RESUMO
Glomerulonephritis (GN), the major worldwide cause of chronic renal disease and renal failure, shows a wide spectrum of histological patterns, severity of injury and clinical outcomes that may be related to the nature of the nephritogenic immune response. In the majority of cases, there is evidence of a central role for cognate immunity in the initiation of human GN and contributions of both humoral and cellular effector mechanisms have been demonstrated in both humans and in animal models. T helper cell subsets are known to activate different immune effector mechanisms which influence disease outcomes in infectious and autoimmune diseases and evidence is now accumulating that Th1 and Th2 subsets direct diverging effector pathways that lead to different patterns and severity of glomerular injury in GN. Th1-predominant responses appear to be associated strongly with proliferative and crescentic forms of GN that result in severe renal injury, while Th2 responses are associated with membranous patterns of injury. The challenge remains to understand fully the relevance of T helper cell subset responses to the spectrum of human GN and to apply this new knowledge to the development of more potent and selective therapeutic strategies.
Assuntos
Glomerulonefrite/imunologia , Células Th1/imunologia , Células Th2/imunologia , Animais , Anticorpos Anticitoplasma de Neutrófilos/análise , Citocinas/imunologia , Modelos Animais de Doenças , Glomerulonefrite/terapia , Humanos , CamundongosRESUMO
The effect of cytotoxic T-lymphocyte-associated molecule 4-immunoglobulin fusion protein (CTLA4-Fc) on humorally-mediated glomerulonephritis was studied in accelerated anti-glomerular basement membrane (anti-GBM) glomerulonephritis induced in BALB/c mice. This strain of mice develops antibody and complement dependent glomerulonephritis under this protocol. Sensitized BALB/c mice developed high levels of circulating autologous antibody titres, intense glomerular deposition of mouse immunoglobulin and complement, significant proteinuria, renal impairment, significant glomerular necrosis and a minor component of crescent formation 10 days after challenge with a nephritogenic antigen (sheep anti-GBM globulin). Early treatment during the primary immune response, or continuous treatment throughout the disease with CTLA4-Fc, significantly suppressed mouse anti-sheep globulin antibody titres in serum, and immunoglobulin and complement deposition in glomeruli. The degree of glomerular necrosis was improved and proteinuria was reduced, particularly in the earlier stages of disease. Late treatment by CTLA4-Fc starting one day after challenge with sheep anti-mouse GBM did not affect antibody production and did not attenuate glomerulonephritis. The low level of crescent formation found in BALB/c mice developing glomerulonephritis was not prevented by the administration of CTLA4-Fc. These results demonstrate that CTLA4-Fc is of benefit in this model of glomerulonephritis by its capacity to attenuate antibody production, without affecting the minor degree of cell-mediated glomerular injury.
Assuntos
Doença Antimembrana Basal Glomerular/tratamento farmacológico , Antígenos de Diferenciação/uso terapêutico , Imunoconjugados , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Glomérulos Renais/lesões , Abatacepte , Animais , Doença Antimembrana Basal Glomerular/patologia , Anticorpos/efeitos adversos , Antígenos CD , Antígenos de Diferenciação/administração & dosagem , Autoanticorpos , Antígeno CTLA-4 , Modelos Animais de Doenças , Globulinas/efeitos adversos , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Glomérulos Renais/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/uso terapêutico , OvinosRESUMO
Conflicting reports exist regarding the effects of interleukin-10 (IL-10) on mesangial cells. There have been reports of both proliferative and antiproliferative effects, and both proinflammatory and anti-inflammatory effects of IL-10 on mesangial cells. However, the potential for IL-10 to affect glomerulonephritis characterized by mesangial proliferation is not known. To test the hypothesis that IL-10 would limit experimental mesangial proliferative glomerulonephritis, IL-10 was administered to rats in which mesangial proliferative glomerulonephritis was induced by administration of anti-Thy 1 antibody. Compared to control treated rats, IL-10 treated rats showed less proliferation, with fewer cells in glomeruli. Glomerular cellular proliferation was reduced, assessed by the numbers of cells within glomeruli expressing either proliferating cell nuclear antigen (PCNA) or bromodeoxyuridine. Glomerular macrophage influx (but not the proportion of glomerular macrophages that were PCNA positive) was reduced by IL-10 administration. There was no significant reduction in glomerular alpha-smooth muscle actin staining. IL-10 treatment resulted in reduced renal IL-1beta mRNA expression and reduced glomerular ICAM-1 expression, but renal expression of MCP-1 and osteopontin mRNA was unaltered. This study demonstrates that in experimental mesangial proliferative glomerulonephritis IL-10 diminishes inflammatory cell recruitment and mesangial cell proliferation. The effects of IL-10 in inhibiting mesangial cell proliferation are likely to be due to a combination of direct effects of IL-10 on mesangial cells and effects mediated by macrophages.
