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1.
Hepatol Commun ; 1(4): 311-325, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-29404461

RESUMO

CAT-2003 is a novel conjugate of eicosapentaenoic acid (EPA) and niacin designed to be hydrolyzed by fatty acid amide hydrolase to release EPA inside cells at the endoplasmic reticulum. In cultured liver cells, CAT-2003 blocked the maturation of sterol regulatory element-binding protein (SREBP)-1 and SREBP-2 proteins and decreased the expression of multiple SREBP target genes, including HMGCR and PCSK9. Consistent with proprotein convertase subtilisin/kexin type 9 (PCSK9) reduction, both low-density lipoprotein receptor protein at the cell surface and low-density lipoprotein particle uptake were increased. In apolipoprotein E*3-Leiden mice fed a cholesterol-containing western diet, CAT-2003 decreased hepatic inflammation and steatosis as evidenced by fewer inflammatory cell aggregates in histopathologic sections, decreased nuclear factor kappa B activity in liver lysates, reduced inflammatory gene expression, reduced intrahepatic cholesteryl ester and triglyceride levels, and decreased liver mass. Plasma PCSK9 was reduced and hepatic low-density lipoprotein receptor protein expression was increased; plasma cholesterol and triglyceride levels were lowered. Aortic root segments showed reduction of several atherosclerotic markers, including lesion size, number, and severity. CAT-2003, when dosed in combination with atorvastatin, further lowered plasma cholesterol levels and decreased hepatic expression of SREBP target genes. Conclusion: SREBP inhibition is a promising new strategy for the prevention and treatment of diseases associated with abnormal lipid metabolism, such as atherosclerosis and nonalcoholic steatohepatitis. (Hepatology Communications 2017;1:311-325).

2.
J Med Chem ; 60(1): 458-473, 2017 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-27976892

RESUMO

A depressed autophagy has previously been reported in cystic fibrosis patients with the common F508del-CFTR mutation. This report describes the synthesis and preliminary biological characterization of a novel series of autophagy activators involving fatty acid cysteamine conjugates. These molecular entities were synthesized by first covalently linking cysteamine to docosahexaenoic acid. The resulting conjugate 1 synergistically activated autophagy in primary homozygous F508del-CFTR human bronchial epithelial (hBE) cells at submicromolar concentrations. When conjugate 1 was used in combination with the corrector lumacaftor and the potentiator ivacaftor, it showed an additive effect, as measured by the increase in the chloride current in a functional assay. In order to obtain a more stable form for oral dosing, the sulfhydryl group in conjugate 1 was converted into a functionalized disulfide moiety. The resulting conjugate 5 is orally bioavailable in the mouse, rat, and dog and allows a sustained delivery of the biologically active conjugate 1.


Assuntos
Autofagia/efeitos dos fármacos , Cisteamina/farmacologia , Regulador de Condutância Transmembrana em Fibrose Cística/química , Ácidos Graxos/química , Cisteamina/química , Dobramento de Proteína
3.
J Med Chem ; 59(3): 1217-31, 2016 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-26784936

RESUMO

This report describes the synthesis and preliminary biological characterization of novel fatty acid niacin conjugates and fatty acid salicylate conjugates. These molecular entities were created by covalently linking two bioactive molecules, either niacin or salicylic acid, to an omega-3 fatty acid. This methodology allows the simultaneous intracellular delivery of two bioactives in order to elicit a pharmacological response that could not be replicated by administering the bioactives individually or in combination. The fatty acid niacin conjugate 5 has been shown to be an inhibitor of the sterol regulatory element binding protein (SREBP), a key regulator of cholesterol metabolism proteins such as PCSK9, HMG-CoA reductase, ATP citrate lyase, and NPC1L1. On the other hand, the fatty acid salicylate conjugate 11 has been shown to have a unique anti-inflammatory profile based on its ability to modulate the NF-κB pathway through the intracellular release of the two bioactives.


