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1.
Acute Med ; 22(4): 261-263, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38284639

RESUMO

A 32-year-old lady with a history of bulimia nervosa was noted to have a raised adjusted calcium of 2.94mmol/L associated with high parathyroid hormone (PTH) 17.2pmol/L. On review, she had an apparent hypercalcaemia for at least three years, and also had a chronic, severe alkalosis with a bicarbonate up to 81.9mEQ/L. Ionised calcium during that time had actually been low, down to 1.03mmol/L. This case highlights the effects of alkalosis on calcium, as more albumin is available for binding to ionised calcium. This results in a low ionised calcium, which triggers PTH release and overall leads to raised adjusted calcium levels. Clinicians may misdiagnose a similar patient with primary hyperparathyroidism and treatment would cause worsening of true hypocalcaemia.


Assuntos
Alcalose , Hiperparatireoidismo Primário , Feminino , Humanos , Adulto , Cálcio , Hiperparatireoidismo Primário/diagnóstico , Hormônio Paratireóideo/metabolismo
2.
Haemophilia ; 22(4): e251-8, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27328112

RESUMO

INTRODUCTION: BAX 855 is a pegylated full-length recombinant factor VIII (rFVIII) with an extended half-life, built on a licensed rFVIII (ADVATE(®) ). BAX 855 demonstrated efficacy and safety in prophylaxis and the treatment of bleeding episodes in previously treated patients (PTPs) with severe haemophilia A. AIM: This phase 3 surgery study evaluates the haemostatic efficacy and safety of BAX 855 for perioperative haemostasis in PTPs with severe haemophilia A undergoing surgery. METHODS: Elective procedures were prospectively classified as major or minor. The dose and frequency of BAX 855 administered perioperatively were to be guided by each patient's pharmacokinetic profile for major procedures or BAX 855 incremental recovery for minor procedures. Haemostatic efficacy was evaluated using a predefined scale. Blood loss was compared to the expected average and maximum blood loss predicted preoperatively. RESULTS: A total of 15 male patients (aged 19-52 years) underwent 15 procedures (11 major and four minor). The overall intra- and perioperative haemostatic efficacy of BAX 855 was 'excellent' in all 15 subjects (100%). Postoperatively, evaluated at postoperative Day 1, all treatments were 'excellent' except for one minor (dental) procedure which was rated 'good'. No related adverse events, allergic reactions, thrombotic events, nor signs of immunogenicity in terms of induction of binding antibodies to FVIII, PEG or PEG-VIII, or FVIII inhibitors were observed. CONCLUSION: These results demonstrate that BAX 855 is safe and haemostatically effective in patients with severe haemophilia A undergoing surgery.


Assuntos
Coagulantes/uso terapêutico , Fator VIII/uso terapêutico , Hemofilia A/tratamento farmacológico , Adulto , Anticorpos Neutralizantes/sangue , Coagulantes/química , Coagulantes/farmacocinética , Fator VIII/genética , Fator VIII/metabolismo , Meia-Vida , Hemofilia A/sangue , Hemorragia/prevenção & controle , Hemostasia , Humanos , Masculino , Pessoa de Meia-Idade , Assistência Perioperatória , Polietilenoglicóis/química , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/uso terapêutico , Procedimentos Cirúrgicos Operatórios , Resultado do Tratamento , Adulto Jovem
3.
Clin Exp Allergy ; 44(7): 976-85, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24807637

RESUMO

BACKGROUND: Interleukin-21 (IL-21) has been implicated in the development of Th2-mediated immune responses; however, the exact role it plays in allergic diseases is not well understood. OBJECTIVE: To elucidate the contribution of IL-21 receptor signalling to Th2-dependent immune responses in the lung. METHODS: We compared allergic airway responses in wild-type BALB/c and Il21r-deficient mice exposed to local airway challenge with house dust mite (HDM). RESULTS: We demonstrate that IL-21R-deficiency reduces HDM-driven airway hyperresponsiveness (AHR) with only partial effects on airway inflammation. Concomitant with the reduction in AHR in Il21r-deficient mice, significant suppression was observed in protein levels of the Th2 cytokines IL-4, and IL-13. In contrast, IL-21R-deficiency was associated with an increase in PBS- and allergen-driven IgE levels, while IgG1 and IgG2a levels were decreased. Moreover, our results suggest that IL-21 may contribute to AHR through its ability to both directly induce Th2 cell survival and to impair regulatory T-cell suppression of Th2 cytokine production. Importantly, we show that IL-21-positive cells are increased in the bronchial mucosa of asthmatics compared with non-asthmatics. CONCLUSION: These results suggest that IL-21 plays an important role in the allergic diathesis by enhancing Th2 cytokine production through multiple mechanisms including the suppression of Treg inhibitory effects on Th2 cell cytokine production.