Assuntos
Glomerulonefrite Membranoproliferativa/tratamento farmacológico , Interleucina-10/uso terapêutico , Animais , Anticorpos/farmacologia , Divisão Celular/efeitos dos fármacos , Movimento Celular , Quimiocina CCL2/biossíntese , Quimiocina CCL2/genética , Mesângio Glomerular/efeitos dos fármacos , Mesângio Glomerular/metabolismo , Mesângio Glomerular/patologia , Glomerulonefrite Membranoproliferativa/metabolismo , Glomerulonefrite Membranoproliferativa/patologia , Molécula 1 de Adesão Intercelular/biossíntese , Molécula 1 de Adesão Intercelular/genética , Interleucina-1/biossíntese , Interleucina-1/genética , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Osteopontina , RNA Mensageiro/biossíntese , Ratos , Ratos Sprague-Dawley , Sialoglicoproteínas/biossíntese , Sialoglicoproteínas/genética , Antígenos Thy-1/imunologiaRESUMO
Crescentic forms of glomerulonephritis are characterized by the accumulation of fibrin and cells in Bowman's space and are associated with a rapid loss of renal function. Accumulation of fibrin in the glomerular tufts is thought to promote macrophage infiltration and glomerular injury. To directly explore the role of fibrin(ogen) in the development of crescentic glomerulonephritis, antiglomerular basement membrane nephritis was induced in fibrinogen-deficient and control mice. Glomeruli from control mice developed severe disease including fibrin deposits, inflammatory cell accumulation, and crescent formation (46.3 +/- 7.3% of glomeruli). Fibrinogen-deficient mice developed significantly milder disease with fewer glomerular crescents (24.0 +/- 4.7% of glomeruli; P < 0.03). Glomerular macrophage accumulation was diminished in fibrinogen-deficient mice (0.9 +/- 0.4 macrophages/glomerular cross section) relative to control mice (3.9 +/- 1.4 macrophages/glomerular cross section; P < 0.03). Finally, renal function as assessed by serum creatinine was better maintained in fibrinogen-deficient mice. These results indicate that although fibrin(ogen) is not essential for the development of glomerular crescents, it contributes significantly to the pathogenesis of crescentic glomerulonephritis by promoting glomerular macrophage accumulation and impairing filtration.
Assuntos
Fibrinogênio/genética , Fibrinogênio/fisiologia , Glomerulonefrite/etiologia , Animais , Creatinina/sangue , Fibrinogênio/imunologia , Glomerulonefrite/imunologia , Glomerulonefrite/patologia , Glomerulonefrite/fisiopatologia , Imunoglobulinas/sangue , Imuno-Histoquímica , Rim/fisiopatologia , Glomérulos Renais/patologia , Macrófagos , Camundongos , Camundongos Knockout , Reação do Ácido Periódico de Schiff , Ovinos , Análise de SobrevidaRESUMO
Oral combined hormone replacement therapy (HRT) with oestradiol and norethisterone increases plasma levels of prothrombin fragment 1+2 (F1+2), indicating an increase in thrombin generation, but the mechanisms underlying this increase are uncertain. The aim of this randomized, placebo-controlled study was to determine whether an increase in factor VII, a factor that combines with tissue factor to activate the extrinsic pathway, or a decrease in tissue factor pathway inhibitor (TFPI), an inhibitor of extrinsic pathway activation, may contribute to increases in thrombin generation occurring with HRT. Healthy postmenopausal women aged 50-75 years received placebo (n=19) or oral combined HRT (n=18) and had blood collected for measurement of factor VII coagulation activity (VIIc), activated factor VII (VIIa) and TFPI at baseline and at 6 weeks. Baseline characteristics were similar in the two groups, including age, body mass index and cholesterol levels. As reported previously, HRT increased the F1+2 concentration by 20%. Placebo had no effect on VIIc, VIIa or TFPI, but 6 weeks of combined HRT decreased VIIc [from 1.11+/-0.06 (mean+/-S.E.M.) to 1.03+/-0.06 i.u./ml; P<0.03], VIIa [from 43.9; 10.8-198.3 (median; range) to 35.0; 6.3-66.8 m-units/ml; P<0.03] and TFPI [from 81.3+/-6.5 to 60.4+/-5.5 ng/ml; P<0.0001]. The decrease in TPFI with HRT was not correlated with the elevation in F1+2 levels. In conclusion, the increase in thrombin generation seen with HRT is not due to an effect on factor VII; in addition, while a contribution from the decrease in TFPI is possible, increased thrombin generation is not directly related to the decrease in TFPI.
