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1.
Am J Physiol Lung Cell Mol Physiol ; 293(3): L730-9, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17586699

RESUMO

Asthma is a chronic airway inflammatory disease that encompasses three cardinal processes: T helper (Th) cell type 2 (Th2)-polarized inflammation, bronchial hyperreactivity, and airway wall remodeling. However, the link between the immune-inflammatory phenotype and the structural-functional phenotype remains to be fully defined. The objective of these studies was to evaluate the relationship between the immunologic nature of chronic airway inflammation and the development of abnormal airway structure and function in a mouse model of chronic asthma. Using IL-4-competent and IL-4-deficient mice, we created divergent immune-inflammatory responses to chronic aeroallergen challenge. Immune-inflammatory, structural, and physiological parameters of chronic allergic airway disease were evaluated in both strains of mice. Although both strains developed airway inflammation, the profiles of the immune-inflammatory responses were markedly different: IL-4-competent mice elicited a Th2-polarized response and IL-4-deficient mice developed a Th1-polarized response. Importantly, this chronic Th1-polarized immune response was not associated with airway remodeling or bronchial hyperresponsiveness. Transient reconstitution of IL-4 in IL-4-deficient mice via an airway gene transfer approach led to partial Th2 repolarization and increased bronchial hyperresponsiveness, along with full reconstitution of airway remodeling. These data show that distinct structural-functional phenotypes associated with chronic airway inflammation are strictly dependent on the nature of the immune-inflammatory response.


Assuntos
Dermatophagoides pteronyssinus/imunologia , Pulmão/imunologia , Pulmão/patologia , Adenoviridae , Administração Intranasal , Alérgenos/administração & dosagem , Alérgenos/imunologia , Alérgenos/farmacologia , Animais , Antígenos de Dermatophagoides/administração & dosagem , Antígenos de Dermatophagoides/imunologia , Antígenos de Dermatophagoides/farmacologia , Hiper-Reatividade Brônquica/patologia , Testes de Provocação Brônquica , Lavagem Broncoalveolar , Citocinas/metabolismo , Feminino , Imunoglobulinas/sangue , Inflamação , Interleucina-4/deficiência , Pulmão/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Baço/citologia , Fator de Crescimento Transformador beta/metabolismo
2.
Mol Cell Biol ; 26(17): 6403-11, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16914726

RESUMO

Members of the B7 family of cosignaling molecules regulate T-cell proliferation and effector functions by engaging cognate receptors on T cells. In vitro and in vivo blockade experiments indicated that B7-H4 (also known as B7S1 or B7x) inhibits proliferation, cytokine production, and cytotoxicity of T cells. B7-H4 binds to an unknown receptor(s) that is expressed on activated T cells. However, whether B7-H4 plays nonredundant immune regulatory roles in vivo has not been tested. We generated B7-H4-deficient mice to investigate the roles of B7-H4 during various immune reactions. Consistent with its inhibitory function in vitro, B7-H4-deficient mice mounted mildly augmented T-helper 1 (Th1) responses and displayed slightly lowered parasite burdens upon Leishmania major infection compared to the wild-type mice. However, the lack of B7-H4 did not affect hypersensitive inflammatory responses in the airway or skin that are induced by either Th1 or Th2 cells. Likewise, B7-H4-deficient mice developed normal cytotoxic T-lymphocyte reactions against viral infection. Thus, B7-H4 plays a negative regulatory role in vivo but the impact of B7-H4 deficiency is minimal. These results suggest that B7-H4 is one of multiple negative cosignaling molecules that collectively provide a fine-tuning mechanism for T-cell-mediated immune responses.


Assuntos
Antígeno B7-1/metabolismo , Animais , Doenças Autoimunes/imunologia , Proliferação de Células , Marcação de Genes , Inflamação/imunologia , Vírus da Influenza A/fisiologia , Leishmania major/fisiologia , Vírus da Coriomeningite Linfocítica/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/virologia , Células Th1/citologia , Células Th1/imunologia , Células Th1/parasitologia , Inibidor 1 da Ativação de Células T com Domínio V-Set
3.
J Immunol ; 176(6): 3306-10, 2006 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-16517696

RESUMO

Ligation of CD28 during Ag recognition plays an important role in the generation of effective T cell responses. However, its peripheral control of regulatory T cell function remains obscure. In this study, we show that naive wild-type or CD28(-/-) CD4(+)CD25(-) T cells exposed to peptide in vivo develop regulatory activity that suppresses the response of adoptively transferred naive T cells to a subsequent immunogenic challenge. We find that although CD28 is engaged during the initial peptide-priming event and is essential to sustain T cell survival, it is not sufficient to prevent the dominance of regulatory T cell function. Immunization with adjuvant abrogates regulatory dominance, reducing overall Foxp3 expression in a CD28-dependent manner. We conclude that CD28 licenses active immunization by regulating Ag-induced immunoregulation.