Assuntos
Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Ácidos Graxos/química , Niacina/química , Niacina/farmacologia , Ácido Salicílico/química , Ácido Salicílico/farmacologia , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Linhagem Celular , Cães , Relação Dose-Resposta a Droga , Células Hep G2 , Humanos , Hidrólise , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Estrutura Molecular , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Niacina/administração & dosagem , Ratos , Ratos Sprague-Dawley , Ácido Salicílico/administração & dosagem , Proteína de Ligação a Elemento Regulador de Esterol 1/antagonistas & inibidores , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/antagonistas & inibidores , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo , Relação Estrutura-Atividade , Distribuição Tecidual
4.
Inflamm Res ; 58(11): 819-27, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19517214

RESUMO

OBJECTIVE AND DESIGN: Angiotensin-converting enzyme 2 (ACE2) is expressed in gastrointestinal tissue. Previous studies of GL1001, a potent and selective ACE2 inhibitor, have revealed anti-inflammatory activity in the mouse digestive tract. We hypothesized that GL1001 might also produce beneficial effects in a mouse DSS model of inflammatory bowel disease. MATERIALS: Female mice were used for study. TREATMENT: Animals were treated for 5 days with 5% DSS in the drinking water to induce colitis. For the following 9 days, animals were treated twice daily with GL1001 (30, 100, 300 mg/kg, s.c.), sulfasalazine (150 mg/kg, p.o.), or vehicle. METHODS: Throughout the experiment, body weight, rectal prolapse, stool consistency, and fecal occult blood were monitored. At termination, colon length, histopathology, and myeloperoxidase activity were assessed. RESULTS: High-dose GL1001 ameliorated DSS-induced disease activity, including rectal prolapse and intestinal bleeding. The most robust effect of GL1001 was observed 48-96 h post DSS treatment and was comparable in magnitude to that of sulfasalazine. Colon pathology and myeloperoxidase activity were also markedly attenuated by high-dose GL1001 treatment, with the most profound effects observed in the distal segment. CONCLUSIONS: The findings support the previously observed anti-inflammatory effects of ACE2 inhibition in gastrointestinal tissue and suggest that GL1001 may have therapeutic utility for inflammatory bowel disease.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Colite/induzido quimicamente , Colite/tratamento farmacológico , Sulfato de Dextrana/efeitos adversos , Imidazóis/uso terapêutico , Leucina/análogos & derivados , Enzima de Conversão de Angiotensina 2 , Animais , Peso Corporal/efeitos dos fármacos , Colite/patologia , Colite/fisiopatologia , Colo/enzimologia , Colo/patologia , Modelos Animais de Doenças , Feminino , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/patologia , Leucina/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Peptidil Dipeptidase A/metabolismo , Peroxidase/metabolismo , Distribuição Aleatória
6.
J Immunol ; 179(3): 1740-50, 2007 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-17641040

RESUMO

CCL1 is the predominant chemokine secreted from IgE-activated human and mouse mast cells in vitro, colocalizes to mast cells in lung biopsies, and is elevated in asthmatic airways. CCR8, the receptor for CCL1, is expressed by approximately 70% of CD4(+) T lymphocytes recruited to the asthmatic airways, and the number of CCR8-expressing cells is increased 3-fold in the airways of asthmatic subjects compared with normal volunteers. In vivo, CCL1 expression in the lung is reduced in mast cell-deficient mice after aeroallergen provocation. Neutralization of CCL1 or CCR8 deficiency results in reduced mucosal lung inflammation, airway hyperresponsiveness, and mucus hypersecretion to a similar degree as detected in mast cell-deficient mice. Adenoviral delivery of CCL1 to the lungs of mast cell-deficient mice restores airway hyperresponsiveness, lung inflammation, and mucus hypersecretion to the degree observed in wild-type mice. The consequences of CCR8 deficiency, including a marked reduction in Th2 cytokine levels, are comparable with those observed by depletion of CD4(+) T lymphocytes. Thus, mast cell-derived CCL1- and CCR8-expressing CD4(+) effector T lymphocytes play an essential role in orchestrating lung mucosal inflammatory responses.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Quimiocinas CC/fisiologia , Hipersensibilidade/imunologia , Hipersensibilidade/patologia , Mastócitos/imunologia , Receptores de Quimiocinas/fisiologia , Mucosa Respiratória/imunologia , Mucosa Respiratória/patologia , Animais , Asma/imunologia , Asma/metabolismo , Asma/patologia , Hiper-Reatividade Brônquica/genética , Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/patologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Quimiocina CCL1 , Quimiocinas CC/biossíntese , Quimiocinas CC/genética , Citocinas/biossíntese , Citocinas/genética , Feminino , Humanos , Hipersensibilidade/genética , Imunoglobulina E/farmacologia , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Mastócitos/metabolismo , Mastócitos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ratos , Ratos Endogâmicos WKY , Receptores CCR8 , Receptores de Quimiocinas/biossíntese , Receptores de Quimiocinas/deficiência , Receptores de Quimiocinas/genética , Mucosa Respiratória/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Células Th2/imunologia , Células Th2/metabolismo , Células Th2/patologia , Regulação para Cima/genética , Regulação para Cima/imunologia
7.
Autoimmunity ; 39(6): 469-78, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17060026

