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Biomedical subjects

L S Davis

Publications and source records attributed to L S Davis.

At least 19 recordsLinked to original sources
PubMed1995

Elevated Th1- or Th0-like cytokine mRNA in peripheral circulation of patients with rheumatoid arthritis. Modulation by treatment with anti-ICAM-1 correlates with clinical benefit.

The current studies examined whether cytokine patterns indicative of an imbalance in Th1 and Th2 cells could be identified in PBMC of patients with active rheumatoid arthritis (RA). To investigate this possibility, a reproducible PCR technique to assess cytokine mRNA levels in PBMC was employed that minimized in vitro manipulation of the cells. Seven of 14 RA patients had increased mRNA levels for IL-2, 5/14 for IFN-gamma, 3/14 for IL-4, and 4/14 for the IL-2R alpha-chain, compared with normal donors. Whereas 4 patients had elevated mRNA for IL-2 and IFN-gamma, indicative of an increase in activated Th1 or Th0 cells, 1 of 14 patients expressed low levels of IL-2 and IFN-gamma and high levels of IL-4 mRNA. Seven RA patients were treated with a mAb to ICAM-1 (CD54). To determine whether changes in cytokine mRNA levels might be associated with and/or account for the anti-inflammatory effect of anti-ICAM-1 mAb therapy, changes in cytokine mRNA levels were assessed and correlated with clinical improvement. Anti-ICAM-1 mAb administration was followed by a prompt and transient increase of IFN-gamma mRNA. Elevation of IFN-gamma mRNA expression throughout the treatment period reflected a temporary increase in the number of circulating CD3+CD4+ T cells, suggestive of altered circulatory patterns of activated Th1-like cells and was related to clinical efficacy. The results indicate that elevated cytokine mRNA levels characteristic for Th1 cells can be detected in the PBMC in active RA and, furthermore, that anti-ICAM-1 mAb may be beneficial in RA by altering the recruitment of activated Th1-like cells into the synovium. This assumption further strengthens the hypothesis of a significant contribution of Th1-like cells to the pathogenesis of RA.

Antibodies↗
PubMed1995

Regulation of human B cell function by recombinant CD40 ligand and other TNF-related ligands.

To assess the potential of CD40 ligand (CD40L) and the related molecules CD27 ligand (CD27), CD30 ligand (CD30L), and membrane TNF-alpha to stimulate B cell responses, expression of these proteins in the baculovirus system was performed. Sf9 cells expressing these membrane molecules were cultured with normal human B cells and a variety of B cell lines to assess the functional outcome. The signal provided by CD40L promotes aggregation of B cells, stimulates vigorous proliferation, and induces germ-line transcription of downstream heavy chain constant region genes in the absence of cytokine costimulation. In contrast, CD27L, CD30L, and TNF-alpha had no effects on B cell proliferation. CD27L and TNF-alpha had no effect on the induction of germ-line transcripts, whereas CD30L consistently inhibited constitutive and CD40L-induced germ-line transcription of the epsilon gene by B cell lines that express CD30. These results demonstrate the various members of the TNF family exert specific effects on human B cell function, with CD40L and CD30L providing powerful, but opposing, effects on l epsilon transcription.

Antigens, CD↗
PubMed1995

Expression of CD45RB and CD27 identifies subsets of CD4+ memory T cells with different capacities to induce B cell differentiation.

The capacity of four subsets of CD4+ memory T cells, defined by expression of CD45RB and CD27, to provide help for B cells was examined. Larger amounts of Ig were induced by CD45RBdimCD27- cells compared with the CD45RBdimCD27+ population, whereas CD45RBbrightCD27+ or CD27- cells were poor inducers of Ig synthesis. Mitomycin C treatment, which prevents suppressive activity, markedly enhanced Ig production supported by each subset except for CD45RBbrightCD27- cells. Mitomycin C-treated CD45RBdim cells remained the most efficient inducers of Ig production, but no difference was detected between CD27+ and CD27- cells. The subsets also differed in their ability to proliferate and secrete cytokines, but these differences did not explain variations in the capacity to provide help for B cells. Both CD27- subsets exhibited decreased proliferation and uniquely secreted IL-4, with the CD45RBdimCD27- subset producing the greatest quantities of IL-4. No differences in IL-2 and IFN-gamma production were found. IL-10 secretion increased with the acquisition of the CD45RBdim phenotype and, within the CD45RBdim cells, with the loss of CD27. Staining for cytoplasmic cytokines indicated that individual populations of CD27-CD4+ helper T cells produced either IL-4 or IFN-gamma, whereas more than half of the IL-4 producers also synthesized IL-2. Finally, the different abilities of CD4+ memory T cell subsets to support B cell differentiation did not relate to variations in the expression of CD40 ligand. These results indicate that within the CD4+ memory T cell population an increase of helper activity associates with the shift from a CD45RBbright to a CD45RBdim phenotype. Within the CD45RBdim subset, the loss of CD27 is associated with a reduction of suppressive activity.