Assuntos
Estradiol/fisiologia , Terapia de Reposição de Estrogênios/métodos , Fator VII/fisiologia , Tromboplastina/fisiologia , Fatores Etários , Idoso , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Método Duplo-Cego , Ensaio de Imunoadsorção Enzimática , Fator VII/análise , Feminino , Humanos , Pessoa de Meia-Idade , Noretindrona/farmacologia , Distribuição Normal , Congêneres da Progesterona/farmacologia , Estatísticas não Paramétricas , Trombina/metabolismo , Tromboplastina/análise , Tromboplastina/antagonistas & inibidoresRESUMO
MHC II and CD4+ T cells are required for anti-glomerular basement membrane (GBM) globulin-initiated crescentic glomerulonephritis (GN) in mice, but the role of MHC I and CD8+ T cells is unclear. The cytolytic function of CD8+ T cells requires recognition of peptide antigens presented on MHC I. CD8+ T cells can also perform helper functions via cytokine production. The contribution of MHC I to crescentic GN was investigated using TAP-1 gene knock out (TAP-1-/-) mice, which have deficient MHC I antigen presentation. Heterozygous TAP-1 mice have normal MHC I expression and developed GN with crescents in 42 +/- 4% of glomeruli (normal 0%), proteinuria (9.1 +/- 1.6 mg/20 h, normal 1.5 +/- 0.3 mg/20 h) and impaired renal function (creatinine clearance 110 +/- 8 microl/min, normal 193 +/- 10 microl/min) following administration of sheep anti-mouse GBM globulin. TAP-1-/- mice, which have extremely low MHC I expression and reduced CD8+ T cells, developed similar GN with 39 +/- 3% crescents, proteinuria (12.7 +/- 4.3 mg/20 h) and impaired renal function (creatinine clearance 123 +/- 20 microl/min). In vivo antibody-induced CD8 depletion did not attenuate crescent formation or protect renal function in C57Bl/6 mice developing GN, although significant reduction in proteinuria (5.3 +/- 1.2 mg/20 h, P = 0. 012) and glomerular recruitment of CD4+ T cells and macrophages were observed compared with control treated mice with GN. These data demonstrate that MHC I is not required for development of crescentic GN in mice. The MHC I-independent contribution of CD8+ T cells to proteinuria and inflammatory cell recruitment suggests that they may serve a 'helper' rather than cytolytic role in this disease.
Assuntos
Transportadores de Cassetes de Ligação de ATP/imunologia , Glomerulonefrite/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Complexo Principal de Histocompatibilidade , Membro 2 da Subfamília B de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Animais , Linfócitos T CD8-Positivos/imunologia , Globulinas/imunologia , Depleção Linfocítica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , OvinosRESUMO
IL-18 (formerly known as IFN-gamma-inducing factor) enhances Th1 responses via effects that are thought to be dependent on and synergistic with IL-12. The potential for IL-18 to exert IL-12-independent effects in delayed-type hypersensitivity (DTH) responses was studied in a model of Th1-directed, DTH-mediated crescentic glomerulonephritis induced by planting an Ag in glomeruli of sensitized mice as well as in cutaneous DTH. Sensitized genetically normal (IL-12(+/+)) mice developed proteinuria and crescentic glomerulonephritis with a glomerular influx of DTH effectors (CD4(+) T cells, macrophages, and fibrin deposition) in response to the planted glomerular Ag. IL-12p40-deficient (IL-12(-/-)) mice showed significant reductions in crescent formation, proteinuria, and glomerular DTH effectors. Administration of IL-18 to IL-12(-/-) mice restored the development of histological (including effectors of DTH) and functional glomerular injury in IL-12(-/-) mice to levels equivalent to those in IL-12(+/+) mice. IL-18 administration to IL-12(-/-) mice increased glomerular ICAM-1 protein expression, but did not restore Ag-stimulated splenocyte IFN-gamma, GM-CSF, IL-2, or TNF-alpha production. Sensitized IL-12(+/+) mice also developed cutaneous DTH following intradermal challenge with the nephritogenic Ag. Cutaneous DTH was inhibited in IL-12(-/-) mice, but was restored by administration of IL-18. IL-12(+/+) mice given IL-18 developed augmented injury, with enhanced glomerular and cutaneous DTH, demonstrating the synergistic effects of IL-18 and IL-12 in DTH responses. These studies demonstrate that even in the absence of IL-12, IL-18 can induce in vivo DTH responses and up-regulate ICAM-1 without inducing IFN-gamma, GM-CSF, or TNF-alpha production.
Assuntos
Glomerulonefrite/imunologia , Hipersensibilidade Tardia/imunologia , Interleucina-12/fisiologia , Interleucina-18/fisiologia , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/genética , Adjuvantes Imunológicos/fisiologia , Animais , Citocinas/biossíntese , Glomerulonefrite/genética , Glomerulonefrite/prevenção & controle , Hipersensibilidade Tardia/genética , Hipersensibilidade Tardia/prevenção & controle , Imunidade Celular/genética , Imunoglobulina G/biossíntese , Imunoglobulina G/sangue , Injeções Intraperitoneais , Molécula 1 de Adesão Intercelular/biossíntese , Interleucina-12/biossíntese , Interleucina-12/deficiência , Interleucina-12/genética , Interleucina-18/administração & dosagem , Interleucina-18/genética , Glomérulos Renais/imunologia , Glomérulos Renais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Proteínas Recombinantes/administração & dosagem , Testes Cutâneos , Baço/citologia , Baço/imunologia , Baço/metabolismoRESUMO
Increased understanding of the fundamental importance of the role of chemokines and their receptors in inflammation, together with the demonstration of their involvement in human and experimental inflammatory renal disease, make these molecules potential therapeutic targets. A number of recent studies using genetically deficient mice and chemokine receptor antagonists in animal models have demonstrated that chemokine inhibition can attenuate experimental renal injury. Because there is simultaneous expression of multiple chemokines and receptors in disease, strategies that are aimed at antagonizing multiple chemokines receptor interactions are likely to be more effective than therapies that target a single chemokine. It is also now recognized that chemokines are involved in normal immune development and immune regulation. These observations, together with the results of studies that have demonstrated deleterious effects of chemokine receptor antagonism in experimental renal disease, highlight the need for thorough understanding of the role of individual chemokines in the pathogenesis of different types of renal disease before optimal therapeutic interventions may be achieved.