RESUMO

In the present study we have characterized T cell-driven immune function in mice that are genetically deficient in PKC theta. In response to simple immunologic stimulation invoked by in vivo T cell receptor (TCR) cross-linking, these mice showed significantly depressed plasma cytokine levels for IL-2, IL-4, IFNgamma, and TNFalpha compared to wild-type (WT) mice. In parallel, spleen mRNA levels for these cytokines were reduced, and NF-kappaB activation was also reduced in PKC theta knockouts (KO). Injection of allogeneic cells into the footpad of PKC theta deficient mice provoked a significantly diminished local T cell response compared to WT mice similarly challenged. Unlike comparable cells from wild type mice, CD45RBhi T cells harvested from PKC theta deficient mice failed to induce colitis in the SCID-CD45RB cell transfer model of IBD. In another T cell-dependent model of inflammatory disease, PKC theta deficient animals developed far less severe neurologic signs and reduced spinal cord inflammatory cell infiltrate compared to WT controls in the MOG-induced EAE model. A fundamental role for PKC theta in T cell activation and in the development of T cell-mediated inflammatory diseases is indicated by these results.


Assuntos
Inflamação/imunologia , Isoenzimas/genética , Proteína Quinase C/genética , Receptores de Antígenos de Linfócitos T/imunologia , Animais , Antígenos CD4/imunologia , Proliferação de Células , Citocinas/sangue , Citocinas/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Ativação Enzimática , Feminino , Inflamação/patologia , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/patologia , Isoenzimas/imunologia , Antígenos Comuns de Leucócito/imunologia , Linfonodos/imunologia , Linfonodos/patologia , Ativação Linfocitária , Camundongos , Camundongos Knockout , Camundongos SCID , NF-kappa B/metabolismo , Proteína Quinase C/imunologia , Proteína Quinase C-theta , RNA Mensageiro/sangue , RNA Mensageiro/metabolismo , Medula Espinal/imunologia , Medula Espinal/patologia , Baço/metabolismo
8.
J Immunol ; 177(3): 1886-93, 2006 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-16849501

RESUMO

T cell effector functions contribute to the pathogenesis of rheumatoid arthritis. PKC-theta transduces the signal from the TCR through activation of transcription factors NF-kappaB, AP-1, and NFAT. We examined the effects of PKC-theta deficiency on two Th1-dependent models of Ag-induced arthritis and found that PKC-theta-deficient mice develop disease, but at a significantly diminished severity compared with wild-type mice. In the methylated BSA model, cellular infiltrates and articular cartilage damage were mild in the PKC-theta-deficient mice as compared with wild-type mice. Quantitation of histopathology reveals 63 and 77% reduction in overall joint destruction in two independent experiments. In the type II collagen-induced arthritis model, we observed a significant reduction in clinical scores (p < 0.01) in three independent experiments and diminished joint pathology (p < 0.005) in PKC-theta-deficient compared with wild-type littermates. Microcomputerized tomographic imaging revealed that PKC-theta deficiency also protects from bone destruction. PKC-theta-deficient CD4(+) T cells show an impaired proliferative response, decreased intracellular levels of the cytokines IFN-gamma, IL-2, and IL-4, and significantly diminished cell surface expression of the activation markers CD25, CD69, and CD134/OX40 on memory T cells. We demonstrate decreased T-bet expression and significantly reduced IgG1 and IgG2a anti-collagen II Ab levels in PKC-theta-deficient mice. Collectively, our results demonstrate that PKC-theta deficiency results in an attenuated response to Ag-induced arthritis, which is likely mediated by the reduced T cell proliferation, Th1/Th2 cell differentiation and T cell activation before and during disease peak.


