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Colección Odontología Uruguay
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1.
Cell ; 185(10): 1694-1708.e19, 2022 05 12.
Artículo en Inglés | MEDLINE | ID: mdl-35447074

RESUMEN

Immunotherapy is a promising treatment for triple-negative breast cancer (TNBC), but patients relapse, highlighting the need to understand the mechanisms of resistance. We discovered that in primary breast cancer, tumor cells that resist T cell attack are quiescent. Quiescent cancer cells (QCCs) form clusters with reduced immune infiltration. They also display superior tumorigenic capacity and higher expression of chemotherapy resistance and stemness genes. We adapted single-cell RNA-sequencing with precise spatial resolution to profile infiltrating cells inside and outside the QCC niche. This transcriptomic analysis revealed hypoxia-induced programs and identified more exhausted T cells, tumor-protective fibroblasts, and dysfunctional dendritic cells inside clusters of QCCs. This uncovered differential phenotypes in infiltrating cells based on their intra-tumor location. Thus, QCCs constitute immunotherapy-resistant reservoirs by orchestrating a local hypoxic immune-suppressive milieu that blocks T cell function. Eliminating QCCs holds the promise to counteract immunotherapy resistance and prevent disease recurrence in TNBC.


Asunto(s)
Neoplasias de la Mama Triple Negativas , Humanos , Inmunosupresores/uso terapéutico , Inmunoterapia , Recurrencia Local de Neoplasia , Linfocitos T/patología , Neoplasias de la Mama Triple Negativas/patología , Microambiente Tumoral
2.
Cell ; 184(1): 3-9, 2021 01 07.
Artículo en Inglés | MEDLINE | ID: mdl-33417864

RESUMEN

2021 marks the 30th anniversary of the revelation that cyclosporin A and FK506 act in a way previously not seen-as "molecular glues" that induce neo-protein-protein associations. As a torrent of new molecular-glue probes and medicines are fueling interest in this field, I explore the arc of this story.


Asunto(s)
Productos Biológicos/farmacología , Productos Biológicos/química , Ciclosporina/farmacología , Inmunosupresores/farmacología , Tacrolimus/química , Tacrolimus/farmacología
3.
Nat Immunol ; 24(10): 1654-1670, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37667051

RESUMEN

Glioblastoma (GBM) tumors consist of multiple cell populations, including self-renewing glioblastoma stem cells (GSCs) and immunosuppressive microglia. Here we identified Kunitz-type protease inhibitor TFPI2 as a critical factor connecting these cell populations and their associated GBM hallmarks of stemness and immunosuppression. TFPI2 promotes GSC self-renewal and tumor growth via activation of the c-Jun N-terminal kinase-signal transducer and activator of transcription (STAT)3 pathway. Secreted TFPI2 interacts with its functional receptor CD51 on microglia to trigger the infiltration and immunosuppressive polarization of microglia through activation of STAT6 signaling. Inhibition of the TFPI2-CD51-STAT6 signaling axis activates T cells and synergizes with anti-PD1 therapy in GBM mouse models. In human GBM, TFPI2 correlates positively with stemness, microglia abundance, immunosuppression and poor prognosis. Our study identifies a function for TFPI2 and supports therapeutic targeting of TFPI2 as an effective strategy for GBM.


Asunto(s)
Glioblastoma , Animales , Ratones , Humanos , Glioblastoma/metabolismo , Inhibidores de Proteasas/metabolismo , Inhibidores de Proteasas/farmacología , Inhibidores de Proteasas/uso terapéutico , Microambiente Tumoral , Transducción de Señal , Proteínas Portadoras/metabolismo , Inmunosupresores/farmacología , Línea Celular Tumoral , Células Madre Neoplásicas/metabolismo
4.
Cell ; 181(1): 63-80, 2020 04 02.
Artículo en Inglés | MEDLINE | ID: mdl-32243797

RESUMEN

Autoimmune diseases are a result of the immune system being misdirected toward its host and have major and increasing unmet clinical needs. In general, present therapies are broadly acting and non-disease specific; consequently, they are associated with numerous side effects. Precise and early intervention strategies are urgently needed. We highlight the challenges, progress, and prospects in achieving these goals.


