Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0409974 (lupus)
 22,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Groups of female MRL/MpJ-lpr/lpr mice received either saline or FK506 (tacrolimus; 2 mg/kg intraperitoneally) three times weekly, cyclophosphamide (CY; 20 mg/kg) once monthly, or both drugs from 8 weeks of age. Median survival for untreated and CY-treated mice was 26 weeks, and for FK506- and FK506 + CY-treated groups was > or = 44 weeks. Severity of skin lesions and lymph node hyperplasia was markedly reduced by the drug combination, whereas either drug alone was less effective. FK506 or CY alone delayed the onset of proteinuria, but by 24 weeks all of these animals were positive. In contrast, drug combination reduced the prevalence of proteinuria to < or = 60% throughout the 44 weeks of study. Sequential monitoring of peripheral blood lymphocytes revealed that combination therapy but not monotherapy markedly reduced the proportion of atypical CD3+ B220+ and CD3+CD4-CD8- T cells. Neither FK506 nor CY affected the reduction in IL-2 and IL-4 mRNA levels observed in lymph nodes of diseased animals compared with normals. Although the drug combination also did not affect IL-2 mRNA levels, IL-4 mRNA transcripts were increased six-fold compared with saline-treated controls. IL-10 and interferon-gamma (IFN-gamma) mRNAs were induced by FK506, CY and by the drug combination. Serum levels of anti-dsDNA antibodies were reduced in all treatment groups. These data demonstrate improved efficacy of combined T and B cell-directed immunosuppression in murine lupus, associated with marked inhibition of atypical T cells and selective augmentation of IL-4 within the affected lymphoid tissue.
 ...
PMID:Combined effects of FK506 (tacrolimus) and cyclophosphamide on atypical B220+ T cells, cytokine gene expression and disease activity in MRL/MpJ-lpr/lpr mice. 753 8

Multifactorial involvement in the pathogenesis of autoimmune NZB/W F1 mice has been well documented. To further elucidate the role of cytokines in the disease development of murine lupus, single spleen cells isolated from NZB/W F1 and non-autoimmune C57BL/6 mice were stimulated with T cell mitogens or anti-CD3 antibody at pre-determined optimal concentration. Supernatants were collected and assayed for production of cytokines including IL-2, gamma-IFN, IL-3, IL-4, IL-5 and IL-10. In both young and old mice, cytokine profiles by mitogen-stimulated T cells showed higher TH2 (type 2 T helper) cell-related cytokine production in NZB/W F1 mice compared to those in non-autoimmune C57BL/6 mice. In contrast, cytokines produced by TH1 (type 1 T helper) cells, such as gamma-IFN and IL-2, were lower in NZB/W F1 mice by stimulation with either mitogen or anti-CD3 antibody. In addition, cytokine production at different time points also demonstrated decreased gamma-IFN and increased IL-4 levels by anti-CD3 stimulated splenic cells in autoimmune NZB/W F1 mice. Furthermore, the IL-10 levels produced by lipopolysaccharide (LPS)-stimulated splenic and peritoneal exudate cells were higher in young NZB/W F1 mice compared to those in C57BL/6 mice. Our data suggest that dysregulation between TH1 and TH2 cells may play an important role in the pathogenesis of autoimmunity in NZB/W F1 mice.
 ...
PMID:Dysregulation of T helper cell cytokines in autoimmune prone NZB x NZW F1 mice. 756 80

(NZB x NZW)F1 (B/W) mice spontaneously develop a lupus-like syndrome characterized by an increased level of autoantibodies in old mice. We analysed the role of T cells in the regulation of anti-DNA antibody production by B cells in vitro as a function of age. In cultures of old mouse T and B cells, IgG and IgM anti-DNA antibodies were synthesized at high levels, in contrast to consistently lower amounts, particularly of IgG, measured in cultures of young mouse cells. Addition of young mouse T cells to old B cells inhibited IgG, but not IgM, anti-DNA production, whereas T cells from old mice stimulated IgG synthesis by young mouse B cells. Addition of supernatants harvested from concanavalin A (Con A)-stimulated T cells to B-cell cultures induced similar effects. Therefore, we evaluated possible modifications of lymphokine synthesis compared to that of the healthy NZW parent. T cells from old mice were able to secrete normal levels of interferon-gamma (IFN-gamma) and interleukin (IL)-10; however, secretion of IL-2 and IL-4 was dramatically decreased. Semi-quantitative polymerase chain reaction analysis of constitutive RNA messengers showed increased IFN-gamma levels in young and old B/W mice, and normal IL-10 mRNA levels in young and higher levels in old mice. Constitutive IL-2 and IL-4 mRNA were detected only after Con A stimulation and their levels decreased in old compared to young B/W mice; in particular IL-2 mRNA was considerably lower in old B/W than in control NZW mice. Taken together, these results suggest that, despite constitutive T-cell abnormalities, young B/W mice are able partially to control their lymphokine production, whereas aged mice exhibit a deficient synthesis, associated with an increased capacity to produce IFN-gamma.
 ...
PMID:Defects in the regulation of anti-DNA antibody production in aged lupus-prone (NZB x NZW)F1 mice: analysis of T-cell lymphokine synthesis. 763 19

