RESUMO
Deletions of chromosome 17p (del17p) that span the TP53 gene are associated with poor outcome in multiple myeloma (MM), but the prognostic value of del17p cancer clonal fraction (CCF) remains unclear. We applied uniform cytogenetic assessments in a large cohort of newly diagnosed MM (NDMM) patients carrying varying levels of del17p. Incremental CCF change was associated with shorter survival, and a robust CCF threshold of 0.55 was established in discovery and replication data sets. After stratification on the 0.55-CCF threshold, high-risk patients had statistically significantly poorer outcomes compared with low-risk patients (median progression-free survival [PFS] and overall survival [OS], 14 and 32 vs 23.1 and 76.2 months, respectively). Analyses of a third data set comprising whole-exome sequencing data from NDMM patients identified presence of TP53 deletions/mutations as a necessary requirement for high-risk stratification in addition to exceeding the del17p CCF threshold. Meta-analysis conducted across 3 data sets confirmed the robustness of the CCF threshold for PFS and OS. Our analyses demonstrate the feasibility of fluorescence in situ hybridization- and sequencing-based methods to identify TP53 deletions, estimate CCF, and establish that both CCF threshold of 0.55 and presence of TP53 deletion are necessary to identify del17p-carrying NDMM patients with poor prognosis.
Assuntos
Biomarcadores Tumorais/genética , Deleção Cromossômica , Cromossomos Humanos Par 17/genética , Evolução Clonal , Mieloma Múltiplo/genética , Mieloma Múltiplo/mortalidade , Proteína Supressora de Tumor p53/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mieloma Múltiplo/patologia , Mutação , Prognóstico , Taxa de SobrevidaRESUMO
The recommended management of inhalational anthrax, a high-priority bioterrorist threat, includes antibiotics and antitoxins. Obiltoxaximab, a chimeric monoclonal antibody against anthrax protective antigen (PA), is licensed under the U.S. Food and Drug Administration's (FDA's) Animal Rule for the treatment of inhalational anthrax. Because of spore latency, disease reemergence after treatment cessation is a concern, and there is a need to understand the development of endogenous protective immune responses following antitoxin-containing anthrax treatment regimens. Here, acquired protective immunity was examined in New Zealand White (NZW) rabbits challenged with a targeted lethal dose of Bacillus anthracis spores and treated with antibiotics, obiltoxaximab, or a combination of both. Survivors of the primary challenge were rechallenged 9 months later and monitored for survival. Survival rates after primary and rechallenge for controls and animals treated with obiltoxaximab, levofloxacin, or a combination of both were 0, 65, 100, and 95%, and 0, 100, 95, and 89%, respectively. All surviving immune animals had circulating antibodies to PA and serum toxin-neutralizing titers prior to rechallenge. Following rechallenge, systemic bacteremia and toxemia were not detected in most animals, and the levels of circulating anti-PA IgG titers increased starting at 5 days postrechallenge. We conclude that treatment with obiltoxaximab, alone or combined with antibiotics, significantly improves the survival of rabbits that received a lethal inhalation B. anthracis spore challenge dose and does not interfere with the development of immunity. Survivors of primary challenge are protected against reexposure, have rare incidents of systemic bacteremia and toxemia, and have evidence of an anamnestic response.
