PubMed Health⌕ Search

Biomedical subjects

R M Pope

Publications and source records attributed to R M Pope.

At least 55 records · Page 3Linked to original sources
PubMed1993

Expression and function of CD5 and CD28 in patients with rheumatoid arthritis.

To assess the role of CD5 and CD28 in the pathogenesis of the decreased cellular immune function in patients with rheumatoid arthritis (RA) we analysed the expression and function of these T-cell surface molecules. The expression of CD5 as well as of CD28 in synovial and peripheral blood T cells was similar to that of control T cells. Monoclonal antibodies (mAb) directed at CD28 and CD5 were able to provide an accessory signal to anti-CD3 activated T cells both from the synovial fluid and from the peripheral blood. However, the proliferation induced by anti-CD3 mAb in conjunction with anti-CD5 or anti-CD28 mAb was always higher in peripheral blood (PB) T cells compared to the paired synovial fluid T cells. After simultaneous ligation of CD5 and CD28, proliferation was induced in the PB T cells. However, when compared to control PB T cells, this proliferation was significantly lower in the RA patients. Purified normal memory (CD45RO+) T cells proliferated less strongly than naive (CD45RA+) T cells, but no difference was observed between rheumatoid and normal memory T-cell proliferative responses. However, enriched PB CD45RA+ T cells from rheumatoid patients proliferated less vigorously to CD5 and CD28 ligation when compared to normal enriched CD45RA+ T cells. Synovial fluid (SF) T cells, which are mainly of the memory cell type, did not proliferate after simultaneous ligation of CD5 and CD28. This refractory state of synovial T cells could not be explained by a difference in the surface expression of CD5 or CD28. Our data suggest that the cellular immune dysfunction in the PB from rheumatoid patients may be due to a decreased responsiveness of the naive T-cell subset to accessory signals provided by CD5 and CD28. In addition, SF T cells appear hyporesponsive to stimulating signals provided through CD5 and CD28.

Antibodies, Monoclonal↗
PubMed1993

Delayed type hypersensitivity in patients with rheumatoid arthritis.

Our study examines the relationship between in vivo delayed type hypersensitivity (DTH) and clinical and laboratory variables associated with rheumatoid arthritis (RA). Eleven patients with RA were examined. They were receiving no disease modifying drugs, immunosuppressive agents or corticosteroids. Skin tests were performed with the Multitest CMI system employing 7 antigens simultaneously. No patients were truly anergic, however, 3 of the 11 patients were hyporesponsive. No difference was noted between the total in vivo DTH responses of the patient and control populations. A significant correlation was observed between total DTH and the overall activity of the RA as measured by the erythrocyte sedimentation rate (ESR). However, there was no relationship between the total DTH scores and the degree of synovitis. There was no correlation between DTH and a variety of laboratory variables including the autologous mixed lymphocyte response, and the percentage of activated CD4+ or CD8+ T lymphocytes. These observations indicate that while anergy was uncommon in our population of patients with RA, decreased DTH responses were associated with greater disease activity as determined by the ESR.

Adult↗
PubMed1992

Activation of synovial fluid T lymphocytes by 60-kd heat-shock proteins in patients with inflammatory synovitis.

OBJECTIVE: Synovial fluid lymphocytes from patients with rheumatoid arthritis and with other forms of inflammatory synovitis demonstrate enhanced proliferative responses to Mycobacterium tuberculosis antigens, in particular, the 65-kd heat-shock protein. There is a high degree of homology between the human and the mycobacterial 60-kd family of heat-shock proteins. These studies were performed to determine if the enhanced response to the mycobacterial 65-kd heat-shock protein was due to cross-reactivity of an immune response generated against the human homolog. METHODS: These studies were performed by in vitro culture of isolated synovial fluid mononuclear cells with crude and purified antigens. RESULTS: The synovial fluid lymphocytes of a majority of patients with rheumatoid arthritis recognized the mycobacterial 65-kd heat-shock protein, as evidenced by T cell proliferation. In contrast, only 18% of all samples tested responded to a highly purified recombinant human 60-kd heat-shock protein. With only one exception, proliferative responses to the mycobacterial antigen were stronger than those to the human homolog. The proliferative responses generated against mycobacterial 65-kd heat-shock proteins from different sources were highly correlated. CONCLUSION: The findings suggest that the enhanced proliferative response to the mycobacterial 65-kd heat-shock protein noted in most patients with rheumatoid arthritis and other forms of inflammatory synovitis is not due to cross-reactivity of an immune response directed against the human heat-shock protein.