Adult↗
PubMed1995

The CD40 ligand expressed by human B cells costimulates B cell responses.

The possibility that activated B cells might express a ligand for CD40 that was of functional importance for B cell responses was examined by using highly purified human peripheral blood B cells, as well as a variety of B lymphoblastoid cell lines and hybridomas. Following stimulation with the combination of a calcium ionophore and a phorbol ester, human B cells bound a soluble fusion protein containing the extracellular portion of CD40 and the Fc region of IgG1 (CD40.Ig). A variety of B cell lines and hybridomas also bound CD40.Ig, either constitutively or after activation. In addition, CD40.Ig specifically immunoprecipitated a 33-kDa glycoprotein from surface 125I-labeled activated B cells. The nucleotide sequence of the coding region of the CD40 ligand mRNA amplified by RT-PCR from activated T cells and B cell lines was identical. The CD40 ligand expressed on human B cells was important functionally because homotypic aggregation of CD40 ligand-expressing B cells was inhibited by the CD40.Ig construct. Additionally, RNA and DNA synthesis as well as Ig production by polyclonally activated, highly purified peripheral B cells and a variety of B cell lines were inhibited significantly by the CD40.Ig construct. Finally, B cell lines expressing the CD40 ligand induced Ig production from resting normal B cells in a CD40-dependent manner. These results indicate that human B cells express a ligand for CD40 that is identical with that expressed by activated T cells and that the B cell-expressed CD40 ligand plays an important role in facilitating responses of activated B cells.

Adult↗
PubMed1995

Induction of persistent T cell hyporesponsiveness in vivo by monoclonal antibody to ICAM-1 in patients with rheumatoid arthritis.

Rheumatoid arthritis patients undergoing treatment with a murine mAb (BIRR1) to ICAM-1 were studied to determine the effects of the treatment on T cell responsiveness assayed in vitro. Previous studies had demonstrated that over the 5-day treatment period, there was a transient increase in circulating T cells that returned to base line 3 days after therapy. The transient lymphocytosis correlated with a loss in delayed-type hypersensitivity reactivity during the time of Ab administration. However, neither the increase in T cell numbers nor the inhibition of delayed-type hypersensitivity responses correlated with the immediate clinical benefit of therapy or the prolonged nature of the response to therapy in some patients. The current studies show that after the return of lymphocyte numbers to pretreatment levels, a decrease in T lymphocyte responses to suboptimal activation signals, including accessory cell-dependent (low dose PHA and soluble anti-CD3 mAb) and accessory cell-independent stimuli (immobilized anti-CD3 mAb), was observed. However, responses to recall Ags were preserved. Depressed T cell responses were not the result of diminished accessory cell function or production of suppressive factors by monocytes, but rather reflected decreased IL-2 production. The duration of T cell hyporesponsiveness was variable in length but lasted up to 5 mo after treatment with anti-ICAM-1 mAb. The induction and persistence of T cell hyporesponsiveness correlated with an improvement in disease activity in treated patients. These studies show that treatment with anti-ICAM-1 mAb can induce T cell hyporesponsiveness that correlates with and may explain sustained therapeutic benefit in patients with rheumatoid arthritis.

Antibodies, Monoclonal↗
PubMed1995

Treponema pallidum and Borrelia burgdorferi lipoproteins and synthetic lipopeptides activate monocytes/macrophages.

