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1.
J Pharmacol Exp Ther ; 371(1): 202-207, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31371481

RESUMO

Fenebrutinib (GDC-0853) is an orally administered small molecule inhibitor of Bruton's tyrosine kinase being investigated for treatment of rheumatoid arthritis in patients with inadequate responses to methotrexate (MTX). This study interrogated the potential for pharmacokinetic drug interactions between fenebrutinib and MTX. Eighteen healthy male subjects were enrolled in the study. They received a single oral dose of MTX (7.5 mg) on day 1 followed by a 13-day washout period. Subsequently, on days 15-20 the participants received 200 mg of fenebrutinib twice daily. On day 21, they received a 7.5 mg dose of MTX and a 200 mg dose of fenebrutinib under fasting conditions. The geometric mean ratios of MTX area under the plasma concentration-time curve (AUC) and C max on day 21 relative to day 1 (90% confidence interval [CI]) were 0.96 (0.88-1.04) and 1.05 (0.94-1.18), respectively. The geometric mean ratios of fenebrutinib AUC and C max for day 21 relative to day 20 (90% CI) were 1.03 (0.95-1.11) and 1.02 (0.90-1.15), respectively. The combination treatment was well tolerated, with an adverse event profile similar to that reported in other MTX trials. These results indicate that there is no clinically significant pharmacokinetic interaction between fenebrutinib and MTX.

2.
Curr Treat Options Oncol ; 20(7): 62, 2019 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-31227926

RESUMO

OPINION STATEMENT: The thymus is a key organ involved in establishing central immune tolerance. Thymic epithelial tumors (TETs) include thymomas and thymic carcinomas. Thymomas, which are histologically distinct from thymic carcinomas, lead to dysregulated thymopoiesis via decreased thymic epithelial expression of AIRE and MHC Class II, as well as via alterations in thymic architecture, thereby resulting in autoimmune complications that manifest as paraneoplastic disorders (PNDs). Although progress has been made in elucidating the mechanisms underlying thymoma-associated PNDs, there remains a great need to further define the underlying mechanisms and to identify additional immune biomarkers, such as novel antibodies (in "seronegative" cases) to facilitate diagnosis and monitoring of patients. In addition, a better understanding of the pathogenesis of PNDs could lead to improved treatment strategies for both thymomas and their immune complications. In advanced, refractory cases of TETs (both thymoma and thymic carcinoma), additional therapeutic approaches are needed. Immune checkpoint inhibitors have revolutionized the treatment of several malignancies and hold promise in the treatment of TETs; however, the risks for immune-related adverse events (especially for inducing PNDs as well as in the setting of pre-existing PNDs) underscore the need to optimize patient selection and improve clinical management before there can be widespread acceptance of checkpoint inhibitor therapy in patients with TETs.

3.
Lupus Sci Med ; 6(1): e000308, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31080631

RESUMO

Objective: The outcome of participants with nephrotic syndrome in clinical trials of lupus nephritis has not been studied in detail. Methods: Collated data from two randomised controlled trials in lupus nephritis, Lupus Nephritis Assessment of Rituximab (LUNAR) and A Study to Evaluate Ocrelizumab in Patients With Nephritis due to Systemic Lupus Erythematosus (BELONG) were analysed. Nephrotic syndrome was defined as albumin <3 g/dL and urine protein/creatinine ratio ≥3.5 g/g at start of trial. Renal response was defined as a first morning urine protein/creatinine ratio ≤0.5 g/g in addition to ≤25% increase in creatinine from trial entry assessed at week 48. Logistic regression was used to evaluate the association of nephrotic syndrome with renal response while adjusting for treatment received and ACE inhibitor or angiotensin receptor blocker use. Results: 28 (26%) participants with nephrotic syndrome achieved renal response as compared with 130 (52.5%) of those without (p<0.001). Having nephrotic syndrome at baseline significantly lowered the likelihood of achieving renal response (OR 0.32, 95 % CI 0.19 to 0.54, p<0.001). 125 (80%) participants achieved resolution of their nephrotic syndrome in a median time of 16 weeks. Conclusions: Nephrotic syndrome at baseline decreases the likelihood of renal response at 1 year. Longer clinical trials or better short-term predictors of long-term outcomes may better assess the effect of novel therapeutic approaches on subjects with nephrotic syndrome.