Assuntos
Antígenos CD28/imunologia , Linfócitos T Reguladores/imunologia , Vacinação , Animais , Antígenos CD28/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Receptores de Interleucina-2/imunologia , Receptores de Interleucina-2/metabolismo , Transdução de Sinais , Linfócitos T Reguladores/metabolismo
4.
J Immunol ; 174(5): 3000-5, 2005 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-15728513

RESUMO

The recently described ICOS-B7RP-1 costimulatory pathway has been implicated in the generation of effector Th2 responses and, hence, has become an attractive therapeutic target for allergic diseases. In the present study, we used B7RP-1-deficient mice to investigate the role of B7RP-1 in the generation and maintenance of Th2 responses in a model of mucosal allergic airway inflammation. We found that exposure of B7RP-1 knockout mice to aerosolized OVA in the context of GM-CSF leads to airway eosinophilic inflammation. This response was long lasting because rechallenge of mice with the same Ag recapitulated airway eosinophilia. Moreover, significant expression of T1/ST2 on T cells and production of Th2-affiliated cytokines (IL-5, IL-4, and IL-13) and Igs (IgE and IgG1) conclusively demonstrate the generation of a Th2 response in the absence of B7RP-1. In addition, expression of two major Th2-associated costimulatory molecules-CD28 and ICOS-indicates T cell activation in the absence of B7RP-1 signaling. Finally, B7RP-1 knockout mice are resistant to the induction of inhalation tolerance as indicated by the sustained eosinophilia in the lung and IL-5 production. In summary, our results demonstrate that in a model of mucosal allergic sensitization, the ICOS-B7RP-1 pathway is redundant for the generation of Th2 responses but essential for the induction of inhalation tolerance.


Assuntos
Alérgenos/imunologia , Antígeno B7-1/genética , Tolerância Imunológica , Pulmão/patologia , Hipersensibilidade Respiratória/imunologia , Células Th2/imunologia , Células Th2/metabolismo , Administração por Inalação , Alérgenos/administração & dosagem , Animais , Antígenos de Diferenciação de Linfócitos T/biossíntese , Antígeno B7-1/fisiologia , Antígenos CD28/biossíntese , Modelos Animais de Doenças , Humanos , Tolerância Imunológica/genética , Memória Imunológica/genética , Ligante Coestimulador de Linfócitos T Induzíveis , Proteína Coestimuladora de Linfócitos T Induzíveis , Inflamação/genética , Inflamação/imunologia , Pulmão/imunologia , Pulmão/metabolismo , Camundongos , Camundongos Knockout , Ovalbumina/administração & dosagem , Ovalbumina/imunologia , Hipersensibilidade Respiratória/genética , Hipersensibilidade Respiratória/patologia , Mucosa Respiratória/imunologia , Mucosa Respiratória/patologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia
5.
Eur J Immunol ; 34(9): 2375-86, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15307170

RESUMO

We previously showed that granulocyte-macrophage colony-stimulating factor (GM-CSF) breaks tolerance induction. The objective of this study was to determine whether GM-CSF breaks established inhalation tolerance. To induce tolerance, BALB/c mice were exposed to aerosolized ovalbumin (OVA) for 10 consecutive days. A control group was exposed to saline. Subsequently, tolerant and control animals were exposed to OVA in a GM-CSF-enriched airway microenvironment. Tolerant animals, unlike control animals, did not develop airway and peripheral blood eosinophilia, had diminished levels of OVA-specific IgE, and reduced airway hyper-responsiveness. While tolerant animals did not express IL-4, IL-5 and IL-13, levels of the regulatory cytokines IL-10, IFN-gamma and transfoming growth factor (TGF)-beta were similar between tolerant and non-tolerant animals. Lung CD4+ T cells were activated according to CD69, CD25 and T1/ST2 expression, but systemic responses characterized by splenocyte proliferation and Th2 effector function were dramatically reduced. Concurrent expression of GM-CSF and decorin, a natural inhibitor of TGF-beta, reversed eosinophilic unresponsiveness. Our study suggests that the breakdown of tolerance and, by extension, the emergence of eosinophilic inflammation, requires two signals: one that triggers sensitization and one that interferes with negative regulation. Moreover, our study shows that dysregulated expression of an extracellular matrix protein may break established tolerance and lead to eosinophilic airway inflammation.


Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos/fisiologia , Tolerância Imunológica , Pulmão/fisiologia , Proteoglicanas/fisiologia , Administração por Inalação , Animais , Líquido da Lavagem Broncoalveolar/imunologia , Linfócitos T CD4-Positivos/imunologia , Decorina , Eosinofilia/etiologia , Proteínas da Matriz Extracelular , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/imunologia
6.
Am J Respir Crit Care Med ; 169(3): 378-85, 2004 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-14597485

RESUMO

It is now fully appreciated that asthma is a disease of a chronic nature resulting from intermittent or continued aeroallergen exposure leading to airway inflammation. To investigate responses to continuous antigen exposure, mice were exposed to either house dust mite extract (HDM) or ovalbumin intranasally for five consecutive days, followed by 2 days of rest, for up to seven consecutive weeks. Continuous exposure to HDM, unlike ovalbumin, elicited severe and persistent eosinophilic airway inflammation. Flow cytometric analysis demonstrated an accumulation of CD4+ lymphocytes in the lung with elevated expression of inducible costimulator a marker of T cell activation, and of T1/ST2, a marker of helper T Type 2 effector cells. We also detected increased and sustained production of helper T cell Type 2-associated cytokines by splenocytes of HDM-exposed mice on in vitro HDM recall. Histologic analysis of the lung showed evidence of airway remodeling in mice exposed to HDM, with goblet cell hyperplasia, collagen deposition, and peribronchial accumulation of contractile tissue. In addition, HDM-exposed mice demonstrated severe airway hyperreactivity to methacholine. Finally, these responses were studied for up to 9 weeks after cessation of HDM exposure. We observed that whereas airway inflammation resolved fully, the remodeling changes did not resolve and airway hyperreactivity resolved only partly.


Assuntos
Alérgenos/efeitos adversos , Asma/imunologia , Hiper-Reatividade Brônquica/imunologia , Mediadores da Inflamação/análise , Inflamação/fisiopatologia , Resistência das Vias Respiratórias , Animais , Asma/patologia , Biópsia por Agulha , Hiper-Reatividade Brônquica/patologia , Doença Crônica , Citocinas/análise , Modelos Animais de Doenças , Poeira , Feminino , Imunoglobulinas/análise , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos BALB C , Ácaros , Probabilidade , Eosinofilia Pulmonar/imunologia , Eosinofilia Pulmonar/fisiopatologia , Sensibilidade e Especificidade
7.
Curr Drug Targets Inflamm Allergy ; 2(4): 279-92, 2003 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-14561147

RESUMO

The interaction between dendritic cells (DC) and naïve T cells is the first step in the evolution of an immune response, either tolerogenic or inflammatory. Therefore, the status of DC residing at mucosal sites, such as the airway, has a definitive impact on the character of the ensuing immune response. In the absence of pathogenic stimulation, DC serve to regulate immunological homeostasis in the lung; the generation of Th2-associated (allergic) inflammatory responses, which are directed at presumably innocuous antigens, represent a deviation from normal DC function. The dysregulation of DC phenotype leading to the development of allergy might be programmed by genetic pedigree, or might be induced by factors released in the airway. One potential candidate, GM-CSF, is abundant in the allergic airway and can condition DC to propagate Th2 responses. Moreover, that allergens, alone or in combination with other factors, can spontaneously induce GM-CSF production in the airway thus present a compelling etiological argument for the role of GM-CSF in allergic sensitization. The interplay between DC and mediators present in the allergic airway is likely critical to the establishment of allergic airway inflammation. Understanding these interactions may, therefore, afford insight into prospective therapeutic interventions to circumvent, and even reverse the allergic diathesis.


Assuntos
Células Dendríticas/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Hipersensibilidade/fisiopatologia , Inflamação/fisiopatologia , Sistema Respiratório/patologia , Animais , Antiasmáticos/farmacologia , Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Asma/imunologia , Asma/fisiopatologia , Humanos , Hipersensibilidade/patologia , Hipersensibilidade/terapia , Inflamação/patologia , Inflamação/terapia , Células Th2/imunologia , Células Th2/fisiologia
8.
Nat Immunol ; 4(9): 899-906, 2003 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12925852

RESUMO

We investigated the in vivo function of the B7 family member B7-H3 (also known as B7RP-2) by gene targeting. B7-H3 inhibited T cell proliferation mediated by antibody to T cell receptor or allogeneic antigen-presenting cells. B7-H3-deficient mice developed more severe airway inflammation than did wild-type mice in conditions in which T helper cells differentiated toward type 1 (T(H)1) rather than type 2 (T(H)2). B7-H3 expression was consistently enhanced by interferon-gamma but suppressed by interleukin 4 in dendritic cells. B7-H3-deficient mice developed experimental autoimmune encephalomyelitis several days earlier than their wild-type littermates, and accumulated higher concentrations of autoantibodies to DNA. Thus, B7-H3 is a negative regulator that preferentially affects T(H)1 responses.