Asunto(s)
Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/terapia , Inmunosupresores/uso terapéutico , Inmunoterapia/métodos , Humanos
5.
Annu Rev Immunol ; 30: 39-68, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22136167

RESUMEN

mTOR is an evolutionarily conserved serine/threonine kinase that plays a central role in integrating environmental cues in the form of growth factors, amino acids, and energy. In the study of the immune system, mTOR is emerging as a critical regulator of immune function because of its role in sensing and integrating cues from the immune microenvironment. With the greater appreciation of cellular metabolism as an important regulator of immune cell function, mTOR is proving to be a vital link between immune function and metabolism. In this review, we discuss the ability of mTOR to direct the adaptive immune response. Specifically, we focus on the role of mTOR in promoting differentiation, activation, and function in T cells, B cells, and antigen-presenting cells.


Asunto(s)
Inmunidad , Serina-Treonina Quinasas TOR/metabolismo , Animales , Células Presentadoras de Antígenos/citología , Células Presentadoras de Antígenos/inmunología , Células Presentadoras de Antígenos/metabolismo , Linfocitos B/inmunología , Linfocitos B/metabolismo , Diferenciación Celular/inmunología , Activación Enzimática , Humanos , Inmunosupresores/farmacología , Activación de Linfocitos/inmunología , Inhibidores de Proteínas Quinasas/farmacología , Transducción de Señal , Linfocitos T/citología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Linfocitos T Reguladores/inmunología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores
6.
Annu Rev Immunol ; 30: 69-94, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22149932

RESUMEN

Much has been learned about how cells enter lymphoid tissues. But how do they leave? Sphingosine-1-phosphate (S1P) has emerged over the past decade as a central mediator of lymphocyte egress. In this review, we summarize the current understanding of how S1P promotes exit from the secondary lymphoid organs and thymus. We review what is known about additional requirements for emigration and summarize the mostly distinct requirements for exit from the bone marrow. Egress from lymphoid organs is limited during immune responses, and we examine how this regulation works. There is accumulating evidence for roles of S1P in directing immune cell behavior within lymphoid tissues. How such actions can fit together with the egress-promoting role of S1P is discussed. Finally, we examine current understanding of how FTY720, a drug that targets S1P receptors and is approved for the treatment of multiple sclerosis, causes immune suppression.


Asunto(s)
Linfocitos/inmunología , Linfocitos/metabolismo , Tejido Linfoide/inmunología , Tejido Linfoide/metabolismo , Lisofosfolípidos/metabolismo , Esfingosina/análogos & derivados , Animales , Médula Ósea/efectos de los fármacos , Médula Ósea/inmunología , Médula Ósea/metabolismo , Clorhidrato de Fingolimod , Humanos , Inmunosupresores/farmacología , Ganglios Linfáticos/efectos de los fármacos , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/metabolismo , Linfocitos/efectos de los fármacos , Tejido Linfoide/efectos de los fármacos , Lisofosfolípidos/inmunología , Modelos Biológicos , Glicoles de Propileno/farmacología , Esfingosina/inmunología , Esfingosina/metabolismo , Esfingosina/farmacología , Timo/efectos de los fármacos , Timo/inmunología , Timo/metabolismo
7.
Nat Immunol ; 22(7): 880-892, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-34099917

RESUMEN

Multidimensional single-cell analyses of T cells have fueled the debate about whether there is extensive plasticity or 'mixed' priming of helper T cell subsets in vivo. Here, we developed an experimental framework to probe the idea that the site of priming in the systemic immune compartment is a determinant of helper T cell-induced immunopathology in remote organs. By site-specific in vivo labeling of antigen-specific T cells in inguinal (i) or gut draining mesenteric (m) lymph nodes, we show that i-T cells and m-T cells isolated from the inflamed central nervous system (CNS) in a model of multiple sclerosis (MS) are distinct. i-T cells were Cxcr6+, and m-T cells expressed P2rx7. Notably, m-T cells infiltrated white matter, while i-T cells were also recruited to gray matter. Therefore, we propose that the definition of helper T cell subsets by their site of priming may guide an advanced understanding of helper T cell biology in health and disease.