4.
Clin J Am Soc Nephrol ; 13(10): 1502-1509, 2018 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-30089664

RESUMO

BACKGROUND AND OBJECTIVES: Incomplete peripheral blood B cell depletion after rituximab in lupus nephritis might correlate with inability to reduce tubulointerstitial lymphoid aggregates in the kidney, which together could be responsible for inadequate response to treatment. We utilized data from the Lupus Nephritis Assessment with Rituximab (LUNAR) study to characterize the variability of peripheral blood B cell depletion after rituximab and assess its association with complete response in patients with lupus nephritis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We analyzed 68 participants treated with rituximab. Peripheral blood B cell depletion was defined as 0 cells/µl, termed "complete peripheral depletion," assessed over 78 weeks. Logistic regression was used to estimate the association between characteristics of complete peripheral depletion and complete response (defined as urine protein-to-creatinine ratio <0.5 mg/mg, and normal serum creatinine or an increase in creatinine <15%, if normal at baseline), assessed at week 78. RESULTS: A total of 53 (78%) participants achieved complete peripheral depletion (0 cells/µl) in a median time of 182 days (interquartile range, 80-339).The median duration of complete peripheral depletion was 71 days (interquartile range, 14-158). Twenty-five (47%) participants with complete peripheral depletion achieved complete response, compared with two (13%) without. Complete peripheral depletion was associated with complete response (unadjusted odds ratio [OR], 5.8; 95% confidence interval [95% CI], 1.2 to 28; P=0.03). Longer time to achieving complete peripheral depletion was associated with a lower likelihood of complete response (unadjusted OR, 0.89; 95% CI, 0.81 to 0.98; P=0.02). Complete peripheral depletion lasting >71 days (the median) was associated with complete response (unadjusted OR, 4.1; 95% CI, 1.5 to 11; P=0.008). CONCLUSIONS: There was substantial variability in peripheral blood B cell depletion in patients with lupus nephritis treated with rituximab from the LUNAR trial. Achievement of complete peripheral depletion, as well as the rapidity and duration of complete peripheral depletion, were associated with complete response at week 78. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2018_09_06_CJASNPodcast_18_10_.mp3.


Assuntos
Linfócitos B , Fatores Imunológicos/uso terapêutico , Nefrite Lúpica/sangue , Nefrite Lúpica/tratamento farmacológico , Depleção Linfocítica , Rituximab/uso terapêutico , Adulto , Feminino , Humanos , Masculino , Indução de Remissão , Resultado do Tratamento
5.
Clin Pharmacol Ther ; 103(6): 1020-1028, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29484638

RESUMO

GDC-0853 is a small molecule inhibitor of Bruton's tyrosine kinase (BTK) that is highly selective and noncovalent, leading to reversible binding. In double-blind, randomized, and placebo-controlled phase I healthy volunteer studies, GDC-0853 was well tolerated, with no dose-limiting adverse events (AEs) or serious AEs. The maximum tolerated dose was not reached during dose escalation (≤600 mg, single ascending dose (SAD) study; ≤250 mg twice daily (b.i.d.) and ≤500 mg once daily, 14-day multiple ascending dose (MAD) study). Plasma concentrations peaked 1-3 hours after oral administration and declined thereafter, with a steady-state half-life ranging from 4.2-9.9 hours. Independent assays demonstrated dose-dependent BTK target engagement. Based on pharmacokinetic/pharmacodynamic (PK/PD) simulations, a once-daily dosing regimen (e.g., 100 mg, q.d.) is expected to maintain a high level of BTK inhibition over the dosing interval. Taken together, the safety and PK/PD data support GDC-0853 evaluation in rheumatoid arthritis, lupus, and other autoimmune or inflammatory indications.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piridonas/farmacologia , Adolescente , Adulto , Área Sob a Curva , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Meia-Vida , Humanos , Masculino , Dose Máxima Tolerável , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Piperazinas/farmacocinética , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Piridonas/administração & dosagem , Piridonas/efeitos adversos , Piridonas/farmacocinética , Adulto Jovem
6.
Arthritis Rheumatol ; 68(9): 2257-62, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27111861

