RESUMO
NZB/W mice spontaneously develop an autoimmune disease characterized by the formation of anti-DNA antibodies and subsequent development of a fatal immune complex-mediated glomerulonephritis. Treatment of NZB/W F1 female mice with DHEAS, a precursor of DHEA, beginning at 2 months of age delayed the onset of autoimmune disease and prolonged survival. Animals treated with DHEAS beginning at 2 months of age had significantly lower anti-dsDNA serum antibody titers when compared to controls. Interestingly, DHEAS treatment had no effect on titers of anti-phosphatidylcholine (PtC) "natural" antibodies. Serum levels of IL-10, which increase with onset of disease, were also significantly reduced in mice treated with DHEAS beginning at 2 months of age. In contrast, if DHEAS treatment was started at 6 months of age, there was no effect on mortality rates. In addition, treatment of animals with DHEAS beginning at 6 months of age did not lower serum titers of anti-dsDNA and had no ameliorating effect on anti-PtC antibody production. Serum levels of IL-10 were also unaffected in mice treated with DHEAS beginning at 6 months of age. Together, these data suggest that parenteral administration of DHEAS is effective at delaying autoimmune disease and prolonging survival when given prior to the onset of symptoms. However, DHEAS treatment does not affect the course of disease when treatment begins after the onset of disease. We propose that DHEA(S) therapy used under similar conditions would not provide a clinically beneficial effect in the specific symptoms of immune complex-mediated glomerulonephritis.
Assuntos
Doenças Autoimunes/tratamento farmacológico , Sulfato de Desidroepiandrosterona/uso terapêutico , Fatores Etários , Animais , Anticorpos Antinucleares/sangue , Autoanticorpos/sangue , Doenças Autoimunes/imunologia , Doenças Autoimunes/mortalidade , Subpopulações de Linfócitos B/imunologia , Sulfato de Desidroepiandrosterona/administração & dosagem , Progressão da Doença , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Imunoglobulina M/sangue , Interleucina-10/sangue , Camundongos , Camundongos Endogâmicos NZB , Fosfatidilcolinas/imunologiaRESUMO
Peripheral lymphoid cells isolated from the spleens and peritoneal cavities of aged mice were found to constitutively secrete the multifunctional cytokine interleukin (IL)-10 when cultured in vitro. B-Lymphocytes were implicated as the cell type responsible. Abnormal expression of this cytokine was also detected in vivo because high levels of mRNA for IL-10 were present in splenocytes freshly isolated from aged animals. In addition to the spontaneous secretion of IL-10, lymphoid cells from aged donors were hyperresponsive to exogenous stimulation with endotoxin, producing exaggerated quantities of both IL-10 and IL-6 in culture. Treatment of aged animals with dehydroepiandrosterone sulfate (DHEAS), a natural steroid, reversed the age-associated alterations in cytokine production, rendering the treated mice quite similar to mature adult controls. DHEAS treatment of aged mice also resulted in a lowering in the number of B1 cells present in the peritoneal cavity and also reduced the titers of circulating autoantibodies specific for phosphatidylcholine (PtC). Based on its wide range of biologic activities, a dysregulation in the mechanisms that control IL-10 production could be a major contributor to immunosenescence. The ability of DHEAS treatment to restore normal control over the expression of IL-10 may explain how this steroid enhances immunocompetence in aged animals.
Assuntos
Envelhecimento/imunologia , Sulfato de Desidroepiandrosterona/farmacologia , Desidroepiandrosterona/deficiência , Interleucina-10/biossíntese , Animais , Autoanticorpos/sangue , Linfócitos B/metabolismo , Feminino , Camundongos , Camundongos Endogâmicos CBAAssuntos
Células Apresentadoras de Antígenos/imunologia , Linfócitos T CD4-Positivos/imunologia , Moléculas de Adesão Celular/fisiologia , Interleucinas/fisiologia , Transdução de Sinais , Animais , Antígenos de Superfície/análise , Subpopulações de Linfócitos B/imunologia , Adesão Celular , Linhagem Celular Transformada , Células Dendríticas/imunologia , Humanos , Ativação Linfocitária , Camundongos , Modelos BiológicosRESUMO
Previous studies demonstrated that a human pre-B acute lymphoblastic leukemia cell line, NALM-6, failed to stimulate a primary MLR, despite expression of class II MHC and adhesion molecules. Here we demonstrate that this is the result of the fact that NALM-6 cells do not express the ligand for CD28, namely B7. NALM-6 transfectants that expressed high levels of B7 gained the capacity to stimulate IL-2 production by class II MHC molecule-specific alloreactive T cells and to costimulate a polyclonal population of purified T cells cultured with immobilized anti-CD3 mAb. In the presence of PMA, NALM-6 cells transfected with B7 polyclonally stimulated T cells in a cyclosporine A-resistant fashion, a property previously attributed only to agonistic anti-CD28 mAb. The gain of these functions could not be explained solely by an increased capacity of the transfectants to form conjugates with T cells, suggesting that the CD28/B7 interaction transduces a costimulatory signal in T cells.