Assuntos
Hipersensibilidade/imunologia , Hipersensibilidade/metabolismo , Receptores de Interleucina-21/metabolismo , Transdução de Sinais , Células Th2/imunologia , Células Th2/metabolismo , Alérgenos/imunologia , Animais , Hiper-Reatividade Brônquica/genética , Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Hipersensibilidade/genética , Imunoglobulina E/imunologia , Imunoglobulina E/metabolismo , Masculino , Camundongos , Camundongos Knockout , Receptores de Interleucina-21/deficiência , Receptores de Interleucina-21/genética , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo
4.
J Exp Med ; 179(5): 1551-61, 1994 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-7909326

RESUMO

Morbidity in humans infected with Schistosoma mansoni results primarily from the deposition of parasite eggs in portal areas where they induce a granulomatous response. In mice infected with this helminth granuloma formation is a CD4+ T helper (Th) cell-dependent process that is associated with a strong Th2 cytokine response which appears to evolve through a Th0 phase. In this report, we asked whether endogenously synthesized or exogenously induced interferon (IFN)gamma through its suppression of Th2 cell expansion exerts a regulatory role on egg pathology. Depletion of IFN-gamma or natural killer cells resulted in a marked enhancement of granuloma formation around intravenously injected eggs and was associated with increased Th2 and decreased Th1 and interleukin (IL)12 mRNA expression. Similar changes occurred when egg-injected mice were treated with neutralizing monoclonal antibodies specific for IL-12 indicating a role for this cytokine in the regulation of the granulomatous response. In contrast, treatment with exogenous rIL-12 profoundly inhibited primary granuloma formation while increasing IFN-gamma, IL-2, IL-10, and IL-12 pulmonary mRNA levels and suppressing IL-4, IL-5, IL-6, and IL-13 mRNA expression. Cytokine depletion studies indicated that the effects of IL-12 could be attributed primarily to increased IFN-gamma. Importantly, IL-12 also inhibited secondary granuloma formation in mice presensitized with eggs demonstrating a role for the cytokine in reversing established Th2-type responses. Moreover, mice sensitized with eggs in combination with IL-12 to precommit them toward a Th1 response developed only minimal granulomas upon subsequent egg challenge. The latter findings suggest that simultaneous vaccination with antigen plus IL-12 may provide a strategy for the prevention of schistosome egg pathology as well as other diseases stemming from Th2 cytokine production.


Assuntos
Granuloma/imunologia , Interleucinas/fisiologia , Schistosoma mansoni/imunologia , Esquistossomose mansoni/imunologia , Animais , Sequência de Bases , DNA , Feminino , Granuloma/parasitologia , Humanos , Interferon gama/imunologia , Interleucina-12 , Células Matadoras Naturais/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Testes de Neutralização , Óvulo/imunologia , Reação em Cadeia da Polimerase , Schistosoma mansoni/patogenicidade , Esquistossomose mansoni/prevenção & controle , Linfócitos T Auxiliares-Indutores/imunologia
5.
J Exp Med ; 194(10): 1497-506, 2001 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-11714756

RESUMO

Some pathogens (e.g., Mycobacterium tuberculosis, Toxoplasma gondii, Leishmania spp) have been shown to persist in their host after clinical cure, establishing the risk of disease reactivation. We analyzed the conditions necessary for the long term maintenance of Leishmania major in genetically resistant C57BL/6 mice after spontaneous healing of their dermal lesions. Interleukin (IL)-10 was found to play an essential role in parasite persistence as sterile cure was achieved in IL-10-deficient and IL-4/IL-10 double-deficient mice. The requirement for IL-10 in establishing latency associated with natural infection was confirmed in IL-10-deficient mice challenged by bite of infected sand flies. The host-parasite equilibrium was maintained by CD4+ and CD8+ T cells which were each able to release IL-10 or interferon (IFN)-gamma, and were found to accumulate in chronic sites of infection, including the skin and draining lymph node. A high frequency of the dermal CD4+ T cells released both IL-10 and IFN-gamma. Wild-type mice treated transiently during the chronic phase with anti-IL-10 receptor antibodies achieved sterile cure, suggesting a novel therapeutic approach to eliminate latency, infection reservoirs, and the risk of reactivation disease.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Interleucina-10/fisiologia , Leishmania major/fisiologia , Leishmaniose Cutânea/terapia , Receptores de Interleucina/antagonistas & inibidores , Pele/parasitologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Interferon gama/fisiologia , Interleucina-4/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Interleucina-10 , Pele/imunologia
6.
J Exp Med ; 185(11): 1959-68, 1997 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-9166425

RESUMO

CC chemokine receptor 1 (CCR1) is expressed in neutrophils, monocytes, lymphocytes, and eosinophils, and binds the leukocyte chemoattractant and hematopoiesis regulator macrophage inflammatory protein (MIP)-1alpha, as well as several related CC chemokines. Four other CCR subtypes are known; their leukocyte and chemokine specificities overlap with, but are not identical to, CCR1, suggesting that CCR1 has both redundant and specific biologic roles. To test this, we have developed CCR1-deficient mice (-/-) by targeted gene disruption. Although the distribution of mature leukocytes was normal, steady state and induced trafficking and proliferation of myeloid progenitor cells were disordered in -/- mice. Moreover, mature neutrophils from -/- mice failed to chemotax in vitro and failed to mobilize into peripheral blood in vivo in response to MIP-1alpha. Consistent with this, -/- mice had accelerated mortality when challenged with Aspergillus fumigatus, a fungus controlled principally by neutrophils. To test the role of CCR1 in granuloma formation, we injected Schistosoma mansoni eggs intravenously, and observed a 40% reduction in the size of lung granulomas in -/- mice compared to +/+ littermates. This was associated with increased interferon-gamma and decreased interleukin-4 production in -/- versus +/+ lung lymph node cells stimulated with egg-specific antigen, suggesting that CCR1 influences the inflammatory response not only through direct effects on leukocyte chemotaxis, but also through effects on the type 1-type 2 cytokine balance. Thus CCR1 has nonredundant functions in hematopoiesis, host defense, and inflammation.