RESUMO

OBJECTIVE: Scleroderma is a genetically complex autoimmune disease with substantial phenotypic heterogeneity. Previous genome-wide association studies have identified common genetic variants associated with disease risk, but these studies are not designed to capture rare or potential causal variants. Our goal was to identify rare as well as common genetic variants in patients with diffuse cutaneous systemic sclerosis (dcSSc) through whole-exome sequencing (WES) in order to identify potential causal variants. METHODS: We generated WES data for 32 dcSSc patients with or without interstitial lung disease (ILD) and for 17 healthy "in-house" controls. Variants were annotated and filtered by quality, minor allele frequency, and deleterious effects on gene function. We applied a gene burden test to identify novel dcSSc and dcSSc-associated ILD candidate genes that were enriched with deleterious variants in cases compared to in-house controls as well as controls from the 1000 Genomes Project (n = 130). RESULTS: We identified 70 genes that were enriched with deleterious variants in dcSSc patients. Two of them (BANK1 and TERT) were in pathways previously implicated in SSc or ILD pathogenesis or known susceptibility loci. Newly identified genes (COL4A3, COL4A4, COL5A2, COL13A1, and COL22A1) were significantly enriched in the extracellular matrix-related pathway, which is relevant to the fibrotic features of dcSSc, and in the DNA repair pathway (XRCC4). CONCLUSION: This study demonstrates the value of WES for the identification of novel gene variants and pathways that may contribute to scleroderma risk and/or severity. The candidate genes we discovered are potential targets for in-depth functional studies.


Assuntos
Exoma/genética , Esclerodermia Difusa/genética , Idoso , Feminino , Variação Genética , Humanos , Doenças Pulmonares Intersticiais/genética , Masculino , Pessoa de Meia-Idade , Esclerodermia Difusa/complicações , Análise de Sequência de DNA
7.
Transplantation ; 95(7): 975-80, 2013 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-23545509

RESUMO

BACKGROUND: Lung disease is the leading cause of death in systemic sclerosis (SSc). The diagnosis of SSc-related lung disease (SSc-LD) is often a contraindication to lung transplantation (LT) due to concerns that extrapulmonary involvement will yield worse outcomes. We sought to evaluate posttransplantation outcomes in persons with SSc-LD with esophageal involvement compared with persons with nonconnective tissue disease-related interstitial lung disease (nCTD-ILD). METHODS: From 1998 to 2012, persons undergoing LT for SSc-LD were age and gender matched in a 2:1 fashion to controls undergoing LT for nCTD-ILD. Esophageal function was assessed by pH testing and manometry. We defined esophageal dysfunction as the presence of a DeMeester score >14 or dysmotility more severe than "mild nonspecific disorder". The primary outcome was posttransplantation survival. Secondary outcomes included freedom from bronchiolitis obliterans syndrome (fBOS) and rates of acute rejection. Survival and fBOS were estimated with Kaplan-Meier methods. Acute rejection was compared with Student's t test. RESULTS: Survival was similar in 23 persons with SSc-LD and 46 controls who underwent LT (P = 0.47). For the SSc-LD group, 1- and 5-year survival was 83% and 76% compared with 91% and 64% in the nCTD-ILD group, respectively. There were no differences in fBOS (P = 0.83). Rates of acute rejection were less in SSc-ILD (P = 0.05). Esophageal dysfunction was not associated with worse outcomes (P>0.55). CONCLUSIONS: Persons with SSc-LD appear to have similar survival and fBOS as persons transplanted for nCTD-ILD. The risk of acute rejection after transplantation may be reduced in persons with SSc-LD. Esophageal involvement does not appear to impact outcomes.