Asunto(s)
Autoinmunidad , Encéfalo/inmunología , Linaje de la Célula , Encefalomielitis Autoinmune Experimental/inmunología , Intestinos/inmunología , Piel/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Traslado Adoptivo , Animales , Autoinmunidad/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Señalización del Calcio , Líquido Cefalorraquídeo/inmunología , Líquido Cefalorraquídeo/metabolismo , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/metabolismo , Clorhidrato de Fingolimod/farmacología , Perfilación de la Expresión Génica , Genes Codificadores de los Receptores de Linfocitos T , Células HEK293 , Humanos , Inmunosupresores/farmacología , Intestinos/efectos de los fármacos , Microscopía Intravital , Ratones Endogámicos C57BL , Ratones Noqueados , Microscopía Fluorescente , Esclerosis Múltiple Recurrente-Remitente/genética , Esclerosis Múltiple Recurrente-Remitente/inmunología , Esclerosis Múltiple Recurrente-Remitente/metabolismo , Fenotipo , Estudios Prospectivos , RNA-Seq , Receptores CXCR6/genética , Receptores CXCR6/metabolismo , Receptores Purinérgicos P2X7/genética , Receptores Purinérgicos P2X7/metabolismo , Análisis de la Célula Individual , Piel/efectos de los fármacos , Piel/metabolismo , Linfocitos T Colaboradores-Inductores/efectos de los fármacos , Linfocitos T Colaboradores-Inductores/metabolismo , Linfocitos T Colaboradores-Inductores/trasplante , Transcriptoma
10.
Nat Immunol ; 18(2): 196-204, 2017 02.
Artículo en Inglés | MEDLINE | ID: mdl-27941787

RESUMEN

Calcineurin is a phosphatase whose primary targets in T cells are NFAT transcription factors, and inhibition of calcineurin activity by treatment with cyclosporin A (CsA) or FK506 is a cornerstone of immunosuppressive therapies. Here we found that calcineurin was recruited to the T cell antigen receptor (TCR) signaling complex, where it reversed inhibitory phosphorylation of the tyrosine kinase Lck on Ser59 (LckS59). Loss of calcineurin activity impaired phosphorylation of Tyr493 of the tyrosine kinase ZAP-70 (ZAP-70Y493), as well as some downstream pathways in a manner consistent with signaling in cells expressing LckS59A (Lck that cannot be phosphorylated) or LckS59E (a phosphomimetic mutant). Notably, CsA inhibited integrin-LFA-1-dependent and NFAT-independent adhesion of T cells to the intercellular adhesion molecule ICAM-1, with little effect on cells expressing mutant Lck. These results provide new understanding of how widely used immunosuppressive drugs interfere with essential processes in the immune response.


Asunto(s)
Calcineurina/metabolismo , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Linfocitos T/inmunología , Proteína Tirosina Quinasa ZAP-70/metabolismo , Animales , Adhesión Celular/efectos de los fármacos , Ciclosporina/farmacología , Humanos , Inmunosupresores/farmacología , Molécula 1 de Adhesión Intercelular/metabolismo , Células Jurkat , Activación de Linfocitos/efectos de los fármacos , Antígeno-1 Asociado a Función de Linfocito/metabolismo , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/genética , Ratones , Ratones Transgénicos , Factores de Transcripción NFATC/genética , Factores de Transcripción NFATC/metabolismo , Fosforilación/efectos de los fármacos , Fosforilación/genética , Unión Proteica , Transducción de Señal , Linfocitos T/efectos de los fármacos , Tacrolimus/farmacología
11.
Cell ; 155(5): 1178-87, 2013 Nov 21.
Artículo en Inglés | MEDLINE | ID: mdl-24267896