Assuntos
Aspergilose/imunologia , Citocinas/metabolismo , Granuloma/imunologia , Hematopoese , Neutrófilos/imunologia , Receptores de Quimiocinas , Receptores de Citocinas/fisiologia , Animais , Aspergillus fumigatus , Cálcio/metabolismo , Divisão Celular , Quimiocina CCL3 , Quimiocina CCL4 , Quimiotaxia de Leucócito , Marcação de Genes , Células-Tronco Hematopoéticas/fisiologia , Interferon gama/metabolismo , Interleucina-4/metabolismo , Proteínas Inflamatórias de Macrófagos/farmacologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutagênese/genética , Receptores CCR1 , Receptores de Citocinas/deficiência , Receptores de Citocinas/genética , Esquistossomose mansoni/imunologia
7.
J Exp Med ; 184(4): 1295-304, 1996 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-8879201

RESUMO

A number of investigations have established the critical role of interleukin 4 (IL-4) in mediating the development of T helper (Th)2 effector cells in vitro and in vivo. Despite intensive study, the origin of the IL-4 required for Th2 priming and differentiation remains unclear. Natural killer (NK)1.1+ alpha/beta T cell receptor+ T(NT) cells, a unique lineage of cells capable of producing large amounts of IL-4 after activation in vivo, are important candidates for directing Th2 priming. These cells are selected by the nonpolymorphic major histocompatibility complex (MHC) class I molecule, CD1, and are deficient in beta 2-microglobulin (beta 2m)-null mice. We used beta 2m-deficient mice on both BALB/c and C57BL/6 backgrounds to examine their capacity to mount Th2 immune responses after challenge with a number of well-characterized antigens administered by a variety of routes. As assessed by immunization with protein antigen, infection with Leishmania major, embolization with eggs of Schistosoma mansoni, intestinal infection with Nippostrongylus brasiliensis, or induction of airway hyperreactivity to aerosolized antigen, beta 2m-deficient mice developed functional type 2 immune responses that were not substantially different than those in wild-type mice. Production of IL-4 and the generation of immunoglobulin E (IgE) and eosinophil responses were preserved as assessed by a variety of assays. Collectively, these results present a comprehensive analysis of type 2 immune responses in beta 2m-deficient mice, and indicate that beta 2m-dependent NT cells are not required for Th2 development in vivo.


Assuntos
Antígenos , Células Matadoras Naturais/imunologia , Proteínas , Subpopulações de Linfócitos T/imunologia , Células Th2/imunologia , Microglobulina beta-2/deficiência , Animais , Antígenos Ly , Antígenos de Superfície , Estudos de Avaliação como Assunto , Feminino , Granuloma/imunologia , Hemocianinas/imunologia , Imunidade , Lectinas Tipo C , Leishmaniose Cutânea/imunologia , Pneumopatias Parasitárias/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Mucosa/imunologia , Subfamília B de Receptores Semelhantes a Lectina de Células NK , Esquistossomose mansoni/imunologia , Infecções por Strongylida/imunologia
8.
J Exp Med ; 187(4): 619-29, 1998 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-9463412

RESUMO

The effector functions of CD4+ T lymphocytes are generally thought to be controlled by distinct populations of regulatory T cells and their soluble products. The role of B cells in the regulation of CD4-dependent host responses is less well understood. Hepatic egg granuloma formation and fibrosis in murine schistosomiasis are dependent on CD4+ lymphocytes, and previous studies have implicated CD8+ T cells or cross-regulatory cytokines produced by T helper (Th) lymphocytes as controlling elements of this pathologic process. In this report, we demonstrate that B cell-deficient (muMT) mice exposed to Schistosoma mansoni develop augmented tissue pathology and, more importantly, fail to undergo the spontaneous downmodulation in disease normally observed during late stages of infection. Unexpectedly, B cell deficiency did not significantly alter T cell proliferative response or cause a shift in the Th1/Th2 balance. Since schistosome-infected Fc receptor-deficient (FcR gamma chain knockout) mice display the same exacerbated egg pathology as that observed in infected muMT mice, the B cell- dependent regulatory mechanism revealed by these experiments appears to require receptor-mediated cell triggering. Together, the data demonstrate that humoral immune response/FcR interactions can play a major role in negatively controlling inflammatory disease induced by CD4+ T cells.


