Gene/Protein Disease Symptom Drug Enzyme Compound
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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.
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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

(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.
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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 mRNA expression of interleukin (IL)-2, IL-2 receptor-alpha-chain (IL-2R alpha), IL-4 and interferon-gamma (IFN-gamma) in spleen cells from NZB/NZW F1) mice following the stimulation with concanavalin A (Con A) was examined by Northern blot analysis. Kinetic patterns of the mRNA expression after the stimulation were not different between 2-month-old and 6 to 8-month-old B/W F1 mice. However, relative mRNA expression of IL-2 to a cytoskeletal protein, alpha-Tubulin was lower in 6 to 8-month-old B/W F1 mice than in 2-month-old mice. Similar but not significant tendency was observed in IL-2R mRNA expression. In contrast, Relative IL-4 mRNA expression in 6 to 8-month-old B/W F1 mice was significantly higher than that in 2-month-old animals. On the other hand, no apparent change was observed in IFN-gamma mRNA expression. Flow cytometric analysis indicated that there was no apparent difference in proportion of L3T4 positive T cells in spleen cells from 2 and 6 to 8-month-old B/W F1 mice. These results suggest that mRNA expression of IL-2 and IL-4 differentially changes with aging in autoimmune B/W F1 mice.
Lupus 1995 Jun
PMID:Age-related differential mRNA expression of T cell cytokines in NZB/NZW F1 mice. 765 92

NZB.H-2bm12 mice develop an autoimmune syndrome characterized by the overproduction of anti-DNA antibodies and the expansion of B-1 B cells. Thus, these animals provide a useful model to examine the antigenic specificity, cross-reactivity and functional capability of B-1 versus conventional lymphocytes. Neither the repertoire expressed by in vivo activated Ly-1+ splenic lymphocytes, nor their cross-reactivity, differed significantly from that of conventional splenic B cells. When Ly-1+ cells were cultured in vitro in the presence of lipopolysaccharide plus interleukin-4 or interferon gamma, they underwent isotype switching at the same frequency as conventional B cells. Of interest, B-1 cells from the peritoneal cavity were significantly less likely to undergo isotype switching than those from the spleen. These findings indicate that in vivo activated B-1a and conventional B cells from mice with lupus manifest similar functional characteristics.
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PMID:B-1a and conventional B cells from autoimmune NZB.H-2bm12 mice exhibit similar functional characteristics in vivo. 768 8

This report describes T cell lines derived from a patient with subacute cutaneous lupus after treatment with intravenous pulse cyclophosphamide. We selected for mitotically active, hypoxanthine-guanine phosphoribosyltransferase-deficient (HPRT-) T cells, by culture in a selective medium containing 6-thioguanine. When HPRT- cell lines were derived 6 days after pulse cyclophosphamide (CYC) treatment, they were predominantly CD8+ and T cell receptor (TCR) gamma/delta+, producing interferon-gamma (IFN gamma). Cell lines derived 21 days after CYC treatment were CD4+, TCR alpha/beta+ and produced both IFN gamma and interleukin-4. These results support a possible role for gamma/delta+ T cells in subacute cutaneous lupus and suggest a mechanism for the therapeutic effect of CYC.
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PMID:Characteristics of HPRT-mutant T cell lines in a lupus patient treated with cyclophosphamide. 794 81

The plasma levels of interleukin-4 (IL-4), interleukin-2 (IL-2), soluble receptor of IL-2 (IL-2R) and T cell expression of IL-2 receptor chain (CD25+) were determined in an attempt to relate these parameters with disease activity in systemic lupus erythematosus (SLE). IL-4, IL-2 and sIL-2R plasma levels of SLE patients were significantly higher than those of the control group (P < 0.05) while CD25+ expression was similar in both groups. Only sIL-2R levels were significantly higher (P < 0.05) in active than in inactive patients.
Lupus 1993 Aug
PMID:Relationship of IL-2, IL-2R (CD25+), soluble IL-2R and IL-4 with disease activity in SLE patients. 826 74

Interleukin-4 (IL-4) provides support for humoral immune responses through upregulation of T helper (Th) type 2 cell differentiation, but it is not known whether IL-4 promotes antibody-mediated autoimmune diseases such as systemic lupus erythematosus (SLE). Here, we show that the constitutive expression of an IL-4 transgene by B cells completely prevents the development of lethal lupus-like glomerulonephritis in the (NZW x C57BL/6.Yaa)F1 murine model of SLE. This was associated with marked changes in the serum levels of IgG subclasses, rather than in the total levels of anti-DNA antibodies, with a lack of IgG3, a decrease of IgG2a, and an increase in IgG1 subclasses, and by a strong reduction in the serum levels of gp70-anti-gp70 immune complexes. This effect of the transgene appears to result from a modulation of the Th1 versus Th2 autoimmune response, since the protected mice displayed comparably modified IgG2a and IgG3 antibody response against exogenous T cell-dependent antigen, but not against T cell-independent antigens. Thus, IL-4 prevents the development of this lupus-like autoimmune disease, most likely by downregulating the appearance of Th1-mediated IgG subclasses of autoantibodies such as the IgG3 autoantibodies which have been shown to be especially nephritogenic.
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PMID:Interleukin-4 protects against a genetically linked lupus-like autoimmune syndrome. 899 42