Assuntos
Antígenos/administração & dosagem , Artrite Experimental/imunologia , Artrite Experimental/prevenção & controle , Isoenzimas/deficiência , Isoenzimas/genética , Proteína Quinase C/deficiência , Proteína Quinase C/genética , Soroalbumina Bovina/administração & dosagem , Células Th1/imunologia , Animais , Antígenos/imunologia , Artrite Experimental/enzimologia , Artrite Experimental/genética , Autoanticorpos/biossíntese , Autoanticorpos/sangue , Movimento Celular/genética , Movimento Celular/imunologia , Proliferação de Células , Colágeno/administração & dosagem , Colágeno/imunologia , Regulação para Baixo/genética , Regulação para Baixo/imunologia , Feminino , Imunofenotipagem , Isoenzimas/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Knockout , Proteína Quinase C/fisiologia , Proteína Quinase C-theta , Soroalbumina Bovina/imunologia , Proteínas com Domínio T , Linfócitos T/imunologia , Linfócitos T/patologia , Células Th1/patologia , Fatores de Transcrição/biossíntese , Regulação para Cima/imunologia
9.
Blood ; 107(9): 3447-54, 2006 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-16391017

RESUMO

CD4(+) T-cell entry to the intestinal mucosa is central to the generation of mucosal immunity as well as chronic intestinal inflammation, yet the mechanisms regulating this process remain poorly defined. Here we show that murine small intestinal CD4(+) lamina propria lymphocytes express a heterogeneous but restricted array of chemokine receptors including CCR5, CCR6, CCR9, CXCR3, and CXCR6. CD4(+) T-cell receptor transgenic OT-II cells activated in mesenteric lymph nodes acquired a distinct chemokine receptor profile, including expression of CCR6, CCR9, and CXCR3 that was only partially reproduced in vitro after priming with mesenteric lymph node dendritic cells. A subset of these effector CD4(+) T cells, expressing CD69 and alpha(4)beta(7), entered the intestinal lamina propria and the majority of these cells expressed CCR9. CCR9(-/-) OT-II cells were disadvantaged in their ability to localize to the intestinal lamina propria; however, they were readily detected at this site and expressed alpha(4)beta(7), but little CCR2, CCR5, CCR6, CCR8, CCR10, CXCR3, or CXCR6. Thus, whereas CD4(+) T cells activated in gut-associated lymphoid tissue express a restricted chemokine receptor profile, including CCR9, targeting both CCR9-dependent and CCR9-independent entry mechanisms is likely to be important to maximally inhibit accumulation of these cells within the small intestinal mucosa.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Mucosa Intestinal/imunologia , Tecido Linfoide/imunologia , Receptores de Quimiocinas/metabolismo , Animais , Quimiotaxia de Leucócito , Técnicas In Vitro , Mucosa Intestinal/citologia , Intestino Delgado/citologia , Intestino Delgado/imunologia , Ativação Linfocitária , Tecido Linfoide/citologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Receptores de Antígenos de Linfócitos T/genética , Receptores CCR , Receptores de Quimiocinas/deficiência , Receptores de Quimiocinas/genética , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/imunologia
10.
J Clin Invest ; 115(12): 3460-72, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16284650