Assuntos
Linfócitos B/fisiologia , Linfócitos T CD4-Positivos/imunologia , Regulação para Baixo , Granuloma/patologia , Receptores Fc/fisiologia , Esquistossomose/patologia , Animais , Linfócitos B/imunologia , Granuloma/imunologia , Granuloma/parasitologia , Fígado/imunologia , Fígado/parasitologia , Fígado/patologia , Hepatopatias/imunologia , Hepatopatias/parasitologia , Hepatopatias/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Óvulo/imunologia , Esquistossomose/imunologia , Transdução de Sinais , Linfócitos T Auxiliares-Indutores/imunologia
9.
Science ; 262(5140): 1721-4, 1993 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-7903123

RESUMO

Peripheral blood mononuclear cells (PBMCs) from many asymptomatic individuals infected with human immunodeficiency virus-type 1 (HIV) are unresponsive as measured by in vitro T cell proliferation and interleukin-2 (IL-2) production to influenza virus and synthetic peptides of HIV envelope (Env). Strong influenza virus- and Env-stimulated IL-2 responses and T cell proliferation were restored when cultures were stimulated in the presence of IL-12. Interferon-gamma production by PBMCs from HIV seropositive (HIV+) patients was also restored with IL-12. Furthermore, in vitro antigen-specific production of IL-2 and proliferation of PBMCs from HIV- donors were suppressed by antibody to IL-12, but were not enhanced by addition of exogenous IL-12. Thus, IL-12 may be limiting in PBMCs from HIV+ but not HIV- individuals. These findings demonstrate that IL-12 can restore HIV-specific cell-mediated immunity in vitro in HIV-infected individuals and suggest a potential use of IL-12 in augmenting the diminished immunologic functions associated with HIV infection.


Assuntos
Infecções por HIV/imunologia , HIV-1/imunologia , Interleucinas/farmacologia , Linfócitos T Auxiliares-Indutores/imunologia , Células Cultivadas , Produtos do Gene env/imunologia , Humanos , Imunidade Celular , Vírus da Influenza A/imunologia , Interferon gama/biossíntese , Interleucina-12 , Interleucina-2/biossíntese , Interleucina-2/farmacologia , Interleucinas/imunologia , Células Matadoras Naturais/imunologia , Leucócitos Mononucleares/imunologia , Ativação Linfocitária , Fito-Hemaglutininas/imunologia , Proteínas Recombinantes/farmacologia
10.
Clin Exp Allergy ; 38(4): 594-601, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18307523

RESUMO

BACKGROUND: IL-13 plays a key regulatory role in asthmatic responses and immunity to parasitic infection. In vivo, IL-13R-alpha2 is a critical modulator of IL-13 bioactivity. When inducibly expressed on the surface of fibroblasts and other cell types under inflammatory conditions, IL-13R-alpha2 contributes to resolution of IL-13 responses. A soluble form of IL-13R-alpha2 (sIL-13R-alpha2) can be detected in murine circulation, and functions as a regulator of IL-13 bioactivity. In humans, sIL-13R-alpha2 has been more difficult to detect. Recently, novel assay systems have been described to quantitate sIL-13R-alpha2 in human circulation, and revealed unexpectedly high levels of sIL-13R-alpha2 in healthy subjects. OBJECTIVE: To verify sIL-13R-alpha2 quantitation in human plasma samples under stringent conditions of signal verification and false-positive detection. METHODS: A standard ELISA protocol was evaluated for specificity using false-positive detection reagents. A more stringent ELISA protocol was developed by optimizing the composition of blocking and dilution buffers. RESULTS: Using the stringent assay protocol, endogenous sIL-13R-alpha2 was undetectable in plasma samples from a total of 120 asthmatics and 20 healthy subjects, and in bronchoalveolar lavage fluid from 10 asthmatics and eight healthy subjects undergoing allergen challenge. CONCLUSION: These results underscore the necessity to perform rigorous assay controls in the biological matrix to be tested. Because the soluble form could not be demonstrated, our findings question a role for sIL-13R-alpha2 in the regulation of IL-13 bioactivity, and highlight the potentially important contribution of the membrane-bound form of IL-13R-alpha2 in humans.


Assuntos
Asma/sangue , Subunidade alfa2 de Receptor de Interleucina-13/sangue , Líquido da Lavagem Broncoalveolar/química , Ensaio de Imunoadsorção Enzimática/métodos , Ensaio de Imunoadsorção Enzimática/normas , Reações Falso-Positivas , Humanos , Subunidade alfa2 de Receptor de Interleucina-13/biossíntese , Valor Preditivo dos Testes , Valores de Referência , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Solubilidade
11.
Cancer Treat Rev ; 63: 28-39, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29202445

RESUMO

Radiation exposure to the thyroid gland during treatment of childhood, adolescent and young adult cancer (CAYAC) may cause differentiated thyroid cancer (DTC). Surveillance recommendations for DTC vary considerably, causing uncertainty about optimum screening practices. The International Late Effects of Childhood Cancer Guideline Harmonization Group, in collaboration with the PanCareSurFup Consortium, developed consensus recommendations for thyroid cancer surveillance in CAYAC survivors. These recommendations were developed by an international multidisciplinary panel that included 33 experts in relevant medical specialties who used a consistent and transparent process. Recommendations were graded according to the strength of underlying evidence and potential benefit gained by early detection and appropriate management. Of the two available surveillance strategies, thyroid ultrasound and neck palpation, neither was shown to be superior. Consequently, a decision aid was formulated to guide the health care provider in counseling the survivor. The recommendations highlight the need for shared decision making regarding whether to undergo surveillance for DTC and in the choice of surveillance modality.