Assuntos
Doenças Pulmonares Intersticiais/cirurgia , Transplante de Pulmão , Escleroderma Sistêmico/complicações , Doença Aguda , Adulto , Idoso , Bronquiolite Obliterante/etiologia , Distribuição de Qui-Quadrado , Transtornos da Motilidade Esofágica/etiologia , Feminino , Rejeição de Enxerto/etiologia , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Doenças Pulmonares Intersticiais/etiologia , Transplante de Pulmão/efeitos adversos , Transplante de Pulmão/mortalidade , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , São Francisco , Escleroderma Sistêmico/mortalidade , Fatores de Tempo , Resultado do Tratamento
8.
J Clin Invest ; 123(5): 2037-48, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23543053

RESUMO

Increased airway smooth muscle (ASM) contractility and the development of airway hyperresponsiveness (AHR) are cardinal features of asthma, but the signaling pathways that promote these changes are poorly understood. Tyrosine phosphorylation is tightly regulated by the opposing actions of protein tyrosine kinases and phosphatases, but little is known about whether tyrosine phosphatases influence AHR. Here, we demonstrate that genetic inactivation of receptor-like protein tyrosine phosphatase J (Ptprj), which encodes CD148, protected mice from the development of increased AHR in two different asthma models. Surprisingly, CD148 deficiency minimally affected the inflammatory response to allergen, but significantly altered baseline pulmonary resistance. Mice specifically lacking CD148 in smooth muscle had decreased AHR, and the frequency of calcium oscillations in CD148-deficient ASM was substantially attenuated, suggesting that signaling pathway alterations may underlie ASM contractility. Biochemical analysis of CD148-deficient ASM revealed hyperphosphorylation of the C-terminal inhibitory tyrosine of SRC family kinases (SFKs), implicating CD148 as a critical positive regulator of SFK signaling in ASM. The effect of CD148 deficiency on ASM contractility could be mimicked by treatment of both mouse trachea and human bronchi with specific SFK inhibitors. Our studies identify CD148 and the SFKs it regulates in ASM as potential targets for the treatment of AHR.


Assuntos
Asma/patologia , Pulmão/patologia , Quinases da Família src/metabolismo , Animais , Asma/metabolismo , Brônquios/patologia , Linhagem da Célula , Feminino , Deleção de Genes , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Miócitos de Músculo Liso/citologia , Ovalbumina/metabolismo , Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/metabolismo , Transdução de Sinais , Traqueia/patologia
10.
Respir Med ; 107(2): 249-55, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23186614

RESUMO

BACKGROUND: The clinical significance of circulating autoantibodies in idiopathic pulmonary fibrosis is unclear. The objective of this study was to determine the frequency and clinical significance of circulating autoantibodies in idiopathic pulmonary fibrosis. METHODS: We measured an extensive panel of autoantibodies (including rheumatoid factor, anti-cyclic citrullinated peptide, and anti-nuclear antibodies by immunofluorescence) associated with connective tissue disease or vasculitis in a cohort of well-characterized patients with idiopathic pulmonary fibrosis (n = 67). The prevalence of circulating autoantibodies was compared between idiopathic pulmonary fibrosis patients and healthy controls (n = 52). We compared the clinical characteristics of patients with and without circulating autoantibodies, and analyzed the relationship between autoantibody positivity and transplant-free survival time. RESULTS: Positive autoantibodies were found in 22% of patients with IPF and 21% of healthy controls. There were no differences in the types of autoantibodies found between patients with idiopathic pulmonary fibrosis and healthy controls. Among patients with idiopathic pulmonary fibrosis, there were no significant differences in clinical characteristics between those with and without circulating autoantibodies. The presence of circulating autoantibodies was associated with longer transplant-free survival time on adjusted analysis, however the significance varied depending on which statistical model was used (HR 0.22-0.47, p value 0.02-0.17). CONCLUSIONS: The frequency of circulating autoantibodies in patients with idiopathic pulmonary fibrosis is no different compared to healthy controls, but may be associated with longer survival.