The nature of the stimuli driving autoantibody production in systemic lupus erythematosus (SLE) is unclear, but cytokines are believed to play an important role. Since cytokines primarily appear to act locally at the tissue level, we analysed mRNA expression of several cytokines (IL-1 alpha, IL-1 beta, IL-2, IL-4, IL-5, IL-6, IL-10, IFN gamma, TNF alpha, TNF beta and TGF beta 1) in the lymph nodes of lupus-prone mice, in models of early onset disease. We constructed a multispecific competitor fragment that allowed quantification of these cytokine transcripts by competitive PCR assay. The results reveal considerable overexpression of IL-1 beta, IL-10 and IFN gamma transcripts in SLE-prone MRL-lpr/lpr (MRL/l) and BXSB male (BXSBm) mice, but with some strain differences. IFN gamma was most markedly augmented in MRL/l mice (in some cases over 100-fold greater than control mice), IL-1 beta was most severely overexpressed in BXSBm mice while IL-10 was equally increased in both strains. In addition, TGF beta 1 expression was moderately elevated in the lymph nodes of BXSBm (but not MRL/l) mice. We found no abnormality in the expression of the other cytokines. Cytokine transcript levels were only slightly altered at 4 weeks of age, but were elevated from 10 to 22 weeks of age. The latter phase corresponds to a period where lupus-like disease escalates, resulting in frequent mortality. Interestingly, our results do not reveal a clear Th1 or Th2 cytokine expression pattern in these lupus-prone mice. IL-1 beta, IFN gamma and IL-10 are pleiotropic cytokines with pro-inflammatory and B-cell stimulatory effects. These results point to certain cytokines as potential targets for immunotherapy in lupus.
 ...
PMID:Quantitative polymerase chain reaction analysis reveals marked overexpression of interleukin-1 beta, interleukin-1 and interferon-gamma mRNA in the lymph nodes of lupus-prone mice. 778 52

Cytokines are important in developmental and effector pathways of lymphocyte function. Our objective was to elucidate the profile of cytokines produced by circulating mononuclear cells from patients with systemic lupus erythematosus as estimated from studies of cytokine-gene activation. cDNA prepared by reverse transcription of lymphocyte mRNA was amplified using the polymerase chain reaction and normalized on the basis of beta-actin gene expression. Of 10 cytokines investigated in 16 individuals, differences between SLE and controls were found in only three. IL-2 transcripts were detected in four of six cases of subjects hospitalized for active SLE, but in only one of seven healthy controls, and none of three cases with pulmonary tuberculosis. By contrast, IL-4 transcripts were decreased compared with healthy controls and patients with tuberculosis. Also, TGF beta transcripts appeared to be decreased in SLE. All individuals studied regularly demonstrated high levels of transcripts for IL-1 beta, IL-6 and TNF alpha and transcripts for IFN gamma, TNF beta, IL-5 and IL-10 were variably expressed. In a second group of six SLE patients with less active disease, there was also a decrease in IL-4 expression compared with six healthy controls. Moreover, assays performed on sera from patients with active SLE revealed that IL-4 levels were not increased. Although in mice this cytokine has a well documented role in supporting antibody production, this study provides no evidence that IL-4 is involved in the B cell hyperactivity characteristic of human SLE.
Lupus 1994 Oct
PMID:Cytokine gene profile in circulating blood mononuclear cells from patients with systemic lupus erythematosus: increased interleukin-2 but not interleukin-4 mRNA. 784 98