The observation that the major membrane immunogens of the spirochetal pathogens. Treponema pallidum and Borrelia burgdorferi are lipoproteins prompted studies to investigate macrophage activation by the 47-kDa lipoprotein of T. pallidum and the acylated outer surface protein A (OspA) of B. burgdorferi. Both lipoproteins induced the synthesis of biologically active TNF-alpha and chloramphenicol acetyltransferase in a murine macrophage cell line transfected with a chloramphenicol acetyltransferase reporter gene controlled by a TNF promoter (TB2 cells). Nonacylated forms of these polypeptides did not induce cell activation. Comparison between purified OspA and B. burgdorferi cellular lipids revealed that the former was the more potent inducer of TNF-alpha. Synthetic lipohexapeptides corresponding to the N-termini of the 47-kDa lipoprotein of T. pallidum and OspA also activated TB2 cells in a dose-dependent fashion, whereas the nonlipidated hexapeptides were without effect, further underscoring the importance of protein acylation to cell activation. Among several lines of evidence supporting that macrophage stimulation by LPS and lipopeptides proceeds via different mechanisms, the most notable was that lipopeptides activated peritoneal macrophages from LPS-nonresponsive C3H/HeJ mice. The potential for spirochetal lipoproteins to function as general macrophage activators was demonstrated by the ability of the synthetic analogues to induce IL-1 beta, IL-6, and IL-12, in addition to TNF, in murine and/or human macrophages. Our findings indicate that spirochetal lipoproteins may be important immunomodulators in syphilis and Lyme disease and that the synthetic lipopeptides will be useful surrogates for studying immune mechanisms operative in the two spirochetal diseases.

Acylation↗
PubMed1995

De novo dup (5p) in a patient with congenital hypoplasia of the adrenal gland.

We report on a black male child with congenital hypoplasia of the adrenal gland (CHA) with a de novo duplication of 5p [dir dup(5) (p13.3-->p15.1)], confirmed by fluorescence in situ hybridization (FISH). In addition to a characteristic clinical course, the patient has hyperpigmentation (melanoderma) since birth, normal external genitalia, marked elevation of ACTH, and absent response to an IV ACTH challenge. To the best of our knowledge, this is the first case of congenital hypoplasia of the adrenal gland associated with a chromosome abnormality. Reviews of dup (5p) and of our patient suggest that duplication of 5p13.3-pter has only minor phenotypic effect, while duplication of the relatively small critical segment p11-p13.2 apparently causes far more deleterious changes. The concurrence of CHA and dup(5p) in our patient may indicate the possible gene localization of an autosomal form of CHA to either at or near 5p13.3 or 5p15.1.

Adrenal Glands↗
PubMed1995

Elevated interleukin-10 levels in patients with rheumatoid arthritis.

OBJECTIVE: Interleukin-10 (IL-10) has been shown to exert both antiinflammatory and immunostimulatory effects in vivo and in vitro. We therefore sought to examine the role of this cytokine in rheumatoid arthritis (RA) by assessing serum and synovial fluid IL-10 levels. METHODS: Serum and synovial fluid samples were collected from patients with RA and patients with various inflammatory, infectious, and noninflammatory arthritides (controls). IL-10 was assayed using an IL-10-specific enzyme-linked immunosorbent assay, and messenger RNA (mRNA) levels were assessed by semi-quantitative polymerase chain reaction (PCR) techniques. RESULTS: Both RA serum and synovial fluid contained significantly elevated IL-10 levels compared with levels in normal subjects or in control patients (P < 0.01). Some patients with spondylarthropathy also manifested increased serum levels of IL-10. Serum levels of IL-10 did not correlate with standard measures of clinical activity, but were shown to correlate significantly with serum rheumatoid factor (RF) titers and in vitro levels of spontaneous IgM-RF production (P < 0.05). PCR analyses demonstrated the constitutive expression of IL-10 mRNA by the non-T cell population, and semiquantitative PCR analysis documented elevated levels of IL-10 mRNA in circulating mononuclear cells of those RA patients who were not treated with slow-acting antirheumatic drugs. Analysis of IL-10 mRNA revealed the cytokine to be of human, and not viral, origin. CONCLUSION: These data suggest that there is increased production of IL-10 by non-T cells in patients with RA. This may contribute to the diminished T cell function and increased antibody and RF production in these patients.

Adult↗
PubMed1995

Erythromelanosis follicularis faciei in women.

Erythromelanosis follicularis faciei is an infrequently diagnosed disorder thought to be more common in men, with only seven reported cases in women. This condition consists of the clinical triad of well-demarcated erythema, hyperpigmentation, and follicular plugging on the face. We describe two additional female patients with this condition and present a review of the literature.

Adult↗
PubMed1995

Use of visual perception in estimating static postural stresses: magnitudes and sources of errors.

Very little is known about the magnitudes and sources of errors associated with the visual estimation of postural classification displayed on TV screens. This study was conducted to address this issue. Sixty-three subjects participated in the experiments. The findings indicate that: (1) subjects found it difficult to evaluate upper extremity postures (particularly the elbow and the wrist), while the postures around the lower back were the easiest to evaluate; (2) the lower extremity positions affected the ability of the subjects to accurately classify postures around the wrist, elbow, shoulder, neck, and lower back, with the estimates being > 70% for sitting and > 60% for standing (except for the elbow); and (3) in general, flexion and extension are easier to evaluate than neutral and non-neutral postures.