Assuntos
Neoplasias/radioterapia , Exposição à Radiação/efeitos adversos , Glândula Tireoide/efeitos da radiação , Neoplasias da Glândula Tireoide/etiologia , Detecção Precoce de Câncer/métodos , Humanos , Sobreviventes
12.
J Clin Invest ; 104(6): 777-85, 1999 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-10491413

RESUMO

In schistosomiasis, chronic parasite egg-induced granuloma formation can lead to tissue destruction and fibrosis, which causes much of the morbidity and mortality associated with this disease. Here we show the importance of IL-13 in the pathogenesis of schistosomiasis, and demonstrate, perhaps for the first time, the therapeutic efficacy of an IL-13 inhibitor, sIL-13Ralpha2-Fc, in the control of hepatic fibrosis. T-helper type 2 (Th2) cytokines dominate the immune response in mice infected with Schistosoma mansoni, yet the specific contributions of IL-13 and IL-4 to the development of fibrosis were not previously investigated. Our studies demonstrate that both cytokines play redundant roles in granuloma formation, which explains the ability of IL-4-deficient mice to form granulomas around eggs. More importantly, however, these studies demonstrate that IL-13 is the dominant Th2-type cytokine regulating fibrosis. IL-13 stimulated collagen production in fibroblasts, and procollagen I and procollagen III mRNA expression was decreased in sIL-13Ralpha2-Fc-treated mice. Moreover, the reduction in fibrosis observed in IL-4-deficient mice was much less pronounced than that in sIL-13Ralpha2-Fc-treated animals. Fibrosis is a major pathological manifestation of a number of allergic, autoimmune, and infectious diseases. Thus, our findings provide evidence that IL-13 inhibitors may be of general therapeutic benefit in preventing damaging tissue fibrosis resulting from Th2-dominated inflammatory responses.


Assuntos
Interleucina-13/antagonistas & inibidores , Cirrose Hepática Experimental/prevenção & controle , Esquistossomose mansoni/terapia , Células Th2/imunologia , Células 3T3 , Animais , Citocinas/biossíntese , Citocinas/genética , Feminino , Interleucina-4/deficiência , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pró-Colágeno/genética , RNA Mensageiro/análise , Esquistossomose mansoni/complicações , Esquistossomose mansoni/imunologia , Células Th1/imunologia
13.
J Clin Invest ; 91(3): 759-65, 1993 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-8450057

RESUMO

Infection with HIV results in an incremental loss of T helper cell (TH) function, which can occur years before CD4 cell numbers are critically reduced and AIDS is diagnosed. All TH function is not affected, however, because B cell activation and hypergammaglobulinema are also characteristic of this period. Recently, in a murine model of AIDS an early loss in production of the CD4 cytokines IL-2 and IFN-gamma was correlated with an increase in the B cell stimulatory cytokines IL-4, IL-5, and IL-10. We therefore assessed the production of IL-4 generated by PBL from HIV-seropositive (HIV+) individuals who did not have AIDS, yet who exhibited different TH functional categories based on their IL-2 production profiles. We observed that the decreases in recall antigen-stimulated IL-2 production were accompanied by an increase in IL-4 production. The loss of recall antigen-stimulated responses in HIV+ individuals could be reversed in vitro by anti-IL-4 antibody. Our results suggest that the TH functions assessed by IL-4 production replace the normally dominant TH function of antigen-stimulated IL-2 production in the progression toward AIDS, and raise the possibility of cytokine cross-regulation in AIDS therapy.


Assuntos
Soropositividade para HIV/imunologia , HIV , Interleucina-2/biossíntese , Interleucina-4/biossíntese , Linfócitos/imunologia , Subpopulações de Linfócitos T/imunologia , Elementos Antissenso (Genética) , Sequência de Bases , Relação CD4-CD8 , Células Cultivadas , Anticorpos Anti-HIV/sangue , Soropositividade para HIV/sangue , Soropositividade para HIV/fisiopatologia , Humanos , Interleucina-2/sangue , Interleucina-4/sangue , Interleucina-4/genética , Ativação Linfocitária , Dados de Sequência Molecular , Oligodesoxirribonucleotídeos , Reação em Cadeia da Polimerase , RNA Mensageiro/análise , Valores de Referência
14.
J Clin Invest ; 93(2): 768-75, 1994 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-8113410