Assuntos
Quimiocinas CX3C , Quimiocinas/fisiologia , Nefropatias/tratamento farmacológico , Nefropatia Associada a AIDS/imunologia , Animais , Quimiocina CCL2/fisiologia , Quimiocina CX3CL1 , Quimiocinas CXC/fisiologia , Glomerulonefrite/tratamento farmacológico , Humanos , Nefropatias/imunologia , Transplante de Rim/imunologia , Proteínas de Membrana/fisiologia , Camundongos , Receptores CCR1 , Receptores de Quimiocinas/fisiologiaRESUMO
Crescentic glomerulonephritis (GN) is the histopathological correlate of the clinical syndrome of rapidly progressive glomerulonephritis. Glomerular crescent formation complicates proliferative forms of GN and indicates severe disease with a poor renal prognosis. In the past 10 years evidence from experimental models of GN and from human disease has accumulated suggesting that crescentic glomerulonephritis is a manifestation of a delayed type hypersensitivity (DTH)-like response to nephritogenic antigens. The elucidation of T helper 1 (Th1) and Th2 subsets in mice and in humans has led to the hypothesis that crescentic GN is a manifestation of a Th1 predominant DTH mediated immune response. Recent experiments performed mainly in a murine model of crescentic glomerulonephritis have tested this hypothesis. Crescent formation in this model is substantially interleukin (IL)-12 and interferon-gamma (IFN-gamma) dependent. Administration of IL-12, deletion of endogenous IL-4 or IL-10 results in enhanced disease, while administration of exogenous IL-4 and/or IL-10 reduces crescentic injury. These findings, together with the available evidence from human studies (examining the pattern of immune effectors in glomeruli, data on cytokine production by peripheral blood mononuclear cells and case reports of the induction of proliferative and/or crescentic GN by administration of IFN-gamma or IL-2) suggest that human crescentic GN is manifestation of a Th1 mediated DTH-like nephritogenic immune response.
Assuntos
Glomerulonefrite/imunologia , Células Th1/imunologia , Animais , Membrana Basal/imunologia , Glomerulonefrite/classificação , Humanos , Hipersensibilidade Tardia/imunologia , Glomérulos Renais/imunologia , Células Th2/imunologiaRESUMO
The contribution of B7.1 and B7.2 co-stimulation to Th1-directed, cell-mediated renal injury was studied in a murine model of crescentic glomerulonephritis (GN) initiated by a "planted" antigen. Mice treated with anti-B7.2 monoclonal antibody (mAb), starting prior to disease initiation, developed more severe renal injury with increased glomerular crescent formation (p = 0.031), glomerular accumulation of T cells (p = 0.014) and proteinuria (p = 0.022) compared to mice treated with control antibodies. Mice treated with anti-B7.1 mAb had reduced crescent formation (p = 0.019) compared to control treated mice, but reductions in glomerular CD4(+) T cell accumulation and proteinuria were not statistically significant. B7. 1 mAb treatment significantly reduced all parameters of renal injury (above) compared to anti-B7.2 mAb treatment. Neither treatment altered the circulating antibody titer or cutaneous delayed type hypersensitivity to the nephritogenic antigen. Antibody subclasses and antigen-stimulated ex vivo splenocyte IL-4, IL-10 and IFN-gamma production did not indicate effects on Th subset responses. Treatment with CTLA4-Fc or combined treatment with anti-B7.1 and B7. 2 antibodies did not significantly attenuate crescentic GN. These data indicate that B7.1 and B7.2 are important co-stimulatory molecules involved in crescentic GN, which have opposing effects on disease development without altering the T helper cell subset response to the nephritogenic antigen.