Assuntos
Antígenos CD/fisiologia , Antígenos de Diferenciação de Linfócitos T/fisiologia , Antígenos de Superfície/fisiologia , Interleucina-2/biossíntese , Ativação Linfocitária , Linfócitos T/imunologia , Células Apresentadoras de Antígenos/fisiologia , Antígeno B7-1 , Antígenos CD28 , Adesão Celular , Humanos , Receptores de Antígenos de Linfócitos T/fisiologia , Acetato de Tetradecanoilforbol/farmacologia , TransfecçãoRESUMO
The costimulatory effects of anti-CD28 antibody or accessory cells on T cells were shown to be very similar. Both stimuli: (a) allowed T cell proliferation and IL-2 production in response to immobilized anti-CD3 antibody or antigen presented by APC whose costimulatory capacity had been damaged by fixation; and (b) stimulated cyclosporin A-resistant T cell proliferation in the presence of a phorbol ester. These similarities raise the possibility that anti-CD28 antibody binding to T cells delivers a costimulatory signal that is normally delivered by the interaction of CD28 with a complementary ligand on APC.
Assuntos
Células Apresentadoras de Antígenos/fisiologia , Antígenos CD/fisiologia , Antígenos de Diferenciação de Linfócitos T/fisiologia , Ativação Linfocitária , Linfócitos T/imunologia , Adulto , Antígenos CD28 , Humanos , Interleucina-2/biossíntese , Acetato de Tetradecanoilforbol/farmacologiaRESUMO
CD4+ T cells require two signals to produce maximal amounts of IL-2, i.e., TCR occupancy and an unidentified APC-derived costimulus. Here we show that this costimulatory signal can be delivered by the T cell molecule CD28. An agonistic anti-CD28 mAb, but not IL-1 and/or IL-6, stimulated T cell proliferation by tetanus toxoid-specific T cells cultured with Ag-pulsed, costimulation-deficient APC. Furthermore, the ability of B cell tumor lines to provide costimulatory signals to purified T cells correlated well with expression of the CD28 ligand B7/BB-1. Finally, like anti-CD28 mAb, autologous human APC appeared to stimulate a cyclosporine A-resistant pathway of T cell activation. Together, these results suggest that the two signals required for IL-2 production by CD4+ T cells can be transduced by the TCR and CD28.
Assuntos
Antígenos CD/fisiologia , Antígenos de Diferenciação de Linfócitos T/fisiologia , Interleucina-2/biossíntese , Transdução de Sinais , Linfócitos T/metabolismo , Anticorpos Monoclonais/imunologia , Células Apresentadoras de Antígenos/fisiologia , Antígenos de Diferenciação de Linfócitos T/imunologia , Antígenos de Superfície/fisiologia , Antígeno B7-1 , Antígenos CD28 , Complexo CD3 , Humanos , Ativação Linfocitária , Receptores de Antígenos de Linfócitos T/imunologia , Toxoide Tetânico/imunologia , Acetato de Tetradecanoilforbol/farmacologiaRESUMO
In Th1 clones, TCR occupancy together with a costimulatory signal from APC results in IL-2 production. TCR occupancy alone results in unresponsiveness (anergy) to antigenic stimulation, a phenomenon that may be important for self-tolerance in vivo. Inasmuch as inositol phosphate production occurs during the induction of anergy other biochemical signals must be necessary for IL-2 production. Here we assess the role of tyrosine-specific protein kinases using the specific inhibitor, genistein. IL-2 secretion and responsiveness were very dependent on tyrosine-specific protein kinase activation and could be completely blocked under conditions where inositol phosphate generation occurred normally. Although anergy induction could also be blocked by inhibition of tyrosine-specific protein kinase activation this probably occurred indirectly via inhibition of inositol phospholipid hydrolysis. The differential susceptibility of IL-2 secretion and anergy induction to inhibition by genistein indicates that positive and negative outcomes of TCR occupancy may be mediated by distinct biochemical pathways.
Assuntos
Tolerância Imunológica/imunologia , Fosfatos de Inositol/biossíntese , Interleucina-2/metabolismo , Proteínas Tirosina Quinases/fisiologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Células Apresentadoras de Antígenos/imunologia , Antígenos/imunologia , Cálcio/metabolismo , Células Clonais , Genisteína , Tolerância Imunológica/efeitos dos fármacos , Isoflavonas/farmacologia , Camundongos , Fosfatidilinositóis/metabolismo , Proteínas Tirosina Quinases/antagonistas & inibidores , Linfócitos T/efeitos dos fármacosAssuntos
Tolerância Imunológica , Linfócitos T/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Diferenciação Celular , Células Clonais/imunologia , Ativação Linfocitária , Camundongos , Camundongos Transgênicos , Quimera por Radiação/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/citologiaRESUMO
The activation of Ag-specific, Ia molecule-restricted, TCR V beta 3+ T cell clones by staphylococcal toxic shock syndrome toxin-1 (TSST-1), was investigated. The results show that although Ag- and TSST-1-induced activation of T cell clones both require TCR expression and similar biologic activation signals, the Ia molecule requirement for TSST-1 recognition was much less stringent than that observed for antigenic peptide recognition. In addition, T cell clones recognized TSST-1 without processing by APC. These results suggest that the ability of TSST-1 to polyclonally activate T cells is dependent on TCR recognition of the intact toxin molecule bound to a nonpolymorphic region(s) of the Ia molecule resulting in the same activation events induced by Ag recognition.