RESUMEN

There are few substantive methods to measure the health of the immune system, and the connection between immune strength and the viral component of the microbiome is poorly understood. Organ transplant recipients are treated with posttransplant therapies that combine immunosuppressive and antiviral drugs, offering a window into the effects of immune modulation on the virome. We used sequencing of cell-free DNA in plasma to investigate drug-virome interactions in a cohort of organ transplant recipients (656 samples, 96 patients) and find that antivirals and immunosuppressants strongly affect the structure of the virome in plasma. We observe marked virome compositional dynamics at the onset of the therapy and find that the total viral load increases with immunosuppression, whereas the bacterial component of the microbiome remains largely unaffected. The data provide insight into the relationship between the human virome, the state of the immune system, and the effects of pharmacological treatment and offer a potential application of the virome state to predict immunocompetence.


Asunto(s)
Antivirales/uso terapéutico , Sangre/virología , Trasplante de Corazón , Inmunosupresores/uso terapéutico , Trasplante de Pulmón , Virus/aislamiento & purificación , Adulto , Profilaxis Antibiótica , Sangre/microbiología , Niño , ADN/sangre , ADN/genética , Humanos , Virus/clasificación
12.
Immunol Rev ; 321(1): 152-168, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38063042

RESUMEN

Glioma, the predominant form of central nervous system (CNS) malignancies, presents a significant challenge due to its high prevalence and low 5-year survival rate. The efficacy of current treatment methods is limited by the presence of the blood-brain barrier, the immunosuppressive microenvironment, and other factors. Immunotherapy has emerged as a promising approach, as it can overcome the blood-brain barrier. A tumor's immune privilege, which is induced by an immunosuppressive environment, constricts immunotherapy's clinical impact in glioma. Pyroptosis, a programmed cell death mechanism facilitated by gasdermins, plays a significant role in the management of glioma. Its ability to initiate and regulate tumor occurrence, progression, and metastasis is well-established. However, it is crucial to note that uncontrolled or excessive cell death can result in tissue damage, acute inflammation, and cytokine release syndrome, thereby potentially promoting tumor advancement or recurrence. This paper aims to elucidate the molecular pathways involved in pyroptosis and subsequently discuss its induction in cancer therapy. In addition, the current treatment methods of glioma and the use of pyroptosis in these treatments are introduced. It is hoped to provide more ideas for the treatment of glioma.


Asunto(s)
Glioma , Piroptosis , Humanos , Glioma/terapia , Apoptosis , Muerte Celular , Inmunoterapia , Inmunosupresores , Microambiente Tumoral
13.
Immunol Rev ; 325(1): 107-130, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38864582

RESUMEN

Autoimmune (or rheumatic) diseases are increasing in prevalence but selecting the best therapy for each patient proceeds in trial-and-error fashion. This strategy can lead to ineffective therapy resulting in irreversible damage and suffering; thus, there is a need to bring the promise of precision medicine to patients with autoimmune disease. While host factors partially determine the therapeutic response to immunosuppressive drugs, these are not routinely used to tailor therapy. Thus, non-host factors likely contribute. Here, we consider the impact of the human gut microbiome in the treatment of autoimmunity. We propose that the gut microbiome can be manipulated to improve therapy and to derive greater benefit from existing therapies. We focus on the mechanisms by which the human gut microbiome impacts treatment response, provide a framework to interrogate these mechanisms, review a case study of a widely-used anti-rheumatic drug, and discuss challenges with studying multiple complex systems: the microbiome, the human immune system, and autoimmune disease. We consider open questions that remain in the field and speculate on the future of drug-microbiome-autoimmune disease interactions. Finally, we present a blue-sky vision for how the microbiome can be used to bring the promise of precision medicine to patients with rheumatic disease.