Assuntos
Antígenos CD/imunologia , Antígeno B7-1/imunologia , Glomerulonefrite/imunologia , Glicoproteínas de Membrana/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Antígeno B7-2 , Citocinas/imunologia , Glomerulonefrite/etiologia , Glomerulonefrite/patologia , Camundongos , Receptores de Antígenos de Linfócitos T/imunologia , OvinosRESUMO
Protease-activated receptor (PAR)-1 is a cellular receptor for thrombin that is activated after proteolytic cleavage. The contribution of PAR-1 to inflammatory cell-mediated renal injury was assessed in murine crescentic glomerulonephritis (GN). A pivotal role for thrombin in this model was demonstrated by the capacity of hirudin, a selective thrombin antagonist, to attenuate renal injury. Compared with control treatment, hirudin significantly reduced glomerular crescent formation, T cell and macrophage infiltration, fibrin deposition, and elevated serum creatinine, which are prominent features of GN. PAR-1-deficient (PAR-1(-/-)) mice, which have normal coagulation, also showed significant protection from crescentic GN compared with wild-type mice. The reductions in crescent formation, inflammatory cell infiltration, and serum creatinine were similar in PAR-1(-/-) and hirudin-treated mice, but hirudin afforded significantly greater protection from fibrin deposition. Treatment of wild-type mice with a selective PAR-1-activating peptide (TRAP) augmented histological and functional indices of GN, but TRAP treatment did not alter the severity of GN in PAR(-/-) mice. These results indicate that activation of PAR-1 by thrombin or TRAP amplifies crescentic GN. Thus, in addition to its procoagulant role, thrombin has proinflammatory, PAR-1-dependent effects that augment inflammatory renal injury.
Assuntos
Glomerulonefrite/fisiopatologia , Glomérulos Renais/fisiopatologia , Receptores de Trombina/metabolismo , Trombina/farmacologia , Animais , Antitrombinas/farmacologia , Glomerulonefrite/etiologia , Glomerulonefrite/genética , Hirudinas/farmacologia , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/metabolismo , Masculino , Camundongos , Tempo de Tromboplastina Parcial , Fragmentos de Peptídeos/farmacologia , Contagem de Plaquetas , Inibidores de Proteases/farmacologia , Receptor PAR-1 , Receptores de Trombina/agonistas , Receptores de Trombina/genética , Trombina/fisiologiaRESUMO
BACKGROUND: Interleukin (IL)-10 plays a pivotal role in regulating the Th1/Th2 predominance of immune responses. Exogenously administered IL-10 suppresses nephritogenic Th1 responses, inhibits macrophage function, and attenuates crescentic glomerulonephritis (GN). To determine the role of endogenous IL-10, the development of the nephritogenic immune response and crescentic GN was compared in IL-10-deficient (IL-10-/-) and normal (IL-10+/+) C57BL/6 mice. METHODS: GN was initiated in sensitized mice by the intravenous administration of sheep antimouse glomerular basement membrane globulin. Renal injury was evaluated 21 days later. RESULTS: Following the administration of anti-glomerular basement membrane globulin, normal (IL-10+/+) C57BL/6 mice developed proliferative GN with occasional crescents, glomerular CD4+ T-cell and macrophage accumulation, and fibrin deposition. Using an identical induction protocol, IL-10-/-mice developed more severe GN. Crescent formation (IL-10-/-, 23 +/- 2% of glomeruli; IL-10+/+, 5 +/- 2%), glomerular CD4+ T cells [IL-10-/-, 1. 0 +/- 0.2 cells per glomerular cross-section (c/gcs); IL-10 +/+, 0.3 +/- 0.05 c/gcs], glomerular macrophages (IL-10-/-, 4.8 +/- 0.3 c/gcs; IL-10 +/+, 1.7 +/- 0.2 c/gcs), fibrin deposition [fibrin score (range 0 to 3+); IL-10-/-, 1.10 +/- 0.04; IL-10+/+, 0.6 +/- 0. 07], and serum creatinine (IL-10-/-, 30 +/- 2 micromol/L; IL-10 +/+, 23 +/- 1 micromol/L) were all significantly increased in IL-10-/- mice (P < 0.05). Circulating antibody (IL-10-/-, 1.05 +/- 0.16 OD units; IL-10+/+, 0.63 +/- 0.08 OD units) and cutaneous delayed-type hypersensitivity (skin swelling; IL-10-/-, 0.21 +/- 0.03 mm; IL-10+/+, 0.12 +/- 0.02 mm) to the nephritogenic antigen (sheep globulin) were also increased (both P < 0.05). Interferon-gamma production by cultured splenocytes was increased (IL-10-/- 7.9 +/- 2. 5 ng/4 x 106 cells, IL-10+/+ 0.28 +/- 0.09 ng/4 x 106 cells, P < 0. 05), but IL-4 production was unchanged. CONCLUSIONS: Endogenous IL-10 counter-regulates nephritogenic Th1 responses and attenuates crescentic GN.