RESUMO

Th1 inflammation and remodeling characterized by tissue destruction frequently coexist in human diseases. To further understand the mechanisms of these responses, we defined the role(s) of CCR5 in the pathogenesis of IFN-gamma-induced inflammation and remodeling in a murine emphysema model. IFN-gamma was a potent stimulator of the CCR5 ligands macrophage inflammatory protein-1alpha/CCL-3 (MIP-1alpha/CCL-3), MIP-1beta/CCL-4, and RANTES/CCL-5, among others. Antibody neutralization or null mutation of CCR5 decreased IFN-gamma-induced inflammation, DNA injury, apoptosis, and alveolar remodeling. These interventions decreased the expression of select chemokines, including CCR5 ligands and MMP-9, and increased levels of secretory leukocyte protease inhibitor. They also decreased the expression and/or activation of Fas, FasL, TNF, caspase-3, -8, and -9, Bid, and Bax. In accordance with these findings, cigarette smoke induced pulmonary inflammation, DNA injury, apoptosis, and emphysema via an IFN-gamma-dependent pathway(s), and a null mutation of CCR5 decreased these responses. These studies demonstrate that IFN-gamma is a potent stimulator of CC and CXC chemokines and highlight the importance of CCR5 in the pathogenesis of IFN-gamma-induced and cigarette smoke-induced inflammation, tissue remodeling, and emphysema. They also demonstrate that CCR5 is required for optimal IFN-gamma stimulation of its own ligands, other chemokines, MMPs, caspases, and cell death regulators and the inhibition of antiproteases.


Assuntos
Enfisema/patologia , Interferon gama/metabolismo , Receptores CCR5/fisiologia , Fumar , Animais , Anexina A5/química , Apoptose , Lavagem Broncoalveolar , Morte Celular , Quimiocinas/metabolismo , DNA/metabolismo , Primers do DNA/química , Enfisema/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Inflamação , Ligantes , Pulmão/metabolismo , Macrófagos/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação , Fenótipo , Alvéolos Pulmonares/metabolismo , RNA Mensageiro/metabolismo , Receptores CCR5/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo
11.
J Exp Med ; 201(2): 303-16, 2005 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-15642741

RESUMO

T cell activation by intestinal dendritic cells (DC) induces gut-tropism. We show that, reciprocally, DC from peripheral lymph nodes (PLN-DC) induce homing receptors promoting CD8 T cell accumulation in inflamed skin, particularly ligands for P- and E-selectin. Differential imprinting of tissue-tropism was independent of Th1/Th2 cytokines and not restricted to particular DC subsets. Fixed PLN-DC retained the capacity to induce selectin ligands on T cells, which was suppressed by addition of live intestinal DC. By contrast, fixed intestinal DC failed to promote gut-tropism and instead induced skin-homing receptors. Moreover, the induction of selectin ligands driven by antigen-pulsed PLN-DC could be suppressed "in trans" by adding live intestinal DC, but PLN-DC did not suppress gut-homing receptors induced by intestinal DC. Reactivation of tissue-committed memory cells modified their tissue-tropism according to the last activating DC's origin. Thus, CD8 T cells activated by DC acquire selectin ligands by default unless they encounter fixation-sensitive signal(s) for gut-tropism from intestinal DC. Memory T cells remain responsive to these signals, allowing for dynamic migratory reprogramming by skin- and gut-associated DC.


Assuntos
Linfócitos T CD8-Positivos/metabolismo , Movimento Celular/fisiologia , Células Dendríticas/metabolismo , Tecido Linfoide/metabolismo , Animais , Citocinas/metabolismo , Trato Gastrointestinal/metabolismo , Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/metabolismo , Pele/metabolismo , Células Th1/metabolismo , Células Th2/metabolismo , Vênulas/metabolismo
12.
Nat Immunol ; 4(11): 1093-101, 2003 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-14556005

RESUMO

Although T helper (T(H)) cell-mediated immunity is required to effectively eliminate pathogens, unrestrained T(H) activity also contributes to tissue injury in many inflammatory and autoimmune diseases. We report here that the T(H) type 1 (T(H)1)-specific Tim-3 (T cell immunoglobulin domain, mucin domain) protein functions to inhibit aggressive T(H)1-mediated auto- and alloimmune responses. Tim-3 pathway blockade accelerated diabetes in nonobese diabetic mice and prevented acquisition of transplantation tolerance induced by costimulation blockade. These effects were mediated, at least in part, by dampening of the antigen-specific immunosuppressive function of CD4(+)CD25(+) regulatory T cell populations. Our data indicate that the Tim-3 pathway provides an important mechanism to down-regulate T(H)1-dependent immune responses and to facilitate the development of immunological tolerance.