Assuntos
Antraz , Antibacterianos , Anticorpos Monoclonais , Antitoxinas , Bacillus anthracis , Levofloxacino , Infecções Respiratórias , Esporos Bacterianos , Animais , Feminino , Masculino , Coelhos , Antraz/imunologia , Antraz/microbiologia , Antraz/mortalidade , Antraz/prevenção & controle , Antibacterianos/farmacologia , Anticorpos Antibacterianos/biossíntese , Anticorpos Monoclonais/farmacologia , Antígenos de Bactérias/sangue , Antígenos de Bactérias/imunologia , Antitoxinas/farmacologia , Bacillus anthracis/efeitos dos fármacos , Bacillus anthracis/imunologia , Bacillus anthracis/patogenicidade , Toxinas Bacterianas/antagonistas & inibidores , Toxinas Bacterianas/sangue , Toxinas Bacterianas/imunologia , Quimioterapia Combinada , Imunização Passiva/métodos , Imunoglobulina G/biossíntese , Memória Imunológica/efeitos dos fármacos , Levofloxacino/farmacologia , Distribuição Aleatória , Infecções Respiratórias/imunologia , Infecções Respiratórias/microbiologia , Infecções Respiratórias/mortalidade , Infecções Respiratórias/prevenção & controle , Esporos Bacterianos/efeitos dos fármacos , Esporos Bacterianos/imunologia , Esporos Bacterianos/patogenicidade , Análise de SobrevidaRESUMO
The Centers for Disease Control and Prevention recommend adjunctive antitoxins when systemic anthrax is suspected. Obiltoxaximab, a monoclonal antibody against protective antigen (PA), is approved for treatment of inhalational anthrax in combination with antibiotics and for prophylaxis when alternative therapies are not available. The impact of toxin neutralization with obiltoxaximab during pre- and postexposure prophylaxis was explored, and efficacy results that supported the prophylaxis indication are presented here. New Zealand White rabbits and cynomolgus macaques received obiltoxaximab as a single intramuscular or intravenous dose of 2 to 16 mg/kg of body weight at various times relative to Bacillus anthracis aerosol spore challenge. The primary endpoint was survival, and effect of treatment timing was explored. In rabbits, obiltoxaximab administration 9 h postchallenge singly or combined with a 5-day levofloxacin regimen protected 89% to 100% of animals compared to 33% with levofloxacin monotherapy. In cynomolgus macaques, a single intramuscular dose of 16 mg/kg obiltoxaximab led to 100% survival when given 1 to 3 days preexposure and 83% to 100% survival when given 18 to 24 h postexposure and prior to systemic bacteremia onset. Obiltoxaximab administration after bacteremia onset resulted in lower (25% to 50%) survival rates reflective of treatment setting. Prophylactic administration of obiltoxaximab before spore challenge or to spore-challenged animals before systemic bacterial dissemination is efficacious in promoting survival, ameliorating toxemia, and inhibiting bacterial spread to the periphery.
Assuntos
Antraz/mortalidade , Antraz/prevenção & controle , Anticorpos Monoclonais/farmacologia , Antitoxinas/farmacologia , Bacillus anthracis/patogenicidade , Infecções Respiratórias/mortalidade , Infecções Respiratórias/prevenção & controle , Animais , Antraz/tratamento farmacológico , Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/farmacocinética , Antitoxinas/administração & dosagem , Bacillus anthracis/efeitos dos fármacos , Bacteriemia/tratamento farmacológico , Bacteriemia/microbiologia , Modelos Animais de Doenças , Feminino , Injeções Intramusculares , Injeções Intravenosas , Macaca fascicularis , Masculino , Profilaxia Pós-Exposição , Profilaxia Pré-Exposição , Coelhos , Infecções Respiratórias/tratamento farmacológico , Taxa de SobrevidaRESUMO
Inhalational anthrax has high mortality even with antibiotic treatment, and antitoxins are now recommended as an adjunct to standard antimicrobial regimens. The efficacy of obiltoxaximab, a monoclonal antibody against anthrax protective antigen (PA), was examined in multiple studies conducted in two animal models of inhalational anthrax. A single intravenous bolus of 1 to 32 mg/kg of body weight obiltoxaximab or placebo was administered to New Zealand White rabbits (two studies) and cynomolgus macaques (4 studies) at disease onset (significant body temperature increase or detection of serum PA) following lethal challenge with aerosolized Bacillus anthracis spores. The primary endpoint was survival. The relationship between efficacy and disease severity, defined by pretreatment bacteremia and toxemia levels, was explored. In rabbits, single doses of 1 to 16 mg/kg obiltoxaximab led to 17 to 93% survival. In two studies, survival following 16 mg/kg obiltoxaximab was 93% and 62% compared to 0% and 0% for placebo (P = 0.0010 and P = 0.0013, respectively). Across four macaque studies, survival was 6.3% to 78.6% following 4 to 32 mg/kg obiltoxaximab. In two macaque studies, 16 mg/kg obiltoxaximab reduced toxemia and led to survival rates of 31%, 35%, and 47% versus 0%, 0%, and 6.3% with placebo (P = 0.0085, P = 0.0053, P = 0.0068). Pretreatment bacteremia and toxemia levels inversely correlated with survival. Overall, obiltoxaximab monotherapy neutralized PA and increased survival across the range of disease severity, indicating clinical benefit of toxin neutralization with obiltoxaximab in both early and late stages of inhalational anthrax.