Assuntos
Antígeno B7-1/imunologia , Células Th1/imunologia , Animais , Autoanticorpos/imunologia , Autoanticorpos/metabolismo , Antígenos B7 , Antígeno B7-1/biossíntese , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Regulação para Baixo/imunologia , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Citometria de Fluxo , Interferon gama/imunologia , Interleucina-4/imunologia , Ativação Linfocitária/imunologia , Vírus da Coriomeningite Linfocítica/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Orthomyxoviridae/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Vírus da Estomatite Vesicular Indiana/imunologia
9.
Nat Immunol ; 4(8): 765-72, 2003 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12833154

RESUMO

Costimulation through the inducible costimulator (ICOS) and its ligand (ICOSL) is essential for T cell-dependent B cell responses, but the cellular and temporal dynamics underlying its in vivo effects are poorly defined. Here we have shown that Icosl(-/-) and Icos(-/-) mice had similar phenotypes and that ICOS-ICOSL costimulation modulated the early but not late phases of IgG1 affinity maturation. Exploiting the adoptive transfer of T or B cells from primed Icosl(-/-) mice, we provided genetic evidence that costimulation through ICOSL was essential for primary but not secondary helper T cell responses and for the control of both T and B cell activities, resulting in T cell-dependent IgG1 production.


Assuntos
Antígenos de Diferenciação de Linfócitos T/imunologia , Linfócitos B/imunologia , Cooperação Linfocítica/imunologia , Proteínas/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Deleção de Genes , Imunoglobulina G/imunologia , Ligante Coestimulador de Linfócitos T Induzíveis , Proteína Coestimuladora de Linfócitos T Induzíveis , Camundongos , Proteínas/genética
10.
J Allergy Clin Immunol ; 111(5): 1076-86, 2003 May.
Artigo em Inglês | MEDLINE | ID: mdl-12743573

RESUMO

BACKGROUND: Conventional models of allergic airway inflammation involve intraperitoneal administration of ovalbumin in conjunction with a chemical adjuvant (generally aluminum hydroxide) to generate allergic airways inflammation. Here we have investigated the effect of respiratory mucosal exposure to a ragweed extract in the absence of chemical adjuvant on the generation of allergic responses. OBJECTIVES: We sought to develop a mouse model of ragweed-induced allergic airway inflammation through mucosal sensitization and to investigate the role of GM-CSF in this process. METHODS: Ragweed was delivered intranasally to an airway microenvironment enriched with GM-CSF, which was achieved by means of either multiple coadministrations of recombinant GM-CSF or a single delivery of an adenoviral vector carrying the GM-CSF transgene. RESULTS: Administration of a purified ragweed extract leads to T(H)2 sensitization (and not inhalation tolerance) accompanied by mild airway inflammation, modest clinical symptoms, and moderate production of T(H)2 cytokines by splenocytes on ragweed restimulation. The administration of anti-GM-CSF antibodies in conjunction with ragweed diminished T(H)2-associated cytokine production. These responses were amplified by enriching the airway microenvironment with GM-CSF. Under these conditions, all T(H)2-associated immune-inflammatory responses, as well as the clinical responses, were considerably enhanced. To investigate the mechanism underlying these effects, we examined lung mononuclear cells by means of flow cytometry and detected a substantial expansion of antigen-presenting cells, particularly dendritic cells, as well as a substantially increased activation of these antigen-presenting cells, as demonstrated by the expression of B7 molecules, particularly B7.2. CONCLUSION: GM-CSF plays an important role in the generation of allergic immune-inflammatory responses to ragweed.