Asunto(s)
Enfermedades Autoinmunes , Microbioma Gastrointestinal , Medicina de Precisión , Humanos , Microbioma Gastrointestinal/inmunología , Enfermedades Autoinmunes/terapia , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/microbiología , Animales , Autoinmunidad , Inmunosupresores/uso terapéutico
14.
N Engl J Med ; 390(1): 9-19, 2024 Jan 04.
Artículo en Inglés | MEDLINE | ID: mdl-37888915

RESUMEN

BACKGROUND: Among patients with chronic limb-threatening ischemia (CLTI) and infrapopliteal artery disease, angioplasty has been associated with frequent reintervention and adverse limb outcomes from restenosis. The effect of the use of drug-eluting resorbable scaffolds on these outcomes remains unknown. METHODS: In this multicenter, randomized, controlled trial, 261 patients with CLTI and infrapopliteal artery disease were randomly assigned in a 2:1 ratio to receive treatment with an everolimus-eluting resorbable scaffold or angioplasty. The primary efficacy end point was freedom from the following events at 1 year: amputation above the ankle of the target limb, occlusion of the target vessel, clinically driven revascularization of the target lesion, and binary restenosis of the target lesion. The primary safety end point was freedom from major adverse limb events at 6 months and from perioperative death. RESULTS: The primary efficacy end point was observed (i.e., no events occurred) in 135 of 173 patients in the scaffold group and 48 of 88 patients in the angioplasty group (Kaplan-Meier estimate, 74% vs. 44%; absolute difference, 30 percentage points; 95% confidence interval [CI], 15 to 46; one-sided P<0.001 for superiority). The primary safety end point was observed in 165 of 170 patients in the scaffold group and 90 of 90 patients in the angioplasty group (absolute difference, -3 percentage points; 95% CI, -6 to 0; one-sided P<0.001 for noninferiority). Serious adverse events related to the index procedure occurred in 2% of the patients in the scaffold group and 3% of those in the angioplasty group. CONCLUSIONS: Among patients with CLTI due to infrapopliteal artery disease, the use of an everolimus-eluting resorbable scaffold was superior to angioplasty with respect to the primary efficacy end point. (Funded by Abbott; LIFE-BTK ClinicalTrials.gov number, NCT04227899.).


Asunto(s)
Angioplastia , Implantación de Prótesis Vascular , Isquemia Crónica que Amenaza las Extremidades , Stents Liberadores de Fármacos , Enfermedad Arterial Periférica , Arteria Poplítea , Humanos , Implantes Absorbibles , Angioplastia/efectos adversos , Angioplastia/métodos , Angioplastia de Balón/efectos adversos , Angioplastia de Balón/métodos , Implantación de Prótesis Vascular/métodos , Enfermedad Crónica , Isquemia Crónica que Amenaza las Extremidades/etiología , Isquemia Crónica que Amenaza las Extremidades/cirugía , Everolimus/administración & dosificación , Everolimus/efectos adversos , Everolimus/uso terapéutico , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Isquemia/tratamiento farmacológico , Isquemia/etiología , Isquemia/cirugía , Enfermedad Arterial Periférica/complicaciones , Enfermedad Arterial Periférica/tratamiento farmacológico , Enfermedad Arterial Periférica/cirugía , Arteria Poplítea/cirugía , Andamios del Tejido , Resultado del Tratamiento
15.
16.
Trends Immunol ; 45(1): 48-61, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-38123369

RESUMEN

In the quest for more precise and effective organ transplantation therapies, chimeric antigen receptor (CAR) regulatory T cell (Treg) therapies represent a potential cutting-edge advance. This review comprehensively analyses CAR Tregs and how they may address important drawbacks of polyclonal Tregs and conventional immunosuppressants. We examine a growing body of preclinical findings of CAR Treg therapy in transplantation, discuss CAR Treg design specifics, and explore established and attractive new targets in transplantation. In addition, we explore present impediments where future studies will be necessary to determine the efficacy of CAR Tregs in reshaping alloimmune responses and transplant microenvironments to reduce reliance on chemical immunosuppressants. Overall, ongoing studies and trials are crucial for understanding the full scope of CAR Treg therapy in transplantation.