Assuntos
Antraz/tratamento farmacológico , Antibacterianos/farmacologia , Anticorpos Monoclonais/farmacologia , Antitoxinas/farmacologia , Infecções Respiratórias/tratamento farmacológico , Animais , Antraz/etiologia , Antraz/mortalidade , Antibacterianos/farmacocinética , Anticorpos Monoclonais/farmacocinética , Feminino , Macaca fascicularis , Masculino , Coelhos , Infecções Respiratórias/etiologia , Infecções Respiratórias/mortalidade , Taxa de Sobrevida , Resultado do TratamentoRESUMO
Infection of mice with Listeria monocytogenes induces a robust innate inflammatory response that restricts bacterial growth in the liver and spleen prior to the development of protective T cell responses. Ly6C(hi) monocytes contribute to the innate immune response following L. monocytogenes infection and in their absence, mice rapidly succumb to infection. Emigration of Ly6C(hi) monocytes from the bone marrow into the circulation is the first step in their recruitment to sites of L. monocytogenes infection and is triggered by CCL2- and CCL7-mediated stimulation of CCR2 chemokine receptors on monocytes. CCL2 expression by mesenchymal stem cells in the bone marrow, in response to TLR stimulation, drives monocyte emigration from cellular compartments into vascular sinuses of the bone marrow. In addition to TLR ligands, type I interferon-mediated signals can also drive monocyte emigration from the bone marrow during L. monocytogenes infection. Once Ly6C(hi) monocytes enter the bloodstream, trafficking to sites of infection in the liver and spleen is CCR2 independent. In the liver, CD11b on the monocyte and ICAM-1 on the surface of endothelial cells target Ly6C(hi) monocytes to foci of L. monocytogenes infection. At the site of infection, Ly6C(hi) monocytes undergo MyD88-dependent differentiation into TNF and iNOS-producing dendritic cells (TipDCs) and express MHC class II, B7.1, and CD40 on their cell surface. How TipDCs mediate bacterial clearance during early L. monocytogenes infection remains an active area of investigation.
Assuntos
Citocinas/imunologia , Listeria monocytogenes/imunologia , Listeriose/imunologia , Monócitos/imunologia , Animais , Medula Óssea/imunologia , Diferenciação Celular , Movimento Celular , Modelos Animais de Doenças , Humanos , Listeria monocytogenes/patogenicidade , Camundongos , Monócitos/microbiologia , Transdução de SinaisRESUMO
Inflammatory (Ly6C(hi) CCR2+) monocytes provide defense against infections but also contribute to autoimmune diseases and atherosclerosis. Monocytes originate from bone marrow and their entry into the bloodstream requires stimulation of CCR2 chemokine receptor by monocyte chemotactic protein-1 (MCP1). How monocyte emigration from bone marrow is triggered by remote infections remains unclear. We demonstrated that low concentrations of Toll-like receptor (TLR) ligands in the bloodstream drive CCR2-dependent emigration of monocytes from bone marrow. Bone marrow mesenchymal stem cells (MSCs) and their progeny, including CXC chemokine ligand (CXCL)12-abundant reticular (CAR) cells, rapidly expressed MCP1 in response to circulating TLR ligands or bacterial infection and induced monocyte trafficking into the bloodstream. Targeted deletion of MCP1 from MSCs impaired monocyte emigration from bone marrow. Our findings suggest that bone marrow MSCs and CAR cells respond to circulating microbial molecules and regulate bloodstream monocyte frequencies by secreting MCP1 in proximity to bone marrow vascular sinuses.