Assuntos
Autoanticorpos/sangue , Fibrose Pulmonar Idiopática/imunologia , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Fibrose Pulmonar Idiopática/cirurgia , Estimativa de Kaplan-Meier , Transplante de Pulmão , Masculino , Pessoa de Meia-Idade , Fenótipo , Prognóstico
11.
Int J Rheumatol ; 2011: 208219, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22013449

RESUMO

Interstitial lung disease (ILD) is a commonly encountered complication of systemic sclerosis (SSc) and accounts for a significant proportion of SSc-associated morbidity and mortality. Its pathogenesis remains poorly understood, and therapies that treat SSc ILD are suboptimal, at best. SSc ILD pathogenesis may share some common mechanisms with other fibrotic lung diseases, in which dysregulation of lung epithelium can contribute to pathologic fibrosis via recruitment or in situ generation and activation of fibroblasts. TGFß, a master regulator of fibrosis, is tightly regulated in the lung by the integrin αvß6, which is expressed at low levels on healthy alveolar epithelial cells but is highly induced in the setting of lung injury or fibrosis. Here we discuss the biology of αvß6 and present this integrin as a potentially attractive target for inhibition in the setting of SSc ILD.

12.
Nature ; 472(7344): 471-5, 2011 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-21525931

RESUMO

Innate immune cells must be able to distinguish between direct binding to microbes and detection of components shed from the surface of microbes located at a distance. Dectin-1 (also known as CLEC7A) is a pattern-recognition receptor expressed by myeloid phagocytes (macrophages, dendritic cells and neutrophils) that detects ß-glucans in fungal cell walls and triggers direct cellular antimicrobial activity, including phagocytosis and production of reactive oxygen species (ROS). In contrast to inflammatory responses stimulated upon detection of soluble ligands by other pattern-recognition receptors, such as Toll-like receptors (TLRs), these responses are only useful when a cell comes into direct contact with a microbe and must not be spuriously activated by soluble stimuli. In this study we show that, despite its ability to bind both soluble and particulate ß-glucan polymers, Dectin-1 signalling is only activated by particulate ß-glucans, which cluster the receptor in synapse-like structures from which regulatory tyrosine phosphatases CD45 and CD148 (also known as PTPRC and PTPRJ, respectively) are excluded (Supplementary Fig. 1). The 'phagocytic synapse' now provides a model mechanism by which innate immune receptors can distinguish direct microbial contact from detection of microbes at a distance, thereby initiating direct cellular antimicrobial responses only when they are required.


Assuntos
Imunidade Inata/imunologia , Sinapses Imunológicas/imunologia , Proteínas de Membrana/imunologia , Modelos Imunológicos , Proteínas do Tecido Nervoso/imunologia , Fagocitose/imunologia , Animais , Parede Celular/química , Parede Celular/imunologia , Células Cultivadas , Humanos , Lectinas Tipo C , Antígenos Comuns de Leucócito/deficiência , Antígenos Comuns de Leucócito/metabolismo , Macrófagos/imunologia , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Camundongos , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/genética , Espécies Reativas de Oxigênio/metabolismo , Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/deficiência , Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/metabolismo , Saccharomyces cerevisiae/química , Saccharomyces cerevisiae/imunologia , Transdução de Sinais/imunologia , Solubilidade , beta-Glucanas/química , beta-Glucanas/imunologia
13.
Annu Rev Pathol ; 6: 509-37, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21090968

RESUMO

Systemic sclerosis (SSc), also known as scleroderma, is a rare connective tissue disease characterized by vascular and immune dysfunction, leading to fibrosis that can damage multiple organs. Its pathogenesis is complex and poorly understood. Two major clinical subtypes are the limited and diffuse forms. Research into SSc has been hampered by its rarity, its clinical heterogeneity, and the lack of mouse models that accurately recapitulate the disease. Clinical and basic studies have yielded some mechanistic clues regarding pathogenesis. Recent insights gained through the use of microarrays have revealed distinctive subsets of SSc within and beyond the limited and diffuse subsets. In this review, we discuss potential mechanisms underlying the vascular, autoimmune, and fibrotic points of dysregulation. Proper categorization of SSc patients for research studies by use of microarrays or other biomarkers is critical, as disease heterogeneity may explain some of the inconsistencies of prior studies.