Assuntos
Sistema Imunitário/imunologia , Receptores Virais/metabolismo , Transdução de Sinais/imunologia , Células Th1/metabolismo , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Receptor Celular 2 do Vírus da Hepatite A , Tolerância Imunológica/imunologia , Camundongos , Camundongos Endogâmicos NOD , Receptores de Interleucina-2 , Receptores Virais/genética , Receptores Virais/imunologia , Células Th1/imunologia
13.
J Immunol ; 171(5): 2208-15, 2003 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-12928364

RESUMO

Small intestinal cryptopatches (CP) are the major anatomic site for extrathymic differentiation by precursors destined to become intestinal intraepithelial T lymphocytes (IEL). We found that mice deficient in CCR6 exhibited a 2.7-fold increase in the number of alphabeta TCR IEL, but little or no expansion of gammadelta TCR IEL. Among the alphabeta TCR IEL subsets, the CD4- CD8alphaalpha+ and CD4+ CD8alphaalpha+ subsets were preferentially expanded in CCR6 null mice. Because some CD8alphaalpha+ IEL can arise through extrathymic differentiation in CP, we investigated CCR6 expression by T lymphocyte precursors undergoing extrathymic differentiation in intestinal CP. In sections of CP, 50-60% of c-kit+ precursors were CCR6+. CD11c(+) cells concentrated at the periphery of CP did not express CCR6. A subset of c-kit+, Lin- cells in lamina propria suspensions was CCR6+, but CCR6 was absent from c-kit+ precursors in bone marrow. CCR6 was absent from the vast majority of mature IEL. CCR6 is present on lymphocyte precursors in cryptopatches, expressed transiently during extrathymic IEL development, and is required for homeostatic regulation of intestinal IEL.


Assuntos
Mucosa Intestinal/imunologia , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Nódulos Linfáticos Agregados/imunologia , Nódulos Linfáticos Agregados/metabolismo , Receptores de Quimiocinas/biossíntese , Células-Tronco/imunologia , Células-Tronco/metabolismo , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Antígenos CD8/biossíntese , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Divisão Celular/genética , Divisão Celular/imunologia , Linhagem da Célula/genética , Linhagem da Célula/imunologia , Dimerização , Proteínas de Fluorescência Verde , Mucosa Intestinal/citologia , Mucosa Intestinal/metabolismo , Intestino Delgado/citologia , Intestino Delgado/imunologia , Intestino Delgado/metabolismo , Proteínas Luminescentes/biossíntese , Proteínas Luminescentes/genética , Subpopulações de Linfócitos/citologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nódulos Linfáticos Agregados/citologia , Proteínas Proto-Oncogênicas c-kit/biossíntese , Receptores de Antígenos de Linfócitos T alfa-beta/biossíntese , Receptores CCR6 , Receptores de Quimiocinas/deficiência , Receptores de Quimiocinas/genética , Células-Tronco/citologia , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Antígenos Thy-1/biossíntese , Regulação para Cima/genética , Regulação para Cima/imunologia
14.
Eur J Immunol ; 33(5): 1341-50, 2003 May.
Artigo em Inglês | MEDLINE | ID: mdl-12731060

RESUMO

Maintenance of peripheral tolerance and inactivation of autoreactive T cells is based on a delicate balance between pro-inflammatory and protective cytokines that is poorly understood. We have here addressed how the local expression of the inflammatory cytokine TNF-alpha can impair peripheral tolerance and lead to autoreactivity. After transplantation of pancreata that are immunogenic due to beta-cell expression of B7.1 and TNF-alpha, into thymectomized and euthymic syngeneic mice, we found that only euthymic mice rejected the grafts. This result suggests that under normal circumstances autoreactive T cells are functionally inactivated, and initiation of an autoreactive response requires de-novo generation of T cells. By contrast, thymectomized mice expressing TNF-alpha on the endogenous islets rejected the grafts, showing that expression of TNF-alpha prevents functional silencing of the autoreactive T cells. Thus, this study provides a mechanism by which TNF-alpha and possibly chronic inflammatory responses may promote autoimmune diseases. Furthermore, we have investigated whether B7.1 can enhance T cell responses of already activated T cells leading to islet rejection. By transplantation of wild-type and B7.1-expressing islets into overtly diabetic mice we found that only the wild-type islets could restore normoglycemia, suggesting that costimulation by B7.1 is required in the expansion or effector phase of the response.