Assuntos
Medula Óssea/imunologia , Movimento Celular , Células-Tronco Mesenquimais/imunologia , Monócitos/citologia , Monócitos/imunologia , Receptores Toll-Like/imunologia , Animais , Ligantes , Lipopolissacarídeos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Receptores CCR2/imunologiaRESUMO
CCR2-mediated recruitment of Ly6C(high) monocytes is essential for defense against a range of microbial pathogens. Although our understanding of monocyte trafficking to inflammatory sites is increasing, how innate immune inflammation influences monocyte development and maturation during microbial infection remains undefined. Herein, we demonstrate that infection with the intracellular bacterial pathogen Listeria monocytogenes specifically and selectively promotes monopoiesis. Systemic infection with virulent L. monocytogenes induces marked proliferation of bone marrow monocyte precursors and results in depletion of myeloid progenitors. Proliferation of monocyte precursors correlates with the intensity of systemic infection and is unaffected by the density of monocytes in the bone marrow. Although MyD88/Trif-mediated signaling is not required for early emigration of the mature monocyte population from the bone marrow, replenishment of monocyte populations depends on MyD88/Trif. Our studies demonstrate that TLR-mediated signals play an essential role in the maintenance of monocyte homeostasis during systemic bacterial infection.
Assuntos
Proteínas Adaptadoras de Transporte Vesicular/fisiologia , Infecções Bacterianas/imunologia , Proliferação de Células , Células Precursoras de Monócitos e Macrófagos/citologia , Monócitos/citologia , Fator 88 de Diferenciação Mieloide/fisiologia , Animais , Células da Medula Óssea/citologia , Linhagem da Célula , Quimiotaxia de Leucócito , Homeostase , Listeria monocytogenes , Listeriose/imunologia , Camundongos , Camundongos Knockout , Monócitos/imunologia , Fator 88 de Diferenciação Mieloide/deficiência , Receptores Toll-Like/metabolismoRESUMO
Aspergillus fumigatus is an environmental fungus that causes life-threatening infections in neutropenic patients. In the absence of intact innate immunity, inhaled A. fumigatus spores (conidia) germinate in the lung, forming hyphae that invade blood vessels and disseminate to other tissues. Although macrophages and neutrophils are postulated to provide defense against invasive fungal infection, animal models and human studies suggest that circulating monocytes also contribute to antifungal immunity. Although human monocyte subsets, defined as either CD14(+)CD16(-) or CD14(+)CD16(+), have been extensively characterized, their respective roles during fungal infection remain undefined. We isolated CD14(+)CD16(-) and CD14(+)CD16(+) monocytes from healthy allogeneic hematopoietic stem cell transplantation donors and compared their ability to phagocytose and inhibit A. fumigatus conidia. Both monocyte subsets efficiently phagocytose conidia, but only CD14(+)CD16(-) monocytes inhibit conidial germination yet secrete little TNF. In contrast CD14(+)CD16(+) do not inhibit conidial germination and secrete large amounts of TNF. Although CD14(+)CD16(-) and CD14(+)CD16(+) monocytes differ in their response to dormant conidia, responses are similar if conidia are already germinated at the time of monocyte uptake. Our study demonstrates that functional CD14(+)CD16(-) and CD14(+)CD16(+) monocytes can be isolated from allogeneic hematopoietic stem cell transplantation donors and that these subsets differ in their response to A. fumigatus conidia.
Assuntos
Aspergillus fumigatus/imunologia , Monócitos/imunologia , Monócitos/microbiologia , Esporos Fúngicos/imunologia , Antígenos CD34/biossíntese , Aspergillus fumigatus/crescimento & desenvolvimento , Células Cultivadas , Regulação para Baixo/imunologia , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas , Transplante de Células-Tronco Hematopoéticas , Humanos , Receptores de Lipopolissacarídeos/biossíntese , Monócitos/citologia , Receptores de IgG/biossíntese , Receptores de IgG/metabolismo , Esporos Fúngicos/crescimento & desenvolvimento , Regulação para Cima/imunologiaRESUMO
The mechanisms underlying innate immune cell trafficking and activation during infection remain incompletely defined. In this issue of Immunity, Kang et al. (2008) begin to reveal the cytokine and chemokine cascades that coordinate cellular responses induced by microbial pathogens.