Assuntos
Glomerulonefrite/imunologia , Hipersensibilidade Tardia/imunologia , Interleucina-10/genética , Células Th1/imunologia , Animais , Anticorpos/imunologia , Autoanticorpos , Complemento C3/análise , Complemento C3/imunologia , Citocinas/imunologia , Feminino , Fibrina/imunologia , Expressão Gênica/imunologia , Glomerulonefrite/patologia , Imunoglobulinas/imunologia , Imunoglobulinas/farmacologia , Interferon gama/biossíntese , Interleucina-10/análise , Interleucina-10/imunologia , Glomérulos Renais/imunologia , Glomérulos Renais/patologia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ligação Proteica/imunologia , Ovinos , Especificidade da Espécie , Baço/citologia , Baço/imunologia , Baço/metabolismoRESUMO
The potential for tissue factor (TF) to enhance inflammation by factor VIIa-dependent induction of proinflammatory changes in macrophages was explored. Purified recombinant human factor VIIa enhanced reactive oxygen species production by human monocyte-derived macrophages expressing TF in vitro. This effect was dose- and time-dependent, ligand- and receptor-specific, and independent of other coagulation proteins. This receptor/ligand binding induced phospholipase C-dependent intracellular calcium fluxes. Transfection studies using a human monocyte-derived cell line (U937) demonstrated that an intact intracytoplasmic domain of TF is required for factor VIIa-induced intracellular calcium fluxes. The capacity of TF to enhance proinflammatory functions of rabbit peritoneal-elicited macrophages (production of reactive oxygen species and expression of major histocompatibility complex class II and cell adhesion molecules) was demonstrated in vivo by treatment with an anti-TF antibody. These data demonstrate that, in addition to its role in activation of coagulation, TF can directly augment macrophage activation. These effects are initiated by binding factor VIIa and are independent of other coagulation proteins. These studies provide the first demonstration of a direct proinflammatory role for TF acting as a cell-signaling receptor.
Assuntos
Fator VIIa/metabolismo , Mediadores da Inflamação/metabolismo , Inflamação/metabolismo , Macrófagos/metabolismo , Tromboplastina/metabolismo , Anticorpos/farmacologia , Transporte Biológico , Cálcio/metabolismo , Diferenciação Celular , Citoplasma/metabolismo , Relação Dose-Resposta a Droga , Humanos , Ligantes , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/citologia , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/metabolismo , Monócitos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Trombina/metabolismo , Tromboplastina/imunologia , Fatores de Tempo , Células U937 , Regulação para CimaRESUMO
Crescentic glomerulonephritis provides an important therapeutic challenge because of its rapidly progressive course and poor outcome. Studies in animal models have elucidated some of the pivotal pathogenetic mechanisms, and human studies increasingly support the clinical relevance of these animal data. Accumulating evidence suggests that crescentic glomerulonephritis results from a complex cell-mediated nephritogenic immune response. Interruption of a number of immune and inflammatory mediators can improve the outcome of this disease.
Assuntos
Glomerulonefrite/etiologia , Glomerulonefrite/imunologia , Animais , Doenças Autoimunes/etiologia , Moléculas de Adesão Celular/metabolismo , Divisão Celular , Quimiocinas/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Glomerulonefrite/patologia , Humanos , Mediadores da Inflamação/metabolismoRESUMO
The recognition that human immune responses can be directed by two different subsets of T helper cells (Th1 and Th2) has been an important development in modern immunology. Immune responses polarized by either the Th1 or Th2 subset predominance result in different inflammatory effector pathways and disease outcomes. Many autoimmune diseases are associated with either Th1- or Th2- polarized immune responses. Although these different immune response patterns are relevant to glomerulonephritis (GN), little attention has been paid to the consequences of Th1 or Th2 predominance of nephritogenic immune responses for the pattern and outcome of GN. Unlike other autoimmune conditions, GN results from a variety of different immune responses and has a range of histologic features and immune effectors in glomeruli. This review assesses the data available from studies of experimental and human GN that address the Th1 or Th2 predominance of nephritogenic immune responses and their relevance to the different histopathological patterns and outcomes of GN. In particular, the evidence that Th1-predominant nephritogenic immune responses are associated with severe proliferative and crescentic GN is presented.
Assuntos
Glomerulonefrite/imunologia , Glomerulonefrite/patologia , Subpopulações de Linfócitos T/imunologia , Células Th1/imunologia , Células Th2/imunologia , Animais , Complexo Antígeno-Anticorpo/imunologia , Modelos Animais de Doenças , Glomerulonefrite/terapia , Humanos , Imunoglobulina A/metabolismo , Glomérulos Renais/imunologia , Glomérulos Renais/patologia , Lúpus Vulgar/imunologia , Resultado do TratamentoRESUMO
BACKGROUND: Tissue factor (TF) pathway inhibitor (TFPI), the major endogenous inhibitor of extrinsic coagulation pathway activation, protects renal function in experimental crescentic glomerulonephritis (GN). Its glomerular expression and relationship to TF expression and fibrin deposition in human crescentic GN have not been reported. METHODS: Glomerular TFPI, TF, and fibrin-related antigen (FRA) expression were correlated in renal biopsies from 11 patients with crescentic GN. Biopsies from 11 patients with thin basement membrane disease and two normal kidneys were used as controls. RESULTS: TFPI was undetectable in control glomeruli but was detectable in interstitial microvessels. In crescentic biopsies, TFPI was detected in cellular crescents and was more prominent in fibrous/fibrocellular crescents, indicating a correlation with the chronicity of crescentic lesions. TFPI appeared to be associated with macrophages but not endothelial or epithelial cells. TFPI was generally undetectable in regions of the glomerular tuft with minimal damage. In contrast, TF and FRA were strongly expressed in regions of minimal injury, as well as in more advanced proliferative and necrotizing lesions. Despite prominent TF expression, FRA was less prominent in fibrous/fibrocellular crescents in which TFPI expression was maximal. CONCLUSIONS: These data suggest that TFPI is strongly expressed in the later stages of crescent formation and is inversely correlated with the presence of FRA in human crescentic GN. This late induction of TFPI may inhibit TF activity and favor reduced fibrin deposition in the chronic stages of crescent formation.