Assuntos
Escleroderma Sistêmico , Doenças Vasculares , Animais , Humanos , Escleroderma Sistêmico/etiologia , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/patologia , Doenças Vasculares/etiologia , Doenças Vasculares/imunologia , Doenças Vasculares/patologia
14.
Immunity ; 28(2): 183-96, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18249142

RESUMO

The receptor-type protein tyrosine phosphatase (RPTP) CD148 is thought to have an inhibitory function in signaling and proliferation in nonhematopoietic cells. However, its role in the immune system has not been thoroughly studied. Our analysis of CD148 loss-of-function mice showed that CD148 has a positive regulatory function in B cells and macrophages, similar to the role of CD45 as a positive regulator of Src family kinases (SFKs). Analysis of CD148 and CD45 doubly deficient B cells and macrophages revealed hyperphosphorylation of the C-terminal inhibitory tyrosine of SFKs accompanied by substantial alterations in B and myeloid lineage development and defective immunoreceptor signaling. Because these findings suggest the C-terminal tyrosine of SFKs is a common substrate for both CD148 and CD45 phosphatases and imply a level of redundancy not previously appreciated, a reassessment of the function of CD45 in the B and myeloid lineages based on prior data from the CD45-deficient mouse is warranted.


Assuntos
Linfócitos B/imunologia , Antígenos Comuns de Leucócito/metabolismo , Macrófagos/imunologia , Receptores de Antígenos de Linfócitos B/metabolismo , Quinases da Família src/metabolismo , Animais , Linfócitos B/metabolismo , Cruzamentos Genéticos , Citocinas/metabolismo , Antígenos Comuns de Leucócito/deficiência , Antígenos Comuns de Leucócito/genética , Antígenos Comuns de Leucócito/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Fagocitose , Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/deficiência , Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/genética , Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/imunologia , Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/metabolismo , Receptores de Antígenos de Linfócitos B/imunologia , Transdução de Sinais
15.
J Exp Med ; 201(6): 853-8, 2005 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-15781578

RESUMO

Granulocyte/macrophage colony-stimulating factor (GM-CSF) promotes the survival, proliferation, and differentiation of myeloid lineage cells and regulates chemotaxis and adhesion. However, mice in which the genes encoding GM-CSF (Gmcsf) or the beta common subunit of the GM-CSF receptor (betac) are inactivated display normal steady-state hematopoiesis. Here, we show that host GM-CSF signaling strongly modulates the ability of donor hematopoietic cells to radioprotect lethally irradiated mice. Although bone marrow mononuclear cells efficiently rescue Gmcsf mutant recipients, fetal liver cells and Sca1(+) lin(-/dim) marrow cells are markedly impaired. This defect is partially attributable to accessory cells that are more prevalent in bone marrow. In contrast, Gmcsf-deficient hematopoietic stem cells demonstrate normal proliferative potentials. Short-term survival is also impaired in irradiated betac mutant recipients transplanted with fetal liver or bone marrow. These data demonstrate a nonredundant function of GM-CSF in radioprotection by donor hematopoietic cells that may prove relevant in clinical transplantation.


Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos/fisiologia , Células Progenitoras Mieloides/fisiologia , Mielopoese/efeitos da radiação , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/fisiologia , Irradiação Corporal Total , Animais , Ataxina-1 , Ataxinas , Transplante de Medula Óssea , Proliferação de Células/efeitos da radiação , Separação Celular , Feminino , Feto/citologia , Feto/fisiologia , Raios gama , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Fígado/citologia , Fígado/fisiologia , Camundongos , Mielopoese/fisiologia , Proteínas do Tecido Nervoso , Proteínas Nucleares , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Transdução de Sinais/fisiologia , Transdução de Sinais/efeitos da radiação
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