Assuntos
Infecções Bacterianas/imunologia , Toxinas Bacterianas/imunologia , Citocinas/imunologia , Proteínas de Choque Térmico/imunologia , Proteínas Hemolisinas/imunologia , Imunidade Inata , Fator 88 de Diferenciação Mieloide/metabolismo , Animais , Infecções Bacterianas/metabolismo , Toxinas Bacterianas/metabolismo , Citocinas/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Células Dendríticas/microbiologia , Proteínas de Choque Térmico/metabolismo , Proteínas Hemolisinas/metabolismo , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/microbiologia , Monócitos/imunologia , Monócitos/metabolismo , Monócitos/microbiologia , Fator 88 de Diferenciação Mieloide/deficiênciaRESUMO
Chemokine receptor-mediated recruitment of inflammatory cells is essential for innate immune defense against microbial infection. Recruitment of Ly6C(high) inflammatory monocytes from bone marrow to sites of microbial infection is dependent on CCR2, a chemokine receptor that responds to MCP-1 and MCP-3. Although CCR2(-/-) mice are markedly more susceptible to Listeria monocytogenes infection than are wild-type mice, MCP-1(-/-) mice have an intermediate phenotype, suggesting that other CCR2 ligands contribute to antimicrobial defense. Herein, we show that L. monocytogenes infection rapidly induces MCP-3 in tissue culture macrophages and in serum, spleen, liver, and kidney following in vivo infection. Only cytosol invasive L. monocytogenes induce MCP-3, suggesting that cytosolic innate immune detection mechanisms trigger chemokine production. MCP-3(-/-) mice clear bacteria less effectively from the spleen than do wild-type mice, a defect that correlates with diminished inflammatory monocyte recruitment. MCP-3(-/-) mice have significantly fewer Ly6C(high) monocytes in the spleen and bloodstream, and increased monocyte numbers in bone marrow. MCP-3(-/-) mice, like MCP-1(-/-) mice, have fewer TNF- and inducible NO synthase-producing dendritic cells (Tip-DCs) in the spleen following L. monocytogenes infection. Our data demonstrate that MCP-3 and MCP-1 provide parallel contributions to CCR2-mediated inflammatory monocyte recruitment and that both chemokines are required for optimal innate immune defense against L. monocytogenes infection.
Assuntos
Quimiocina CCL2/imunologia , Quimiocina CCL7/imunologia , Quimiotaxia de Leucócito/imunologia , Listeriose/imunologia , Monócitos/imunologia , Receptores CCR2/imunologia , Animais , Células Cultivadas , Quimiocina CCL2/metabolismo , Quimiocina CCL7/metabolismo , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Inflamação/imunologia , Listeria monocytogenes/imunologia , Macrófagos/imunologia , Camundongos , Camundongos Mutantes , Receptores CCR2/metabolismoRESUMO
Circulating blood monocytes supply peripheral tissues with macrophage and dendritic cell (DC) precursors and, in the setting of infection, also contribute directly to immune defense against microbial pathogens. In humans and mice, monocytes are divided into two major subsets that either specifically traffic into inflamed tissues or, in the absence of overt inflammation, constitutively maintain tissue macrophage/DC populations. Inflammatory monocytes respond rapidly to microbial stimuli by secreting cytokines and antimicrobial factors, express the CCR2 chemokine receptor, and traffic to sites of microbial infection in response to monocyte chemoattractant protein (MCP)-1 (CCL2) secretion. In murine models, CCR2-mediated monocyte recruitment is essential for defense against Listeria monocytogenes, Mycobacterium tuberculosis, Toxoplasma gondii, and Cryptococcus neoformans infection, implicating inflammatory monocytes in defense against bacterial, protozoal, and fungal pathogens. Recent studies indicate that inflammatory monocyte recruitment to sites of infection is complex, involving CCR2-mediated emigration of monocytes from the bone marrow into the bloodstream, followed by trafficking into infected tissues. The in vivo mechanisms that promote chemokine secretion, monocyte differentiation and trafficking, and finally monocyte-mediated microbial killing remain active and important areas of investigation.