Assuntos
Glomerulonefrite/metabolismo , Lipoproteínas/biossíntese , Adulto , Antígenos/biossíntese , Arteríolas/metabolismo , Arteríolas/patologia , Membrana Basal/metabolismo , Membrana Basal/patologia , Biópsia , Progressão da Doença , Feminino , Fibrina/metabolismo , Produtos de Degradação da Fibrina e do Fibrinogênio/imunologia , Glomerulonefrite/imunologia , Glomerulonefrite/patologia , Humanos , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Lipoproteínas/metabolismo , Masculino , Pessoa de Meia-Idade , Tromboplastina/biossínteseRESUMO
A macrophage plays an important role in mediating the inflammatory response. Cytokines released by activated macrophages contribute to inflammation in glomerulonephritis (GN). Clodronate, a biphosphonate, causes macrophage depletion when administered in an encapsulated form in liposomes. We used albumin as the polymer matrix to microencapsulate clodronate to the microspheres (MS) in the 1-micron size range. The purpose of this study was to (a) determine macrophage depletion by clodronate MS, (b) determine the effect of clodronate MS on endotoxin-induced cytokine release in vitro, and (c) assess the effect of clodronate MS on macrophage infiltration in experimental antiglomerular basement membrane nephritis. Macrophage depletion by clodronate MS was assessed by staining for the EDI marker. The results indicate greater than 95% depletion of macrophages from the spleen, liver, kidney, and blood. In the whole blood model, clodronate MS attenuated endotoxin-induced tumor necrosis factor alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) release, and the attenuation by the microencapsulated form of clodronate was also more effective than the free (solution) form of clodronate. Macrophage infiltration into the glomerulus in experimental GN was also blocked very effectively by pretreatment with clodronate MS. In conclusion, macrophage depletion by clodronate MS may be beneficial in reducing cytokine release and renal damage in GN.
Assuntos
Albuminas/administração & dosagem , Ácido Clodrônico/administração & dosagem , Glomerulonefrite/tratamento farmacológico , Interleucina-1/metabolismo , Macrófagos/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Animais , Microesferas , Ratos , Ratos Endogâmicos F344RESUMO
Features of crescentic glomerulonephritis suggest that it results from a T helper 1 (Th1) nephritogenic immune response. Interferon-gamma (IFN-gamma), produced by Th1 cells, is involved in T cell-directed macrophage activation in effector Th1 responses. The hypothesis that endogenous IFN-gamma contributes to the development of crescentic glomerulonephritis was tested by comparing the development of glomerulonephritis (induced by a planted antigen) and immune responses in normal C57BL/6 mice (IFN-gamma +/+) and in mice genetically deficient in IFN-gamma (IFN-gamma -/-). Ten days after the initiation of glomerulonephritis, IFN-gamma -/- mice developed fewer glomerular crescents (5+/-1% versus 26+/-3%, P<0.005), less severe glomerular injury, and less renal impairment. Effectors of delayed-type hypersensitivity (CD4+ T cells, macrophages, and fibrin) in glomeruli were reduced in IFN-gamma -/- mice. Skin delayed-type hypersensitivity to sheep globulin was reduced. Total antigen-specific Ig and splenocyte interleukin-2 production were unchanged, but antigen-specific serum IgG2a was reduced. Markers of an antigen-specific Th2 response (serum IgG1, splenocyte interleukin-4) were unchanged. Studies 22 d after the initiation of glomerulonephritis showed that IFN-gamma -/- mice still had fewer crescents (11+/-2% versus 22+/-3%, P = 0.02) and glomerular CD4+ T cells and macrophages than IFN-gamma +/+ mice. These studies demonstrate that endogenous IFN-gamma mediates crescentic glomerulonephritis by promoting cell-mediated immune injury. They support the hypothesis that crescentic glomerulonephritis is a manifestation of a Th1 nephritogenic immune response.
