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1.
Cell Death Differ ; 26(8): 1516-1530, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30420758

RESUMO

Allogeneic hematopoietic stem cell transplantation (alloSCT) is used to treat over 15,000 patients with acute myeloid leukemia (AML) per year. Donor graft-versus-leukemia (GVL) effect can prevent AML relapse; however, alloSCT is limited by significant toxicity related to conditioning intensity, immunosuppression, opportunistic infections, and graft-versus-host disease (GVHD). Reducing the intensity of conditioning regimens prior to alloSCT has improved their tolerability, but does not alter the pattern of GVHD and has been associated with increased rates of graft rejection and relapse. Here, using a murine pre-clinical model, we describe a novel recipient conditioning approach combining reduced intensity conditioning with either genetic or pharmacological inhibition of NK cell numbers that permits efficient donor engraftment and promotes GVL without inducing GVHD. We show that NK cell-specific deletion of Bcl2 or Mcl1 in mice, or pharmacological inhibition of BCL2 impairs radio-resistant NK cell-mediated rejection of allogeneic engraftment and allows reduction of conditioning intensity below that associated with GVHD priming. The combination of reduced intensity conditioning and NK cell targeting in mice allowed successful donor T cell engraftment and protective immunity against AML while avoiding GVHD. These findings suggest that reduced conditioning in combination with targeted therapies against recipient NK cells may allow the delivery of effective alloSCT against AML while reducing the toxicities associated with more intensive conditioning including GVHD.


Assuntos
Antineoplásicos/farmacologia , Transplante de Medula Óssea , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Células Matadoras Naturais/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Sulfonamidas/farmacologia , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Diferenciação Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Células Matadoras Naturais/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/administração & dosagem , Transplante Homólogo
2.
eNeuro ; 3(1)2016.
Artigo em Inglês | MEDLINE | ID: mdl-27022620

RESUMO

Type-1 interferons (IFNs) are pleiotropic cytokines that signal through the type-1 IFN receptor (IFNAR1). Recent literature has implicated the type-1 IFNs in disorders of the CNS. In this study, we have investigated the role of type-1 IFNs in neuroinflammation following traumatic brain injury (TBI). Using a controlled cortical impact model, TBI was induced in 8- to 10-week-old male C57BL/6J WT and IFNAR1(-/-) mice and brains were excised to study infarct volume, inflammatory mediator release via quantitative PCR analysis and immune cell profile via immunohistochemistry. IFNAR1(-/-) mice displayed smaller infarcts compared with WT mice after TBI. IFNAR1(-/-) mice exhibited an altered anti-inflammatory environment compared with WT mice, with significantly reduced levels of the proinflammatory mediators TNFα, IL-1ß and IL-6, an up-regulation of the anti-inflammatory mediator IL-10 and an increased activation of resident and peripheral immune cells after TBI. WT mice injected intravenously with an anti-IFNAR1 blocking monoclonal antibody (MAR1) 1 h before, 30 min after or 30 min and 2 d after TBI displayed significantly improved histological and behavioral outcome. Bone marrow chimeras demonstrated that the hematopoietic cells are a peripheral source of type-1 IFNs that drives neuroinflammation and a worsened TBI outcome. Type-1 IFN mRNA levels were confirmed to be significantly altered in human postmortem TBI brains. Together, these data demonstrate that type-1 IFN signaling is a critical pathway in the progression of neuroinflammation and presents a viable therapeutic target for the treatment of TBI.


Assuntos
Lesões Encefálicas/metabolismo , Encefalite/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Interferon Tipo I/metabolismo , Receptor de Interferon alfa e beta/metabolismo , Animais , Anticorpos Monoclonais/administração & dosagem , Astrócitos/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Lesões Encefálicas/complicações , Lesões Encefálicas/patologia , Encefalite/etiologia , Humanos , Mediadores da Inflamação/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/metabolismo , RNA Mensageiro/metabolismo , Receptor de Interferon alfa e beta/antagonistas & inibidores , Receptor de Interferon alfa e beta/genética , Receptor de Interferon alfa e beta/imunologia , Transdução de Sinais
3.
Blood ; 126(26): 2863-70, 2015 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-26450986

RESUMO

We used an N-ethyl-N-nitrosurea-based forward genetic screen in mice to identify new genes and alleles that regulate erythropoiesis. Here, we describe a mouse line expressing an activated form of the K-Cl cotransporter Slc12a4 (Kcc1), which results in a semi-dominant microcytosis of red cells. A missense mutation from methionine to lysine in the cytoplasmic tail of Kcc1 impairs phosphorylation of adjacent threonines required for inhibiting cotransporter activity. We bred Kcc1(M935K) mutant mice with a humanized mouse model of sickle cell disease to directly explore the relevance of the reported increase in KCC activity in disease pathogenesis. We show that a single mutant allele of Kcc1 induces widespread sickling and tissue damage, leading to premature death. This mouse model reveals important new insights into the regulation of K-Cl cotransporters and provides in vivo evidence that increased KCC activity worsened end-organ damage and diminished survival in sickle cell disease.


Assuntos
Anemia Falciforme/genética , Anemia Falciforme/patologia , Simportadores/genética , Animais , Modelos Animais de Doenças , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Mutação de Sentido Incorreto , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Cotransportadores de K e Cl-
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