RESUMO

The loss of T helper cell (TH) function in asymptomatic HIV type 1-infected individuals occurs before the decline in CD4+ T cells. At least part of the loss in TH function results from changes in immunoregulatory cytokine profiles. To investigate the role of IL-10 in such dysregulation, we tested whether: (a) expression of IL-10-specific mRNA would be upregulated in PBMC from asymptomatic, HIV-infected (HIV+) individuals; (b) PBMC from these same individuals would produce increased levels of IL-10 when stimulated in vitro with phytohemagglutinin; and (c) defective antigen-specific TH function could be restored by anti-IL-10 antibody. We observed that IL-10-specific mRNA was marginally upregulated, and increased levels of IL-10 were produced by PBMC from HIV+ individuals compared with PBMC from uninfected individuals. Those individuals whose TH function was more severely compromised produced higher levels of IL-10. Additionally, defective antigen-specific TH function in vitro could be reversed by anti-IL-10 antibody, including the response to HIV envelope synthetic peptides. Furthermore, the antigen-specific TH responses of HIV-uninfected PBMC could be reduced with IL-10, a process reversed by anti-IL-10. These results confirm that the early loss of TH function in HIV+ individuals is due at least in part to cytokine-induced immune dysregulation, and support the hypothesis of a switch from a predominant type 1 state to a predominant type 2 condition in HIV infection.


Assuntos
Infecções por HIV/imunologia , Soropositividade para HIV/imunologia , Interleucina-10/biossíntese , Interleucina-10/fisiologia , Linfócitos/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T/imunologia , Antígenos CD/análise , Células Cultivadas , Expressão Gênica , Humanos , Imunofenotipagem , Interleucina-10/farmacologia , Interleucina-2/biossíntese , Ativação Linfocitária , RNA Mensageiro/biossíntese , RNA Mensageiro/metabolismo , Linfócitos T/efeitos dos fármacos
15.
J Clin Invest ; 91(4): 1644-8, 1993 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-8097208

RESUMO

The immunological mechanisms underlying the susceptibility to disseminated visceral parasitism of mononuclear phagocytes in patients with kala-azar remain undefined. Resistance and susceptibility are correlated with distinct patterns of cytokine production in murine models of disseminated leishmanial disease. To assess lesional cytokine profiles in patients with kala-azar, bone marrow aspirates were analyzed using a quantitative reverse transcriptase PCR technique to amplify specific mRNA sequences of multiple Th1-, Th2-, and/or macrophage-associated cytokines. Transcript levels of IL-10 as well as IFN-gamma were significantly elevated in patients with active visceral leishmaniasis; IL-10 levels decreased markedly with resolution of disease. These findings suggest that IL-10, a potent, pleiotropic suppressor of all known microbicidal effector functions of macrophages, may contribute to the pathogenesis of kala-azar by inhibiting the cytokine-mediated activation of host macrophages that is necessary for the control of leishmanial infection.


Assuntos
Medula Óssea/química , Medula Óssea/patologia , Citocinas/fisiologia , Interferon gama/análise , Interleucina-10/análise , Leishmaniose Visceral/metabolismo , Leishmaniose Visceral/patologia , Adolescente , Adulto , Sequência de Bases , Linfócitos T CD4-Positivos/fisiologia , Criança , Citocinas/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Fenótipo , RNA Mensageiro/análise , Subpopulações de Linfócitos T/fisiologia
16.
Curr Opin Immunol ; 7(4): 505-11, 1995 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-7495514

RESUMO

Granuloma induced by the schistosome egg is an inflammatory reaction that is tightly controlled by the interaction of T-helper cell type 1 (Th1) and Th2 cytokines produced locally. Studies focussing on the immunoregulation of the response have yielded numerous insights into the cytokine cascade that controls the formation of the lesions. It is clear from current data that the Th2 cytokines play a primary role in granuloma formation, whereas the Th1-associated lymphokine interferon-gamma acts as an endogenous downregulator of the response. Through recent advances, it may now be possible to design effective cytokine-based vaccination strategies that will suppress the tissue pathology associated with this helminth infection.


Assuntos
Citocinas/fisiologia , Granuloma/etiologia , Esquistossomose/complicações , Animais
17.
Curr Opin Immunol ; 11(4): 420-6, 1999 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-10448138

RESUMO

Helminth infections induce the production of type 2 cytokines, which contribute both to expulsion of the worms and inflammatory responses that can either protect or damage the host. Although IL-4 has been considered the most critical cytokine for both inflammation and protective immunity, recent observations indicate that IL-13 - a related cytokine - can have equal or even greater importance than IL-4 in inflammatory responses and host protection against infection.


