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Biomedical subjects

D S Pisetsky

Publications and source records attributed to D S Pisetsky.

At least 73 records · Page 4Linked to original sources
PubMed1996

CD19 regulates B lymphocyte signaling thresholds critical for the development of B-1 lineage cells and autoimmunity.

CD19 serves as a cell surface response regulator that establishes signaling thresholds critical for B lymphocyte development and activation. B lymphocytes from CD19-deficient mice are hyporesponsive to transmembrane signals, while B lymphocytes from mice that overexpress CD19 to even a small extent (25% increase) become hyperresponsive. The B-1 subpopulation of B lymphocytes is particularly sensitive to CD19 regulation, since their development is severely decreased in CD19-deficient mice. The effect of altered CD19 expression levels on the development of B cells was therefore examined using transgenic mice that express varying levels of cell surface CD19. In this study, immature B cells within the bone marrow of wild-type mice were found to specifically up-regulate CD19 expression levels by twofold as they mature, while CD5+ B cells within the spleen and peritoneum expressed even higher levels of CD19. The development of CD5+ B cells was severely decreased in CD19-deficient mice, while there was a linear correlation between increased CD19 expression levels and the increased frequency of CD5+ B cells within the peritoneum and spleen. In fact, CD5+ B cells became a major B lymphocyte population in mice that overexpressed CD19. Increased expression of CD19 also correlated with increased levels of endogenous anti-DNA Abs and rheumatoid factor. These results indicate that up-regulated expression of CD19 is functionally important for B cell development and that CD19 establishes signaling thresholds that regulate the generation of B-1 lymphocytes as well as the development of autoantibodies.

Animals↗
PubMed1996

Increased expression of blood mononuclear cell nitric oxide synthase type 2 in rheumatoid arthritis patients.

Nitric oxide (NO) is an important inflammatory mediator in nonhuman animal models of rheumatoid arthritis (RA). The purpose of the present study was to determine whether blood mononuclear cells from patients with active RA (as compared to control subjects) have higher levels of NO synthase type 2 (NOS2) and produce more NO in vitro. Leukocytes from 25 RA patients and 20 normal subjects were examined. Arthritis activity was assessed by tender and swollen joint counts, duration of morning stiffness, patient assessment of pain, physician and patient global assessment of disease activity, the modified Stanford Health Assessment Questionnaire, and by blood levels of acute phase reactants. Blood mononuclear cell NOS enzyme activity/antigen content and nitrite/nitrate formation in vitro were measured. Blood mononuclear cells from RA patients had increased NOS activity and increased NOS2 antigen content as compared to those from normal subjects, and responded to interferon-gamma with increased NOS expression and nitrite/nitrate production in vitro. NOS activity of freshly isolated blood mononuclear cells correlated significantly with disease activity, as assessed by render and swollen joint counts. Our results demonstrate that patients with RA have systemic activation for NOS2 expression, and that the degree of activation correlates with disease activity. Increased NOS2 expression and NO generation may be important in the pathogenesis of RA.

Adult↗
PubMed1996

Activation of human B cells by phosphorothioate oligodeoxynucleotides.

To investigate the potential of DNA to elicit immune responses in man, we examined the capacity of a variety of oligodeoxynucleotides (ODNs) to stimulate highly purified T cell-depleted human peripheral blood B cells. Among 47 ODNs of various sequences tested, 12 phosphorothioate oligodeoxynucleotides (sODNs) induced marked B cell proliferation and Ig production. IL-2 augmented both proliferation and production of IgM, IgG, and IgA, as well as IgM anti-DNA antibodies, but was not necessary for B cell stimulation. Similarly, T cells enhanced stimulation, but were not necessary for B cell activation. After stimulation with the active sODNs, more than 95% of B cells expressed CD25 and CD86. In addition, B cells stimulated with sODNs expressed all six of the major immunoglobulin VH gene families. These results indicate that the human B cell response to sODN is polyclonal. Active sODN coupled to Sepharose beads stimulated B cells as effectively as the free sODN, suggesting that stimulation resulted from engagement of surface receptors. These data indicate that sODNs can directly induce polyclonal activation of human B cells in a T cell-independent manner by engaging as yet unknown B cell surface receptors.