Asunto(s)
Trasplante de Órganos , Receptores Quiméricos de Antígenos , Humanos , Inmunoterapia Adoptiva , Inmunosupresores , Linfocitos T Reguladores , Receptores de Antígenos de Linfocitos T
17.
Cell ; 150(6): 1096-9, 2012 Sep 14.
Artículo en Inglés | MEDLINE | ID: mdl-22980971

RESUMEN

The 2012 Lasker-DeBakey Clinical Medical Research Award will be conferred on Thomas Starzl of the University of Pittsburgh School of Medicine in Pittsburgh, Pennsylvania, USA and Roy Calne of the University of Cambridge in Cambridge, UK. They are recognized for pioneering the development of liver transplantation, an intervention that saves 20,000 lives world-wide each year.


Asunto(s)
Distinciones y Premios , Trasplante de Hígado/historia , Historia del Siglo XX , Humanos , Inmunosupresores/uso terapéutico , Hígado/fisiología , Fallo Hepático/terapia , Trasplante de Hígado/inmunología , Obtención de Tejidos y Órganos , Reino Unido , Estados Unidos
18.
Pharmacol Rev ; 76(6): 1133-1158, 2024 Oct 16.
Artículo en Inglés | MEDLINE | ID: mdl-39406508

RESUMEN

Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS), with a putative autoimmune origin and complex pathogenesis. Modification of the natural history of MS by reducing relapses and slowing disability accumulation was first attained in the 1990 s with the development of the first-generation disease-modifying therapies. Glatiramer acetate (GA), a copolymer of L-alanine, L-lysine, L-glutamic acid, and L-tyrosine, was discovered due to its ability to suppress the animal model of MS, experimental autoimmune encephalomyelitis. Extensive clinical trials and long-term assessments established the efficacy and the safety of GA. Furthermore, studies of the therapeutic processes induced by GA in animal models and in MS patients indicate that GA affects various levels of the innate and the adaptive immune response, generating deviation from proinflammatory to anti-inflammatory pathways. This includes competition for binding to antigen presenting cells; driving dendritic cells, monocytes, and B-cells toward anti-inflammatory responses; and stimulating T-helper 2 and T-regulatory cells. The immune cells stimulated by GA reach the CNS and secrete in situ anti-inflammatory cytokines alleviating the pathological processes. Furthermore, cumulative findings reveal that in addition to its immunomodulatory effect, GA promotes neuroprotective repair processes such as neurotrophic factors secretion, remyelination, and neurogenesis. This review aims to provide an overview of MS pathology diagnosis and treatment as well as the diverse mechanism of action of GA. SIGNIFICANCE STATEMENT: Understanding the complex MS immune pathogenesis provided multiple targets for therapeutic intervention, resulting in a plethora of agents, with various mechanisms of action, efficacy, and safety profiles. However, promoting repair beyond the body's limited spontaneous extent is still a major challenge. GA, one of the first approved disease-modifying therapies, induces diverse immunomodulatory effects. Furthermore, GA treatment results in elevated neurotrophic factors secretion, remyelination and neurogenesis, supporting the notion that immunomodulatory treatment can support in situ a growth-promoting and repair environment.


Asunto(s)
Acetato de Glatiramer , Esclerosis Múltiple , Acetato de Glatiramer/farmacología , Acetato de Glatiramer/uso terapéutico , Humanos , Animales , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/inmunología , Inmunomodulación/efectos de los fármacos , Inmunosupresores/farmacología , Inmunosupresores/uso terapéutico , Agentes Inmunomoduladores/farmacología , Agentes Inmunomoduladores/uso terapéutico
19.
Nat Immunol ; 15(8): 749-757, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24973821

RESUMEN

Interleukin 15 (IL-15) controls both the homeostasis and the peripheral activation of natural killer (NK) cells. The molecular basis for this duality of action remains unknown. Here we found that the metabolic checkpoint kinase mTOR was activated and boosted bioenergetic metabolism after exposure of NK cells to high concentrations of IL-15, whereas low doses of IL-15 triggered only phosphorylation of the transcription factor STAT5. mTOR stimulated the growth and nutrient uptake of NK cells and positively fed back on the receptor for IL-15. This process was essential for sustaining NK cell proliferation during development and the acquisition of cytolytic potential during inflammation or viral infection. The mTORC1 inhibitor rapamycin inhibited NK cell cytotoxicity both in mice and humans; this probably contributes to the immunosuppressive activity of this drug in different clinical settings.