Assuntos
Infecções/imunologia , Monócitos/imunologia , Animais , Diferenciação Celular/imunologia , Quimiotaxia/imunologia , Humanos , Imunidade Celular/imunologia , Imunidade nas Mucosas/imunologia , Infecções/microbiologia , Infecções/fisiopatologia , Proteínas Quimioatraentes de Monócitos/fisiologia , Monócitos/citologia , Receptores CCR2/fisiologiaRESUMO
Intravenous immune globulin (IVIG) suppresses autoantibody-mediated inflammation by inducing and activating the inhibitory Fc receptor FcgammaRIIb and downstream negative signaling pathways. We investigated the effects of IVIG on cellular responses to interferon-gamma (IFN-gamma), a potent macrophage activator that exacerbates inflammation. Our study showed that IVIG blocked IFN-gamma signaling and IFN-gamma-induced gene expression and suppressed IFN-gamma function in vivo during immune responses to Listeria monocytogenes and in an IFN-gamma-enhanced model of immune thrombocytopenic purpura. The mechanism of inhibition of IFN-gamma signaling was suppression of expression of the IFNGR2 subunit of the IFN-gamma receptor. The inhibitory effect of IVIG was mediated at least in part by soluble immune complexes and was dependent on FcgammaRIII but independent of FcgammaRIIb. These results reveal an unexpected inhibitory role for the activating FcgammaRIII in mediating suppression of IFN-gamma signaling and suggest that inhibition of macrophage responses to IFN-gamma contributes to the anti-inflammatory properties of IVIG.
Assuntos
Imunoglobulinas Intravenosas/farmacologia , Interferon gama/efeitos dos fármacos , Ativação de Macrófagos/efeitos dos fármacos , Receptores de IgG/imunologia , Transdução de Sinais/imunologia , Animais , Citometria de Fluxo , Expressão Gênica/efeitos dos fármacos , Humanos , Immunoblotting , Imunoglobulinas Intravenosas/imunologia , Interferon gama/imunologia , Listeriose/imunologia , Ativação de Macrófagos/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Receptores de IgG/uso terapêutico , Reação em Cadeia da Polimerase Via Transcriptase Reversa , TransfecçãoRESUMO
Monocytes recruited to tissues mediate defense against microbes or contribute to inflammatory diseases. Regulation of the number of circulating monocytes thus has implications for disease pathogenesis. However, the mechanisms controlling monocyte emigration from the bone marrow niche where they are generated remain undefined. We demonstrate here that the chemokine receptor CCR2 was required for emigration of Ly6C(hi) monocytes from bone marrow. Ccr2(-/-) mice had fewer circulating Ly6C(hi) monocytes and, after infection with Listeria monocytogenes, accumulated activated monocytes in bone marrow. In blood, Ccr2(-/-) monocytes could traffic to sites of infection, demonstrating that CCR2 is not required for migration from the circulation into tissues. Thus, CCR2-mediated signals in bone marrow determine the frequency of Ly6C(hi) monocytes in the circulation.
Assuntos
Infecções Bacterianas/imunologia , Quimiotaxia de Leucócito/imunologia , Monócitos/imunologia , Receptores de Quimiocinas/imunologia , Animais , Antígenos Ly/imunologia , Antígenos Ly/metabolismo , Células da Medula Óssea/citologia , Células da Medula Óssea/imunologia , Diferenciação Celular , Citometria de Fluxo , Camundongos , Monócitos/citologia , Receptores CCR2RESUMO
Chemokine receptor 5 (CCR5) binds macrophage inflammatory protein 1alpha (MIP-1alpha), MIP-1beta, RANTES, and members of the monocyte chemotactic protein family and is also a receptor for human immunodeficiency virus (HIV). CCR5 ligands can suppress HIV-1 entry into cells. In humans, homozygous mutations of the ccr5 gene confer resistance to HIV-1 infection. The role of CCR5 in defense against microbial infection is unclear. In this study we examined the innate and adaptive immune responses of CCR5-deficient mice to the intracellular bacterial pathogen Listeria monocytogenes. We found that migration of monocytic cells, formation of L. monocytogenes-containing lesions, and bacterial clearance occurred normally in the spleens and livers of CCR5-deficient animals. Activation of macrophages and dendritic cells during the first 3 days postinfection was normal in the absence of CCR5, as demonstrated by intact expression of inducible nitric oxide synthase (iNOS) and production of the cytokines tumor necrosis factor alpha, gamma interferon, and interleukin-12. Priming of L. monocytogenes-specific CD8 T cells also occured independently of CCR5 expression. Previously immunized, CCR5-deficient animals mounted normal secondary CD8 T-cell responses and cleared bacteria from infected organs similarly to wild-type controls, suggesting that CCR5 is dispensable for migration and activation of memory CD8 T cells. Our data indicate that CCR5-mediated chemotaxis is not required for defense against infection with L. monocytogenes.