Antigens, CD↗
PubMed1996

Modulation of renal disease in autoimmune NZB/NZW mice by immunization with bacterial DNA.

Preautoimmune New Zealand Black/White (NZB/NZW) mice immunized with Escherichia coli (EC) double standard (ds) DNA produce antibodies that bind mammalian dsDNA and display specificities similar to spontaneous lupus anti-DNA. Since calf thymus (CT) dsDNA fails to induce these antibodies, these results suggest a special potency of foreign DNA in inducing serological manifestations of lupus in a susceptible host. To assess the effects of DNA immunization on clinical manifestations in NZB/NZW mice, we measured renal disease and survival of mice immunized with either (a) EC dsDNA as complexes with methylated bovine serum albumin (mBSA) in adjuvant; (b) CT dsDNA with mBSA in adjuvant; (c)mBSA alone in adjuvant; or (d) unimmunized. After immunization with EC dsDNA, NZB/NZW mice developed significant levels of anti-dsDNA antibodies. Nevertheless, these mice had less proteinuria, nitrate/nitrite excretion, and glomerular pathology than mice immunized with either mBSA alone, CT dsDNA/mBSA complexes, or unimmunized mice. Survival of the EC dsDNA immunized mice was significantly increased compared with the other mice. Furthermore, immunization of mice after the onset of anti-DNA production and proteinuria stabilized nephritis and prolonged survival. The improvement in renal disease occurred despite the expression of autoantibodies that bound mammalian dsDNA as well as glomerular antigens. These results suggest that bacterial DNA has immunological properties that attenuate murine lupus despite the induction of pathogenic antibodies.

Animals↗
PubMed1996

Bacterial DNA induces murine interferon-gamma production by stimulation of interleukin-12 and tumor necrosis factor-alpha.

Bacterial, but not mammalian DNA, can induce interferon-gamma (IFN-gamma) in murine splenocytes. To elucidate the basis of this activity, we have assessed in vitro cytokine production by C3H/HeJ splenocytes stimulated with either DNA from Escherichia coli or a synthetic oligonucleotide containing an active palindromic sequence identified from DNA. Both DNAs induced IFN-gamma production, with the requirement for intact DNA shown by sensitivity to DNase digestion. Fractionated cell populations were evaluated to determine direct or indirect cellular effects of the DNA. Although bacterial DNA failed to induce IFN-gamma in the nonadherent cell population, supernatants from adherent cells stimulated by DNA induced IFN-gamma production by these cells. Interleukin-12 (IL-12) was detectable in supernatants from DNA-stimulated splenocytes before IFN-gamma, and neutralizing antibodies directed against IL-12 markedly inhibited the induction of IFN-gamma. Anti-tumor necrosis factor-alpha (TNF-alpha) antibodies also inhibited IFN-gamma production, and the combination of both anti-IL-12 and anti-TNF-alpha could totally inhibit production of IFN-gamma. Taken together, these results indicate that the stimulation of IFN-gamma production by bacterial DNA is mediated by IL-12 and TNF-alpha and point to macrophages/monocytes as targets of action of this macromolecule.

Animals↗
PubMed1996

Final act.

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Humans↗
PubMed1996

Differences in V kappa gene utilization and VH CDR3 sequence among anti-DNA from C3H-lpr mice and lupus mice with nephritis.

To investigate the molecular properties of anti-DNA from lpr mice that express high levels of anti-DNA without immune-mediated nephritis, the sequences of VH and V kappa genes encoding 11 monoclonal anti-DNA antibodies derived from C3H-lpr/lpr (C3H-lpr) mice were studied. All of the C3H-lpr monoclonal anti-DNA bound single-stranded DNA while five also bound double-stranded DNA. Two of the hybridomas were clonally related as determined by Southern analysis and sequencing. Sequence analysis of C3H-lpr anti-DNA revealed the use of VH genes that encode anti-DNA from the MRL-lpr/lpr and (NZB X NZW) F1 mouse models of lupus, although differences occurred in the VH CDR3 amino acid content. In contrast, the V kappa genes from C3H-lpr mice lacked significant identity with previously reported V kappa genes for anti-DNA from lupus models. These results indicate that anti-DNA from C3H-lpr mice differ from anti-DNA from lupus mice with nephritis in patterns of V gene expression and suggest a molecular basis for the lack of pathogenicity of anti-DNA in these mice.