We have previously shown that continuous administration of anti-interleukin 10 (anti-IL-10) antibodies (Abs) to BALB/c mice modifies endogenous levels of autoantibodies, tumor necrosis factor alpha (TNF-alpha), and interferon gamma, three immune mediators known to affect the development of autoimmunity in "lupus-prone" New Zealand black/white (NZB/W)F1 mice. To explore the consequences of IL-10 neutralization in NZB/W F1 mice, animals were injected two to three times per week from birth until 8-10 mo of age with anti-IL-10 Abs or with isotype control Abs. Anti-IL-10 treatment substantially delayed onset of autoimmunity in NZB/W F1 mice as monitored either by overall survival, or by development of proteinuria, glomerulonephritis, or autoantibodies. Survival at 9 mo was increased from 10 to 80% in anti-IL-10-treated mice relative to Ig isotype-treated controls. This protection against autoimmunity appeared to be due to an anti-IL-10-induced upregulation of endogenous TNF-alpha, since anti-IL-10-protected NZB/W F1 mice rapidly developed autoimmunity when neutralizing anti-TNF-alpha Abs were introduced at 30 wk along with the anti-IL-10 treatment. Consistent with the protective role of anti-IL-10 treatment in these experiments, continuous administration of IL-10 from 4 until 38 wk of age accelerated the onset of autoimmunity in NZB/W F1 mice. The same period of continuous IL-10 administration did not appear to be toxic to, or cause development of lupus-like autoimmunity in normal BALB/c mice. These data suggest that IL-10 antagonists may be beneficial in the treatment of human systemic lupus erythematosus.
 ...
PMID:Continuous administration of anti-interleukin 10 antibodies delays onset of autoimmunity in NZB/W F1 mice. 827 Aug 73

To investigate the respective roles of Th1 and Th2 cells in the pathogenesis of lupus-like autoimmune disease, we have analyzed the spontaneous and antigen-induced productions of IgG1 vs IgG2a and IgG3 subclasses in relation to the mRNA expression of INF-gamma (Th1 cytokine promoting IgG2a and IgG3 production), IL-4 (Th2 cytokine promoting IgG1 production), and IL-10 (Th2 cytokine) in CD4+ T cells from lupus-prone MRL mice. For this purpose, two paired sets of MRL mice were chosen for the comparison of these parameters: (a) MRL-lpr/lpr (lpr for lymphoproliferation) and its recently described substrain with a prolonged survival, termed MRL-lpr/lpr.ll (ll for long lived) and (b) MRL male mice bearing the Yaa (Y-linked autoimmune acceleration) gene (MRL.Yaa) with an accelerated disease and their male counterparts lacking the Yaa gene. We demonstrate herein that the accelerated development of lupus-like autoimmune disease in MRL-lpr/lpr and MRL.Yaa mice, as compared with MRL-lpr/lpr.ll and MRL-+/+ mice, respectively, was correlated with an enhanced expression of IFN-gamma vs IL-4 and IL-10 mRNA in CD4+ T cells, which paralleled with an increase of spontaneous and foreign T cell-dependent antigen-induced productions of IgG2a and IgG3 vs IgG1 antibodies. These data suggest that an imbalance towards Th1 predominance may play a significant role in the acceleration of lupus-like autoimmune disease in MRL mice.
 ...
PMID:Imbalance towards Th1 predominance is associated with acceleration of lupus-like autoimmune syndrome in MRL mice. 860 23