Assuntos
Inflamação/etiologia , Interleucina-13/fisiologia , Infecções por Nematoides/imunologia , Animais , Sistema Digestório/parasitologia , Humanos , Interleucina-4/fisiologia , Linfócitos T/imunologia
18.
J Natl Cancer Inst ; 88(13): 899-907, 1996 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-8656442

RESUMO

BACKGROUND: Experimental and epidemiologic evidence suggests that increased dietary fiber is associated with decreased breast cancer risk. Little is known about the role played by different types of fiber and, particularly, mixtures of soluble and insoluble fibers similar to those consumed by human populations in reducing breast cancer risk. High intake of fiber may suppress bacterial hydrolysis of biliary estrogen conjugates to free (absorbable) estrogens in the colon and thus may decrease the availability of circulating estrogens necessary for the development and growth of breast cancers. PURPOSE: The purpose of this study was to evaluate the effect of wheat bran (an insoluble fiber) and psyllium (a soluble fiber) alone and in combination on overall estrogen status, on fecal bacterial beta-D-glucuronidase (a key diet-responsive estrogen-deconjugating enzyme) activity, and on the induction of mammary tumors in rats treated with N-methylnitrosourea (MNU). METHODS: One hundred fifty virgin female F344 rats were fed the NIH-07 diet from 28 days of age until 50 days of age; they were then given a single dose (40 mg/kg of body weight) of MNU by tail vein injection. Three days later, they were randomly assigned to one of five experimental dietary groups (30 animals per group). Soft, white wheat bran (45% dietary fiber content) and psyllium (80% dietary fiber content) were added to a modified (high-fat) American Institute of Nutrition (AIN)-76A diet at the following percents, respectively: 12% + 0% (group 1), 8% + 2% (group 2), 6% + 3% (group 3), 4% + 4% (group 4), and 0% + 6% (group 5). Blood, urine, and feces were collected and analyzed by radioimmunoassay techniques for estrogens. Cecal contents were analyzed for bacterial beta-D-glucuronidase activity. After 19 weeks on the experimental diets, the rats were killed, and mammary tumors were counted and classified by histologic type. Cumulative tumor incidence was evaluated by the Kaplan-Meier life-table method and the logrank test. Tumor number was evaluated by the chi-squared test of association, and tumor multiplicity was evaluated by the Mantel-Haenszel chi-squared test. All statistical tests were two-tailed. RESULTS: As the level of psyllium relative to that of wheat bran increased, the total tumor number and multiplicity of mammary adenocarcinomas in rats decreased as a statistically significant linear trend across groups 1-5 (P < .05). Compared with the group given wheat bran alone, the group given the 1:1 (wheat bran:psyllium) combination had maximum protection against mammary tumorigenesis, while the groups given the 4:1 or 2:1 (wheat bran:psyllium) combination or psyllium alone had intermediate protection. No statistically significant differences in circulating estrogens or urinary estrogen excretion patterns were observed among the five experimental groups. Fecal estrogen excretion, however, decreased with increasing levels of psyllium (P < .01), and cecal beta-D-glucuronidase activity exhibited a decreasing trend with respect to the increasing psyllium content of the diet across groups 1-5 (P < .01). CONCLUSIONS: The addition of a 4%:4% mixture of an insoluble (wheat bran) fiber and a soluble (psyllium) fiber to a high-fat diet provided the maximum tumor-inhibiting effects in this mammary tumor model. Although increasing levels of dietary psyllium were associated with decreased cecal bacterial beta-D-glucuronidase activity, these changes were not reflected in decreased circulating levels of tumor-promoting estrogens. Therefore, the mechanism(s) by which mixtures of soluble and insoluble dietary fibers protect against mammary tumorigenesis remains to be clarified.


Assuntos
Fibras na Dieta/administração & dosagem , Estrogênios/sangue , Neoplasias Mamárias Experimentais/prevenção & controle , Psyllium/administração & dosagem , Animais , Ceco/enzimologia , Ceco/microbiologia , Relação Dose-Resposta a Droga , Estrogênios/metabolismo , Feminino , Glucuronidase/metabolismo , Neoplasias Mamárias Experimentais/sangue , Neoplasias Mamárias Experimentais/induzido quimicamente , Metilnitrosoureia , Radioimunoensaio , Distribuição Aleatória , Ratos , Ratos Endogâmicos F344 , Aumento de Peso
19.
Cancer Res ; 56(3): 532-7, 1996 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-8564967