Asunto(s)
Interleucina-15/inmunología , Células Asesinas Naturales/inmunología , Activación de Linfocitos/inmunología , Serina-Treonina Quinasas TOR/inmunología , Animales , Proliferación Celular , Células Cultivadas , Infecciones por Herpesviridae/inmunología , Humanos , Inmunosupresores/farmacología , Inflamación/inmunología , Subtipo H1N1 del Virus de la Influenza A/inmunología , Células Asesinas Naturales/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina , Diana Mecanicista del Complejo 2 de la Rapamicina , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Complejos Multiproteicos/antagonistas & inhibidores , Complejos Multiproteicos/genética , Complejos Multiproteicos/inmunología , Muromegalovirus/inmunología , Infecciones por Orthomyxoviridae/inmunología , Poli I-C/inmunología , Factor de Transcripción STAT5/metabolismo , Transducción de Señal/inmunología , Sirolimus/farmacología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/genética
20.
Blood ; 144(17): 1834-1845, 2024 Oct 24.
Artículo en Inglés | MEDLINE | ID: mdl-39028876

RESUMEN

ABSTRACT: Abatacept plus calcineurin inhibitors/methotrexate (CNI/MTX) is the first US Food and Drug Administration (FDA)-approved regimen for acute graft-versus-host disease (aGVHD) prophylaxis during unrelated-donor hematopoietic cell transplantation (URD-HCT). Using Center for International Blood and Marrow Transplant Research data, we investigated its impact in patients receiving 7/8 HLA-mismatched unrelated donor (MMUD) or 8/8 HLA-matched unrelated donor (MUD) URD-HCT between 2011 and 2018. Primary outcomes included day-180, 1-year, and 2-year overall survival (OS) and relapse-free survival (RFS) for abatacept + CNI/MTX vs CNI/MTX, CNI/MTX + antithymocyte globulin (ATG), and posttransplant cyclophosphamide-based prophylaxis (PT-Cy). For 7/8 MMUDs, day-180 OS (primary end point supporting FDA approval) was significantly higher for abatacept + CNI/MTX vs CNI/MTX (98% vs 75%; P = .0028). Two-year RFS was significantly higher for abatacept + CNI/MTX vs CNI/MTX (74% vs 49%; P = .0098) and CNI/MTX + ATG (77% vs 35%; P = .0002), and similar vs PT-Cy (72% vs 56%; P = .1058). For 8/8 MUDs, 2-year RFS for abatacept + CNI/MTX was numerically higher vs CNI/MTX (63% vs 52%; P = .1497), with an improved hazard ratio (HR) of 0.46 (0.25-0.86), and vs CNI/MTX + ATG (66% vs 55%; P = .1193; HR, 0.39 [0.21-0.73]), and was similar vs PT-Cy (68% vs 57%; P = .2356; HR, 0.54 [0.26-1.11]). For 7/8 MMUD and 8/8 MUD recipients, abatacept + CNI/MTX prophylaxis improved survival outcomes vs CNI/MTX and CNI/MTX + ATG; outcomes were similar to PT-Cy-based regimens. Abatacept + CNI/MTX may facilitate unrelated donor pool expansion for HCT.


Asunto(s)
Abatacept , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Donante no Emparentado , Humanos , Enfermedad Injerto contra Huésped/prevención & control , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/mortalidad , Abatacept/uso terapéutico , Abatacept/administración & dosificación , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Femenino , Persona de Mediana Edad , Masculino , Adulto , Anciano , Metotrexato/uso terapéutico , Metotrexato/administración & dosificación , Inmunosupresores/uso terapéutico , Adulto Joven , Enfermedad Aguda , Suero Antilinfocítico/uso terapéutico , Suero Antilinfocítico/administración & dosificación
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