Neonatal exposure to antigen is believed to result in T cell clonal inactivation or deletion. Here we report that, contrary to this notion, neonatal injection of BALB/c mice with a hen egg lysozyme peptide 106-116 in putative "tolergenic" doses induced a T cell proliferative and an immunoglobulin G (IgG) antibody (Ab) response of both T helper cell 1 (Th1)- (IgG2a, IgG2b, and IgG 3) and Th2-dependent (IgG1) isotopes. Upon subsequent challenge with the peptide in complete Freund's adjuvant in adult life, although this neonatal regimen suppressed proliferation and the production of Th1 cytokines (interleukin[IL]-2 and interferon gamma), Th2 cytokine (IL-5, IL-4, and IL-10) secretion was increased, and the serum levels of Th1- and Th2-dependent isotypes of peptide-specific Ab remained elevated. The in vitro proliferative unresponsiveness in Th1 cells could be reversed by Abs to Th2 cytokines (IL-4 and IL-10). Thus, neonatal treatment with a peptide antigen induces T cell priming including production of IgG Abs of both Th1- and Th2-dependent isotypes. Upon subsequent peptide exposure, the peptide-specific T cell responses undergo an effective class switch in the direction of Th2, resulting in T cell proliferative unresponsiveness. Accordingly, this shift towards increased Ab production to autoantigen could be deleterious in individuals prone to antibody-mediated diseases. Indeed, neonatal treatment with a self-autoantigenic peptide from an anti-DNA monoclonal Ab (A6H 58-69) significantly increased the IgG anti-double-stranded DNA Ab levels in lupus-prone NZB/NZW F1 mice, despite suppressing peptide-specific T cell proliferation. This adverse clinical response is in sharp contrast to the beneficial outcome of neonatal treatment with autoantigens in Th1-mediated autoimmune diseases, such as autoimmune encephalomyelitis, as reported by others. A Th1 to Th2 immune deviation can explain the discordant biological responses after the presumed induction of neonatal tolerance in autoantibody- vs. Th-1 mediated autoimmune diseases.
 ...
PMID:Neonatal peptide exposure can prime T cells and, upon subsequent immunization, induce their immune deviation: implications for antibody vs. T cell-mediated autoimmunity. 866 87

Polyclonal B cell activation has been thought to play the critical role in production of autoantibodies, and possible activation of autoreactive T cells in murine lupus, especially abnormal expansion of CD5+ B cells, is one of the characteristic findings in these mice. The aim of this study was to investigate further the characteristics and function of CD5+ and CD5- B cells. Both CD5+ and CD5- B cells were isolated for in vitro autoantibody production, cytokine expression and in vivo anti-DNA antibody production with reconstitution of severe combined immunodeficient (SCID) mice. The data showed: (i) both CD5+ and CD5- B cells produced a high level of anti-DNA antibody after stimulation with lipopolysaccharide (LPS) plus IL-5; (ii) both peritoneal CD5+ and CD5- B cells expressed a high level of IL-10 mRNA after stimulation with LPS, while in contrast CD5- B cells of non-autoimmune BALB/c mice did not express IL-10 mRNA after stimulation; (iii) SCID mice reconstituted with either CD5+ or CD5- B cells all produced significant levels of anti-DNA antibodies in vivo and manifested with proteinuria. These data suggest both CD5+ and CD5- B cells play important roles in polyclonal B cell activation and subsequent autoantibody production. Generalized polyclonal B cell activation, instead of expanding a certain subpopulation of B cells, contributed to the pathogenesis of autoimmunity in murine lupus.
 ...
PMID:In vitro and in vivo functional analysis of CD5+ and CD5- B cells of autoimmune NZB x NZW F1 mice. 891 70

Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by polyclonal B cell activation and by the production of anti-double-stranded (ds) DNA antibodies. Given the inhibitory effects of IL-12 on humoral immune responses, we investigated whether IL-12 displayed such an activity on in vitro immunoglobulin production by SLE PBMC. Spontaneous IgG, IgG1, IgG2, IgG3 and IgM antibody production was dramatically reduced by addition of IL-12. These results were confirmed by Elispot assays detecting IgG- and anti-dsDNA-secreting cells. While IL-6 and TNF titres measured in PBMC supernatants were not modified by addition of IL-12, interferon-gamma (IFN-gamma) titres were up-regulated and IL-10 production down-regulated. Since addition of IFN-gamma did not down-regulate immunoglobulin production and since the inhibitory activity of IL-12 on immunoglobulin synthesis was not suppressed by anti-IFN-gamma antibody, we concluded that the effect of IL-12 on immunoglobulin production was not mediated through IFN-gamma. Our data also argue against the possibility that down-regulation of endogenous IL-10 production was responsible for the effect of IL-12. Thus, inhibition of IL-10 production by IFN-gamma was not accompanied by inhibition of immunoglobulin production, and conversely, restoration of IL-10 production by anti-IFN-gamma antibody did not suppress the inhibitory activity exerted by IL-12 on immunoglobulin production. Taken together, our data indicate that reduction of excessive immunoglobulin and anti-dsDNA antibody production by lupus PBMC can be achieved in vitro by IL-12, independently of IFN-gamma and IL-10 modulation.
 ...
PMID:IL-12 inhibits in vitro immunoglobulin production by human lupus peripheral blood mononuclear cells (PBMC). 915 13


1 2 3 4 5 6 7 8 9 10 Next >>