Adult↗
PubMed1994

Assessment of a positive selection technique using an avidin column to isolate human peripheral blood T cell subsets.

The current studies were designed to assess a new technique for positively selecting human T cells from whole peripheral blood mononuclear cells using the minimal amount of monoclonal antibody required to bind the T cell to an avidin column indirectly via a biotin-conjugated secondary antibody. Positive selection of T cells has previously been avoided because the saturating amounts of antibodies required for other isolation procedures can lead to aberrant results in assays of T cell activation and function. The avidin column technique for obtaining purified T cell subsets was compared to a multi-step procedure that included negative selection panning. The positive selection technique was easily performed within 4 h whereas the negative selection technique required a minimum of 12 h to complete. The avidin column technique proved to be a rapid and simple method for isolating T cell subsets of high purity and normal functional capabilities. Since minimal amounts of monoclonal antibodies were used for the purification protocol, no consistent inhibitory or stimulatory effect of the residual antibody was noted in assays of activation and proliferation of positively selected T cells compared to T cells isolated by negative selection panning.

Adult↗
PubMed1994

Rheumatoid synovium is enriched in mature antigen-presenting dendritic cells.

Monocytes and dendritic cells (DC) can be purified from fresh peripheral blood (PB) based on their expression of CD33, CD13, and CD14. Whereas DC can be identified as CD33+ CD14dim or CD13+CD14dim cells, monocytes can be identified as CD33+CD14bright or CD13+CD14bright cells. Rheumatoid synovial fluid (SF) and synovial tissue (ST) non-T cells were found to be enriched in CD33+CD14dim cells compared with PB. Whereas 4 to 14% of normal or rheumatoid PB non-T cells were CD33+ and CD14dim, in rheumatoid SF or ST these cells comprised 20 to 45% of non-T mononuclear cells. Synovial CD33+CD14dim cells assumed a typical dendritic morphology on in vitro culture. Freshly isolated CD33+CD14dim PB DC precursors express low levels of HLA-DQ, CD40, and B7, which increase after in vitro incubation. In contrast, freshly isolated SF DC constitutively expressed these markers, and increased densities of HLA-DR and MHC class I molecules. Rheumatoid SF DC showed a specifically enhanced ability to stimulate autologous PB T cells compared with PB DC, or PB or SF monocytes. PB DC or monocytes preincubated in granulocyte-macrophage-CSF, TNF-alpha, or both cytokines exhibited enhanced expression of HLA-DR. Furthermore, DC preincubated in both granulocyte-macrophage-CSF and TNF-alpha were better stimulators of the autologous MLR than DC preincubated in medium, or in either cytokine alone. The data indicate that DC are enriched in rheumatoid SF and ST, and display a more differentiated phenotype than PB DC. These results suggest that PB DC accumulate in the synovium where they undergo phenotypic and functional differentiation in situ, which may be mediated by local cytokines. DC may play an important role in the ongoing presentation of antigen to autoreactive T cells in RA synovium.

Adult↗
PubMed1994

Alternative splicing generates multiple isoforms of a rabbit prostaglandin E2 receptor.

Four cDNA clones homologous with a murine prostaglandin E2 receptor have been isolated from a rabbit kidney cortex cDNA library. These cDNAs encode related proteins that differ only in their COOH-terminal sequences. Southern blot analysis of rabbit genomic DNA indicates that these receptor cDNAs represent alternatively spliced variants derived from a single gene. This was confirmed by isolation and sequence analysis of genomic clones containing common region exons and unique 3'-coding exons, which contained intron/exon boundaries at the predicted splice junctions. Transient expression of a novel full-length cDNA in COS1 cells confirmed the ligand binding profile typical of an EP3 receptor subtype. Ribonuclease protection assays indicate that the gene encoding these receptors is most highly expressed in kidney, adrenal, and stomach with lower but significant expression in uterus, lung, heart, ileum, spleen, and brain. Moreover, each of the cloned isoforms is expressed in the kidney. In situ hybridization analyses of rabbit kidney demonstrated that the level of expression is highest in the outer medulla with lesser expression in the cortex and no detectable expression in the inner medulla. The ligand binding profile and tissue distribution of these receptors is consistent with a functional role for this family of EP3 receptors in mediating the renal actions of prostaglandins as well as the effects of prostaglandins on gastric acid secretion and adrenal function.

Alternative Splicing↗