Assuntos
Antígeno B7-1/fisiologia , Diabetes Mellitus Experimental/imunologia , Tolerância Imunológica , Transplante das Ilhotas Pancreáticas/imunologia , Ilhotas Pancreáticas/patologia , Linfócitos T/imunologia , Fator de Necrose Tumoral alfa/fisiologia , Transferência Adotiva , Animais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Baço/citologia , Estreptozocina
15.
J Exp Med ; 196(11): 1461-71, 2002 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-12461081

RESUMO

A characteristic feature of rheumatoid arthritis is the abundance of inflammatory cells in the diseased joint. Two major components of this infiltrate are neutrophils in the synovial fluid and macrophages in the synovial tissue. These cells produce cytokines including tumor necrosis factor alpha and other proinflammatory mediators that likely drive the disease through its effector phases. To investigate what mechanisms underlie the recruitment of these cells into the synovial fluid and tissue, we performed expression analyses of chemoattractant receptors in a related family that includes the anaphylatoxin receptors and the formyl-MetLeuPhe receptor. We then examined the effect of targeted disruption of two abundantly expressed chemoattractant receptors, the receptors for C3a and C5a, on arthritogenesis in a mouse model of disease. We report that genetic ablation of C5a receptor expression completely protects mice from arthritis.


Assuntos
Antígenos CD/fisiologia , Artrite/prevenção & controle , Articulações/patologia , Receptores de Complemento/fisiologia , Membrana Sinovial/patologia , Animais , Antígenos CD/análise , Antígenos CD/genética , Artrite/imunologia , Artrite/patologia , Colágeno/imunologia , Ativação do Complemento , Complemento C5/fisiologia , Selectina E/biossíntese , Expressão Gênica , Humanos , Molécula 1 de Adesão Intercelular/biossíntese , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neutrófilos/fisiologia , Receptor da Anafilatoxina C5a , Receptores de Complemento/análise , Receptores de Complemento/genética , Receptores de Complemento 3b/análise , Receptores de Complemento 3b/fisiologia , Molécula 1 de Adesão de Célula Vascular/biossíntese
16.
J Autoimmun ; 19(1-2): 9-22, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12367555

RESUMO

To analyse the effects of TGF-beta in insulin dependent diabetes mellitus (IDDM), we have developed non-obese diabetic (NOD) transgenic mice expressing TGF-beta under the control of the rat insulin II promoter. Pancreata of TGF-beta transgenic mice were roughly one twentieth of the size of pancreata of wild-type NOD mice and showed small clusters of micro-islets rather than normal adult islets. However, these islets produced sufficient levels of insulin to maintain normal glucose levels and mice were protected from the diabetes, which developed in their negative littermates. A massive fibrosis was seen in the transgenic pancreata that was accompanied with infiltration of mononuclear cells that decreased with age. Interestingly, these mice showed normal anti-islet immune response in their spleens and remained susceptible to adoptive transfer of IDDM by mature cloned CD8 effector cells. TUNEL assays revealed increased apoptosis of invading cells when compared to non-transgenic NOD mice. Taken together, these results suggest that TGF-beta protects islets by a local event.


Assuntos
Diabetes Mellitus Tipo 1/genética , Ilhotas Pancreáticas/metabolismo , Fator de Crescimento Transformador beta/genética , Animais , Apoptose/fisiologia , Diabetes Mellitus Tipo 1/prevenção & controle , Tolerância Imunológica , Insulina/genética , Insulina/metabolismo , Leucócitos Mononucleares/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Pâncreas/patologia , Regiões Promotoras Genéticas , Fator de Crescimento Transformador beta/biossíntese
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