RESUMO

Epidemiological and laboratory animal model studies suggest that the effect of dietary fat in colon carcinogenesis depends not only on the amount but on its fatty acid composition. Animal model studies demonstrated that high dietary corn oil or safflower oil rich in omega-6 fatty acids increased the colon tumor promotion, whereas diets containing fish oil high in omega-3 fatty acids had no such enhancing effect. One of the mechanisms by which high dietary fat enhances colon carcinogenesis may be through the modulation of colonic mucosal phospholipase A2 (PLA2) and phosphatidylinositol-specific phospholipase C (PI-PLC), which are dominant pathways for arachidonic acid release and formation of eicosanoids. PI-PLC is also responsible for diacylglycerol formation and protein kinase C-dependent signal transduction and cell proliferation. In the present study, we investigated the modulating effect of high fat diets rich in omega-3 and omega-6 fatty acids on colonic mucosal PLA2, PI-PLC activities, and eicosanoid (prostaglandins and thromboxane B2) formation from arachidonic acid via cyclooxygenase (COX) during different stages of azoxymethane (AOM)-induced colon carcinogenesis in male F344 rats. At 5 weeks of age, groups of animals were fed the low-fat diet containing 5% corn oil. Beginning at 7 weeks of age, all animals except those intended for vehicle treatment received AOM s.c. once weekly for 2 weeks at a dose rate of 15 mg/kg body weight. Vehicle-treated groups received an equal volume of normal saline. One day after the second AOM or vehicle treatment, groups of animals were transferred to experimental diets containing 23.5% corn oil and 20.5% fish oil + 3% corn oil, whereas one group continued on the low-fat diet containing 5% corn oil. Groups of animals were then sacrificed at weeks 1, 12, and 36 after the second AOM-or saline-treatment. Colonic mucosa harvested at weeks 1, 12, and 36 and colonic tumors obtained at week 36 were analyzed for PLA2, PI-PLC, and eicosanoid formation from arachidonic acid by the action of COX. The results demonstrate that colon carcinogen treatment increases the activities of colonic mucosal PLA2 and PI-PLC and the formation of prostaglandins and thromboxane A2 from arachidonic acid through COX throughout the study period compared to saline-treated animals fed similar diets. The activities of PLA2, PI-PLC, and COX were significantly higher in colon tumors compared to colonic mucosa. These results also demonstrate that a high-fat diet containing corn oil increases colonic mucosal and tumor PLA2 and PI-PLC and the formation of prostaglandins and thromboxane B2 by the action of COX as compared to low dietary corn oil or a diet high in fish oil. The results of our study offer one of the mechanisms by which the amount and types of dietary fat modulate colon carcinogenesis.


Assuntos
Colo/enzimologia , Neoplasias do Colo/enzimologia , Neoplasias do Colo/etiologia , Gorduras Insaturadas na Dieta/efeitos adversos , Mucosa Intestinal/enzimologia , Fosfolipases A/metabolismo , Diester Fosfórico Hidrolases/metabolismo , Prostaglandina-Endoperóxido Sintases/metabolismo , Animais , Ácido Araquidônico/metabolismo , Colo/efeitos dos fármacos , Óleo de Milho/administração & dosagem , Relação Dose-Resposta a Droga , Eicosanoides/biossíntese , Óleos de Peixe/administração & dosagem , Técnicas In Vitro , Mucosa Intestinal/efeitos dos fármacos , Masculino , Fosfatidilinositol Diacilglicerol-Liase , Fosfoinositídeo Fosfolipase C , Fosfolipases A/efeitos dos fármacos , Fosfolipases A2 , Diester Fosfórico Hidrolases/efeitos dos fármacos , Prostaglandina-Endoperóxido Sintases/efeitos dos fármacos , Ratos , Ratos Endogâmicos F344
20.
Mucosal Immunol ; 9(1): 38-55, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25921340

RESUMO

The roles of macrophages in type 2-driven inflammation and fibrosis remain unclear. Here, using CD11b-diphtheria toxin receptor (DTR) transgenic mice and three models of interleukin 13 (IL-13)-dependent inflammation, fibrosis, and immunity, we show that CD11b(+) F4/80(+) Ly6C(+) macrophages are required for the maintenance of type 2 immunity within affected tissues but not secondary lymphoid organs. Direct depletion of macrophages during the maintenance or resolution phases of secondary Schistosoma mansoni egg-induced granuloma formation caused a profound decrease in inflammation, fibrosis, and type 2 gene expression. Additional studies with CD11c-DTR and CD11b/CD11c-DTR double-transgenic mice suggested that macrophages but not dendritic cells were critical. Mechanistically, macrophage depletion impaired effector CD4(+) T helper type 2 (Th2) cell homing and activation within the inflamed lung. Depletion of CD11b(+) F4/80(+) Ly6C(+) macrophages similarly reduced house dust mite-induced allergic lung inflammation and suppressed IL-13-dependent immunity to the nematode parasite Nippostrongylus brasiliensis. Consequently, therapeutic strategies targeting macrophages offer a novel approach to ameliorate established type 2 inflammatory diseases.


Assuntos
Interleucina-13/imunologia , Macrófagos Alveolares/imunologia , Pneumonia/imunologia , Esquistossomose mansoni/imunologia , Infecções por Strongylida/imunologia , Células Th2/imunologia , Animais , Antígenos de Diferenciação/genética , Antígenos de Diferenciação/imunologia , Antígenos Ly/genética , Antígenos Ly/imunologia , Antígeno CD11b/genética , Antígeno CD11b/imunologia , Fibrose , Regulação da Expressão Gênica , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/genética , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/imunologia , Interleucina-13/genética , Pulmão/imunologia , Pulmão/parasitologia , Pulmão/patologia , Macrófagos Alveolares/parasitologia , Macrófagos Alveolares/patologia , Camundongos , Camundongos Transgênicos , Nippostrongylus/imunologia , Nippostrongylus/patogenicidade , Pneumonia/parasitologia , Pneumonia/patologia , Pyroglyphidae/imunologia , Schistosoma mansoni/imunologia , Schistosoma mansoni/patogenicidade , Esquistossomose mansoni/parasitologia , Esquistossomose mansoni/patologia , Transdução de Sinais , Infecções por Strongylida/parasitologia , Infecções por Strongylida/patologia , Células Th2/parasitologia , Células Th2/patologia
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