfermedad Injerto contra Huésped/fisiopatología , Cadenas alfa de Integrinas/metabolismo , Ganglios Linfáticos/citología , Análisis de Varianza , Animales , Citometría de Flujo , Interleucina-12/metabolismo , Interleucina-6/metabolismo , Ganglios Linfáticos/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Transgénicos , Receptor para Productos Finales de Glicación Avanzada , Receptores CCR7/metabolismo , Receptores Inmunológicos/metabolismo , Linfocitos T/inmunología
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