Amino Acid Sequence↗
PubMed1996

A multicenter trial of recombinant human interferon gamma in patients with systemic sclerosis: effects on cutaneous fibrosis and interleukin 2 receptor levels.

OBJECTIVE: To evaluate the acute toxicity, potential efficacy, and effects on the soluble interleukin 2 receptor (sIL-2R) of recombinant human interferon gamma (rIFN-gamma) in patients with systemic sclerosis (SSc). METHODS: A multicentered, pilot clinical trial of rIFN-gamma was performed on 20 patients (15 women, 5 men, mean age 45 years) with active cutaneous SSc (mean disease duration 36 months) to evaluate it potential as a novel therapy for this untreatable disorder. After one week of rIFN-gamma 0.01 mg/m2/day, subjects self-administered rIFN-gamma 0.1 mg/m2/day intramuscularly for a total of 18 weeks. The major outcome variable was a modified skin score (0 = normal skin, 3 = hidebound skin) measured and summed from 15 anatomic areas of the body. sIL-2R levels were measured by ELISA at entry and exit from the study. RESULTS: The clinical results were modest at best. Nine of 20 patients achieved at least a 20% reduction in skin score, with one patient showing almost total remission of all skin abnormalities. The mean skin score at entry for all subjects was 22.8 +/- 8.9 and over the course of the trial improved marginally compared to baseline (mean change -4.72 +/- 6.62; p = 0.008). However, 8 subjects did not change appreciably while in the trial. Antibodies to Scl-70 were observed in only 5 patients (all with diffuse scleroderma) and were not associated with either response to or complications from therapy. The adverse reactions were frequent and occasionally severe. Ten subjects were withdrawn because of exacerbation of Raynaud's symptoms (n = 5), constitutional symptoms (n = 2), development of renal crises (n = 2), and mild pancytopenia (n = 1). Minor laboratory abnormalities were common and included elevation of cholesterol, triglycerides, hepatic transaminases, and reduction in white blood cell count. Compared to controls, mean sIL-2R was markedly elevated at entry (1309 +/- 495 U/ml; p = 0.0001) and did not change appreciably at exit. Spearman correlation analysis showed a trend but no statistically significant association of skin score with sIL-2R (R = 0.408; p = 0.074). However, sIL-2R was significantly correlated with erythrocyte sedimentation rate (R = 0.542; p = 0.0165). A subset analysis revealed that skin score (p = 0.0001) and sIL-2R (p = 0.00170) were significantly higher at baseline for patients with diffuse scleroderma compared to patients with limited disease. CONCLUSION: rIFN-gamma may be beneficial for some patients with SSc, but the benefit appears marginal for most individuals and the side effects frequent. Although sIL-2R was elevated in many of the patients with SSc, it did not appear to be correlated with activity of cutaneous disease or response to therapy.

Adult↗
PubMed1996

Interleukin-2 receptor levels in sera of patients with rheumatoid arthritis treated with sulfasalazine, parenteral gold, or placebo.

OBJECTIVE: To evaluate the associations of soluble serum interleukin-2 receptor (sIL-2R) levels in patients with rheumatoid arthritis (RA) with clinical and laboratory measures of disease activity and the predicted response to therapy. METHODS: sIL-2R levels were determined by ELISA in 137 patients with RA, not previously treated with 2nd line therapy. Patients were enrolled in a prospective, randomized, placebo controlled trial of sulfasalazine (SSZ) versus gold sodium thiomalate (GSTM), sponsored by the Cooperative Systematic Studies of Rheumatic Diseases. Using correlation analysis and regression modeling, the clinical utility of sIL-2R as a measure of disease activity and predictor of outcome was assessed. RESULTS: 91 women and 46 men with a mean age of 51 +/- 13 years and mean duration of disease of 64 +/- 78 months participated in this study. The mean sIL-2R level in all patients with RA was markedly elevated (980 +/- 589 U/ml) compared with that in healthy control subjects (446 +/- 196 U/ml; p = < 0.0001). There was no correlation between the sIL-2R levels and the joint pain/tenderness count, either at study entry or completion. There were significant positive correlations between the baseline sIL-2R and baseline erythrocyte sedimentation rate (ESR) and between the change in sIL-2R and the change in ESR. Both a multiple linear regression model and a multiple logistic regression model showed that baseline sIL-2R levels were not predictive of clinical outcome. CONCLUSION: sIL-2R levels are significantly elevated in patients with active RA and correlate positively with ESR. However, these results indicate that in patients with early RA, sIL-2R levels are neither associated with standard disease activity criteria nor predictive of the response to therapy with SSZ or GSTM, even after controlling for the simultaneous effects of other important clinical variables.