Assuntos
Glomerulonefrite/imunologia , Glomerulonefrite/patologia , Interferon gama/metabolismo , Glomérulos Renais/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Contagem de Linfócito CD4 , Técnicas de Cultura , Modelos Animais de Doenças , Imunidade Celular , Imunoglobulinas/análise , Imunoglobulinas/imunologia , Interferon gama/deficiência , Testes de Função Renal , Glomérulos Renais/patologia , Macrófagos/imunologia , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/imunologia , Neutrófilos/patologia , Valores de Referência , OvinosRESUMO
Use of combined oral contraceptives (OC) is associated with a significant risk of thrombosis. The mechanisms of this effect are not clearly defined. Tissue factor pathway inhibitor (TFPI) is a circulating anti-coagulant that inhibits the earliest steps in activation of the extrinsic coagulation pathway. It plays a central role in control of coagulation but its contribution to the thrombotic risk associated with OC has not been assessed. Plasma TFPI antigen and activity, factor VIIa, prothrombin fragments 1&2, von Willebrand antigen, fibrinogen, and low density lipoprotein cholesterol were measured by standard assays in women taking OC (aged 16 to 45 years, n = 40) and age-matched women not taking OC (controls, n = 40). Plasma TFPI antigen did not vary significantly across the menstrual cycle in controls. Women on OC had a 25% reduction in plasma TFPI antigen (median 51.0 ng/ml; 95% confidence intervals [CI] 37.5 to 85.5; control 68.0 ng/ml, CI 61.0 to 95.0; P < 0.001) and a 29% reduction in TFPI activity (78.5 U/ml, CI 57.5 to 107.5; control 111.0 U/ml, CI 79.5 to 171.0; P < 0.001) compared to controls. Plasma factor VIIa activity and prothrombin fragments 1&2 were also significantly increased in women using OC (both P < 0.001), indicating activation of the extrinsic coagulation pathway. These results demonstrate that normal cyclic variations in estrogen and/or progesterone do not significantly alter plasma TFPI levels. However, estrogens and/or progestogens in OC result in activation of the extrinsic coagulation pathway and significantly reduce plasma TFPI, its major circulating inhibitor. Reduced plasma TFPI levels may underlie the thrombotic effects of OC.
PIP: This article reports the findings of a study that determined whether use of oral contraceptive (OC) is associated with significant changes in plasma tissue factor pathway inhibitor (TFPI), which may contribute to thrombotic risk. Plasma TFPI antigen and activity, factor VIIa, prothrombin fragments 1 and 2, von Willebrand antigen, fibrinogen, and low density lipoprotein cholesterol were measured by standard assays in 40 women aged 16-45 taking OCs and 40 age-matched women not taking OCs. Results revealed that the plasma TFPI antigen did not vary significantly across the menstrual cycle in controls. Women on OCs had a 25% reduction in plasma TFPI antigen (median, 51.0 ng/ml; 95% confidence interval (CI), 37.5-85.5; controls, 68.0 ng/ml; CI, 61.0-95.0) and a 29% reduction in TFPI activity (78.5 U/ml; CI, 57.5-107.5; controls, 111.0 U/ml; CI, 79.5-171.0) compared to controls. Plasma factor VIIa activity and prothrombin fragments 1 and 2 were also significantly increased in women using OCs, indicating activation of the extrinsic coagulation pathway. These results demonstrate that normal cyclic variations in estrogen and/or progesterone do not significantly alter plasma TFPI levels. However, estrogens and/or progesterone in OCs result in activation of the extrinsic coagulation pathway and significantly reduce plasma TFPI, its major circulation inhibitor. In conclusion, reduced plasma TFPI levels may underlie the thrombotic effects of OCs.
Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Anticoncepcionais Orais Combinados/efeitos adversos , Lipoproteínas/sangue , Trombose/sangue , Adolescente , Adulto , LDL-Colesterol/sangue , Regulação para Baixo , Fator VIIa/metabolismo , Feminino , Fibrinogênio/metabolismo , Fibrinolíticos/sangue , Humanos , Pessoa de Meia-Idade , Fragmentos de Peptídeos/metabolismo , Precursores de Proteínas/metabolismo , Protrombina/metabolismo , Trombose/etiologia , Fator de von Willebrand/metabolismoRESUMO
The majority of patients with rapidly progressive crescentic glomerulonephritis show histologic features of extensive necrosis and focal and segmental proliferation with fibrin production, but little or absent Ig deposition in the glomerulus. This subcategory of the disease, labeled "pauci-immune" glomerulonephritis, has recently been shown to be associated with the presence of antineutrophil cytoplasmic antibody in the patient's circulation (but not within the glomerulus). The absence of the effectors of humoral immunity at the site of renal injury led to this investigation of the contribution of cell-mediated immunity to the glomerular injury in this form of glomerulonephritis. In 15 patients presenting acutely with pauci-immune glomerulonephritis, CD3-positive T cells (3.7+/-2.5 [mean +/- SD] cells per glomerular cross section, [c/gcs]), CD45RO-positive T cells (2.7+/-1.9 c/cgs), macrophages (7.3+/-6.1 c/gcs), fibrin (3+), and endothelial-associated tissue factor were demonstrated to be prominent in glomeruli. These mediators were absent in a group of 12 patients with thin basement membrane disease and only occasionally observed in a group of eight patients with "humorally mediated"(noncrescentic) glomerulonephritis. Thus, in pauci-immune glomerulonephritis, there is the development of significant cell-mediated immunity with activated T cells, macrophages, tissue factor, and fibrin at the site of glomerular injury, suggesting that this glomerular disease is most likely a manifestation of T cell-directed cognate immune injury.