It has been established that CD4+ T cells play an essential role in the development of systemic lupus erythematosus (SLE). Since CD4+ T cells differentiate upon activation into two defined subsets, TH1 and TH2, differing in their capacities of cytokine production with distinct immunopathological consequences, it becomes important to understand the respective roles of TH subsets in the pathogenesis of SLE. Our analysis on 4 different substrains of autoimmune-prone MRL mice revealed that the progression of SLE in these mice is correlated with an enhanced expression of interferon-gamma (a TH1 type cytokine regulating the production of IgG2a and IgG3) vs interleukin-4 (IL-4; a TH2 type cytokine regulating the production of IgG1), in parallel with an increased production of IgG2a and IgG3 autoantibodies over IgG1. In addition, studies on lupus-prone mice expressing an IL-4 transgene have shown that the constitutive expression of IL-4, biasing autoimmune responses towards a TH2 phenotype, inhibits the development of lupus nephritis. These results suggest that the development and progression of murine lupus is determined by the type of TH responses (either acceleration by TH1 responses or protection by TH2 responses) inducing the generation of more or less pathogenic autoantibodies. In fact, murine IgG3 has been shown to be extremely nephritogenic, generating "wire-loop" lupus-like glomerular lesions, because of their cryoglobulin activity associated with a unique physicochemical property of IgG3 constant region. Our results underline the importance in the pathogenesis of SLE of the qualitative aspects of autoantibody responses controlled by subpopulations of TH cells.
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PMID:T helper cell subsets in the pathogenesis of systemic lupus erythematosus. 909 56

Systemic lupus erythematosus (SLE) is characterized by autoantibody production of unknown origin. Since T-B cell interaction is a key event to produce antibodies, we investigated this interaction through study of CD69, CD40 ligand (CD40L) and CD23 expression (three very early activation antigens). Peripheral blood mononuclear cells (PBMC) from inactive lupus patients were studied following culture with either medium alone, anti-CD3 monoclonal antibody (mAb), recombinant interleukin-4 (rIL-4) or phorbol myristate acetate (PMA)+/-ionomycin. Analysis of CD23 expression on lupus B cells in basal conditions and after anti-CD3 challenge of PBMC, a reflection of cognate interaction between T and B cells, was clearly defective. Conversely, CD23 expression on lupus B cells following non-cognate T cell signals (rIL-4) was preserved. CD69 and CD40L expression was also impaired in lupus T cells following anti-CD3 challenge. Nonetheless, activation by means of PMA and/or ionomycin was preserved both in T cells (CD69 and CD40L expression) and in B cells (CD23 expression). These results indicate that B cells from inactive lupus patients display a normal early response to direct B-cell stimuli. Conversely, T-dependent B-cell stimuli are clearly defective in SLE patients in remission. These results indicate that T-B cognate interaction related to defective T cell activation located between surface membrane and protein kinase C (PKC)/ionomycin function is an intrinsic characteristic of these patients.
Lupus 1998
PMID:Defective early T and T-dependent B cell activation in systemic lupus erythematosus. 969 35

We previously showed that dietary fish oil (FO) and energy restriction (R) have beneficial anti-inflammatory properties in the peripheral blood and spleens of (NZB x NZW)F1 (B/W) lupus-prone mice. Furthermore, unsaturated fatty acids also were shown in the past to influence mesenteric lymph node (MLN) lymphocyte function in healthy young rats. The MLN play a pivotal role in mediating food allergy. To date, the effect of R on intestinal immunity is not well understood; therefore we determined the effect of diet on MLN lymphocyte function. Mice were given either free access to a 5 g/100 g corn oil (CO) or fish oil (FO) diet or the same corn oil (CR) or fish oil (FR) diets restricted to 60% of the intake of the control group. At the age of 4 (young) and 8 (old) mo, MLN lymphocytes were isolated and B- (CD19(+)) and T-lymphocyte subsets (CD4(+) and CD8(+)) were determined by flow cytometry. Additional MLN lymphocytes were placed in culture with or without concanavalin A and culture supernatants collected after 72 h for cytokine and immunoglobulin (Ig) quantitation by ELISA. Aging significantly (P < 0.05) decreased both CD4(+) and CD8(+) T-lymphocytes. Spontaneous and activation-induced interleukin-4 (IL-4), IL-10, and interferon-gamma secretion were greater while IL-2 was lower in CO-fed old mice compared to CO-fed young mice. In contrast, CR or FO alone partially blunted the age-dependent alterations in T-lymphocyte ratios including cytokine and Ig secretion, whereas the FR diet significantly (P < 0.005) normalized the accelerated aging effects on these immune variables. We show for the first time that FR is a far more potent anti-inflammatory therapy than either CR or FO alone in modulating MLN lymphocyte function.
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PMID:Dietary (n-6) and (n-3) fatty acids and energy restriction modulate mesenteric lymph node lymphocyte function in autoimmune-prone (NZB x NZW)F1 mice. 1086 32


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