Assuntos
Ambrosia/imunologia , Asma/etiologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/fisiologia , Hipersensibilidade/etiologia , Inflamação/etiologia , Animais , Citocinas/biossíntese , Feminino , Citometria de Fluxo , Pulmão/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Modelos Animais , Ovalbumina/imunologia , Proteínas Recombinantes/farmacologia , Células Th2/imunologia
11.
Am J Respir Cell Mol Biol ; 27(4): 428-35, 2002 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-12356576

RESUMO

The development of T helper (Th)2 responses is a key step in the pathogenesis of asthma. Interleukin (IL)-4 is thought to be important, although not strictly necessary, for Th2 differentiation, although triggers of IL-4-independent Th2 polarization have not been identified. We examined whether IL-4 is necessary for Th2-polarized responses during granulocyte macrophage colony-stimulating factor (GM-CSF)-driven respiratory mucosal sensitization. Balb/c wild type (WT) or IL-4 knockout (4KO) mice were exposed to aerosolized ovalbumin (OVA) in the context of airway GM-CSF expression. We examined the extent of Th2 polarization using real-time quantitative polymerase chain reaction on lymph node mRNA, flow cytometric analysis of lung Th cells, and measurement of cells, cytokines, and immunoglobulins in bronchoalveolar lavage (BAL) and serum. GATA-3 and CCR3, -4, and -8 were expressed in the lymph nodes of WT and 4KO mice at similar levels, as were IL-5 and IL-13 levels in the BAL, T1/ST2 on lung Th cells, and BAL eosinophils after recall challenge. With the exception of immunoglobulin production, expression of GATA-3, CCR-3, -4, -8, IL-5, and T1/ST2, and the generation of blood eosinophilia, were intact in mice doubly deficient in both IL-4 and IL-13. We conclude that IL-4 is not required for the generation of Th2-polarized responses in the presence of GM-CSF.


Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Interleucina-4/metabolismo , Mucosa/patologia , Células Th2/metabolismo , Animais , Diferenciação Celular , Citocinas/biossíntese , Proteínas de Ligação a DNA/metabolismo , Ensaio de Imunoadsorção Enzimática , Eosinófilos/metabolismo , Feminino , Citometria de Fluxo , Fator de Transcrição GATA3 , Imunoglobulinas/biossíntese , Interleucina-13/metabolismo , Interleucina-4/genética , Interleucina-5/metabolismo , Pulmão/citologia , Pulmão/patologia , Linfonodos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , RNA/metabolismo , RNA Mensageiro/metabolismo , Receptores CCR3 , Receptores CCR4 , Receptores CCR8 , Receptores de Quimiocinas/metabolismo , Mucosa Respiratória/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transativadores/metabolismo
12.
J Immunol ; 169(7): 3499-506, 2002 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-12244139

RESUMO

In this study we investigated the impact of chronic allergen exposure on airway inflammation and humoral responses in sensitized mice. We observed marked eosinophilia in the bronchoalveolar lavage, lung tissue, and peripheral blood after 2 wk of exposure. In contrast, eosinophilia was markedly reduced by 3 wk and completely resolved by 4 wk of exposure, despite the continued presence of Ag. Decreases in airway eosinophilia were associated with a robust humoral response. We observed that levels of OVA-specific IgE, IgG1, and IgG2a increased during the course of exposure. To assess whether continuous exposure to Ag impacts the ability of the lung to respond to subsequent Ag challenge, mice were exposed to either 2 or 4 wk of OVA in the context of GM-CSF. All groups were then rested for 28 days and exposed to OVA on three consecutive days. We observed a significant decrease in airway eosinophilia and IL-5 expression in the bronchoalveolar lavage and serum in mice initially exposed to 4 wk of OVA, compared with animals exposed to 2 wk only. However, in both groups expression of B7.2 on dendritic cells as well as CD25, CD69, and T1/ST2 on CD4(+) T cells was enhanced, suggesting immune activation. Delivery of rGM-CSF fully restored airway eosinophilia. This study shows that exposure to innocuous Ag alone does not lead to persistent eosinophilic airway inflammation, but rather to abrogated eosinophilia. This suppression can be reversed by GM-CSF.


Assuntos
Antígenos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Tolerância Imunológica , Imunização , Ovalbumina/administração & dosagem , Eosinofilia Pulmonar/imunologia , Eosinofilia Pulmonar/prevenção & controle , Administração Intranasal , Animais , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Antígenos/sangue , Antígenos/imunologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Relação Dose-Resposta Imunológica , Esquema de Medicação , Feminino , Imunização/métodos , Imunização Secundária , Imunoglobulina E/biossíntese , Imunoglobulina G/biossíntese , Memória Imunológica , Imunofenotipagem , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/sangue , Ovalbumina/imunologia , Eosinofilia Pulmonar/sangue , Proteínas Recombinantes , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
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