Adult↗
PubMed1995

The effects of short-term treatment with the prostaglandin E1 (PGE1) analog misoprostol on inflammatory mediator production in murine lupus nephritis.

MRL-lpr/lpr mice spontaneously develop an autoimmune disease with nephritis similar to human systemic lupus erythematosus. In these animals, treatment with E-series prostaglandins ameliorates renal disease and prolongs survival, perhaps by modulating production of cytokines or eicosanoids. To further define the mechanisms of action of E-series prostaglandins in established murine lupus nephritis, we administered the prostaglandin E1 (PGE1) analog misoprostol to 20-week-old MRL-lpr/lpr mice by twice-daily subcutaneous injection. After 2 days of treatment, misoprostol reduced renal cortical interleukin-1 beta (IL-1 beta) mRNA levels compared to vehicle-treated controls (0.19 +/- 0.06 (misoprostol) vs 0.50 +/- 0.04 (vehicle) densitometry units; P < 0.005). A similar reduction in cortical IL-1 beta mRNA levels was found in left kidneys harvested from MRL-lpr/lpr mice following 2 days of treatment with misoprostol compared to right kidneys harvested from the same animal prior to the first dose of PGE1 analog (0.12 +/- .05 (left) vs 0.39 +/- 0.18 (right) densitometry units; P < 0.05). This reduction in cortical IL-1 beta mRNA levels was not associated with alterations in renal production of thromboxane B2, PGE2, or leukotriene B4 or with significant changes in the severity of renal inflammatory cell infiltrates. Time-course studies indicated that IL-1 beta mRNA levels were decreased within 24 hr of initiating misoprostol therapy. This reduction in IL-1 beta mRNA levels was transient because levels were not reduced after 1 week of treatment with the PGE1 analog.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

The influence of variable-region somatic mutations on the specificity and pathogenicity of murine monoclonal anti-DNA antibodies.

Antibodies to DNA (anti-DNA) occur prominently in systemic lupus erythematosus and provoke inflammatory damage in the kidneys. To determine the factors that confer pathogenicity on antibodies of this specificity, we investigated the in vitro and in vivo glomerular binding by members of four clonally related sets of monoclonal anti-DNA antibodies from lupus mice. Somatic mutations within the clonal sets enhanced binding to double-stranded DNA (dsDNA). Binding to permeabilized glomeruli in vitro was observed among affinity-purified preparations of these antibodies independent of specificity for dsDNA. In normal mice injected with hybridoma cell lines, nephritis as assessed by histology and immunofluorescence did not correlate with antibody affinity for DNA. By multivariate analysis, in vitro glomerular binding was the most predictive parameter of histologic outcome. These findings indicate that somatic mutations occurring during maturation of the autoimmune response do not necessarily enhance pathogenicity.

Amino Acid Sequence↗
PubMed1995

In vitro inhibition of murine IFN gamma production by phosphorothioate deoxyguanosine oligomers.

Phosphorothioate (PT) oligonucleotides are designed as specific agents for antisense therapy although they have been reported to exert non-specific immunomodulatory effects. To elucidate further their actions, the effect of PT deoxyguanosine oligomers (S-oligo(dG)) on in vitro cytokine production by mouse splenocytes was studied. S-oligo(dG)20 inhibited production of INF gamma induced by Con A, E. coli DNA or the combination of PMA and calcium ionophore A23187. The diester analogue was inactive, and of PT homo-oligomers tested, S-oligo(dG)20 was the most active. PT compounds with as few as 5 dG residues could also block INF gamma production. These results indicate that base composition and length, as well as the PT backbone, contribute to the inhibition of INF gamma production and extend the range of immunomodulatory effects of PT compounds.

Animals↗