Assuntos
Toxinas Bacterianas , Listeria monocytogenes/imunologia , Listeriose/imunologia , Receptores CCR5/fisiologia , Animais , Linfócitos T CD8-Positivos/imunologia , Movimento Celular , Células Dendríticas/fisiologia , Proteínas de Choque Térmico/imunologia , Proteínas Hemolisinas , Imunidade Inata , Ativação Linfocitária , Macrófagos/fisiologia , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Microbial infections induce chemokine and cytokine cascades that coordinate innate immune defenses. Infection with the intracellular bacterial pathogen Listeria monocytogenes induces CCR2-dependent monocyte recruitment and activation, an essential response for host survival. Herein we show that invasive L. monocytogenes, but not killed or noninvasive bacteria, induce secretion of MCP-1, the requisite chemokine for monocyte recruitment. Induction of MCP-1, but not TNF or IL-12, following L. monocytogenes infection is MyD88 independent. Consistent with these results, MyD88 deficiency does not impair monocyte recruitment to L. monocytogenes infected spleens, but prevents monocyte activation. Our results indicate that distinct microbial signals activate innate immune responses in an ordered, step-wise fashion, providing a mechanism to specify and modulate antimicrobial effector functions.
Assuntos
Antígenos de Diferenciação/imunologia , Imunidade Inata , Listeriose/imunologia , Receptores Imunológicos/imunologia , Proteínas Adaptadoras de Transdução de Sinal , Animais , Quimiocina CCL2/biossíntese , Quimiocina CCL2/genética , Células Dendríticas/imunologia , Macrófagos/metabolismo , Camundongos , Fator 88 de Diferenciação Mieloide , Baço/imunologiaRESUMO
Dendritic cells in the skin, called Langerhans cells, are the obvious candidates for transporting antigen from the epidermis to the lymph nodes and for activating T cell defense. However, as Serbina and Pamer discuss in their Perspective, at least in the case of viral antigens, it seems that other dendritic cell subsets residing in the dermis are the most important players in T cell-mediated defense against viral infection of the skin.
Assuntos
Apresentação de Antígeno , Células Dendríticas/imunologia , Herpes Simples/imunologia , Células de Langerhans/imunologia , Linfócitos T/imunologia , Animais , Antígenos Virais/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular , Células Epidérmicas , Epiderme/imunologia , Herpes Genital/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Listeriose/imunologia , Linfonodos/imunologia , Ativação Linfocitária , Camundongos , Monócitos/citologia , Monócitos/imunologia , Simplexvirus/imunologiaRESUMO
Dendritic cells (DCs) present microbial antigens to T cells and provide inflammatory signals that modulate T cell differentiation. While the role of DCs in adaptive immunity is well established, their involvement in innate immune defenses is less well defined. We have identified a TNF/iNOS-producing (Tip)-DC subset in spleens of Listeria monocytogenes-infected mice that is absent from CCR2-deficient mice. The absence of Tip-DCs results in profound TNF and iNOS deficiencies and an inability to clear primary bacterial infection. CD8 and CD4 T cell responses to L. monocytogenes antigens are preserved in CCR2-deficient mice, indicating that Tip-DCs are not essential for T cell priming. Tip-DCs, as the predominant source of TNF and iNOS during L. monocytogenes infection, orchestrate and mediate innate immune defense against this intracellular bacterial pathogen.