Antigens, Bacterial↗
PubMed1992

Clonal heterogeneity of synovial fluid T lymphocytes in inflammatory synovitis.

Several studies have examined patients with rheumatoid arthritis for the presence of oligoclonal populations of synovial T lymphocytes. The results of these studies have been conflicting. In this study one patient with rheumatoid arthritis and two with other forms of inflammatory synovitis were examined by Southern blot analysis of T cell clones generated from synovial fluid by primary limiting dilution. Evidence of oligoclonality was documented only in a patient with psoriatic arthritis. The distinguishing characteristics of this patient, in addition to the diagnosis, included the fact that only one joint was involved, the synovitis in the affected joint was of recent onset, and the synovial fluid lymphocytes from which the T cells were cloned responded strongly to soluble antigens. Because of the association with the strong response to soluble antigens, synovial fluid T lymphocytes from another patient with rheumatoid arthritis were cloned in response to a crude mycobacterial antigenic mixture. Three of the seven clones examined were identical by Southern blot analysis. These observations suggest that the presence of oligoclonality is limited in patients with inflammatory arthritis. The relationship of a specific antigen-driven response within the joint to the detection of oligoclonal T cells within that joint remains to be determined.

Adult↗
PubMed1992

Prescribing and dispensing of insulin: margins for error?

To investigate recent anecdotal reports of incorrect insulin dispensing, we compared retail pharmacists' and doctors' understanding of commonly used insulin brands. Eighty pharmacists, 29 general practitioners (GPs), and 31 junior hospital doctors were interviewed and completed a questionnaire concerning the duration of action and formulation of 17 insulins. Views on dispensing of alternative insulins were sought from the pharmacists. Fifteen insulin pairs in two columns, 'insulin prescribed' and 'dispense instead', were presented and pharmacists and doctors asked if substitution was appropriate. Mixtard, Penmix and Actrapid were the best understood insulins, Insulatard, Humulin Zn and Protaphane the worst. Both GPs (p = 0.014) and hospital doctors (p < 0.001) scored better than pharmacists. No pharmacist stated that they would routinely dispense alternative insulin, 27 out of 80 not even in an emergency, though 37 were prepared to do so in such a situation after checking, usually with a doctor or in the relevant literature. Sixteen pharmacists, 24 GPs, and all 31 hospital doctors completed the section on insulin pairs but accuracy at identifying appropriate substitutions was poor. These findings coupled with confusing insulin nomenclature may lead to dangerous dispensing errors.

Dosage Forms↗
PubMed1992

Enhanced production of monocyte chemoattractant protein-1 in rheumatoid arthritis.

Cells within the synovial tissue may recruit mononuclear phagocytes into the synovial fluid and tissues of arthritic patients. We investigated the production of the chemotactic cytokine monocyte chemoattractant protein-1 (MCP-1) using sera, synovial fluid, synovial tissue, as well as macrophages and fibroblasts isolated from synovial tissues from 80 arthritic patients. MCP-1 levels were significantly higher (P less than 0.05) in synovial fluid from RA patients (mean 25.5 +/- 8.1 ng/ml [SE]) compared to synovial fluid from osteoarthritis (OA) patients (0.92 +/- 0.08), or from patients with other arthritides (2.9 +/- 1.5). MCP-1 levels in RA sera (8.44 +/- 2.33) were significantly greater than MCP-1 in normal sera (0.16 +/- 0.06). The quantities of RA synovial fluid IL-8, which is chemotactic for neutrophils and lymphocytes, and MCP-1 were strongly positively correlated (P less than 0.05). To examine the cellular source of MCP-1, RA synovial tissue macrophages and fibroblasts were isolated. Synovial tissue fibroblasts did not express MCP-1 mRNA, but could be induced to produce MCP-1 by stimulation with either IL-1 beta, tumor necrosis factor-alpha (TNF-alpha), or LPS. In contrast, unlike normal peripheral blood monocytes or alveolar macrophages, RA synovial tissue macrophages constitutively expressed MCP-1 mRNA and antigen. Immunohistochemical analysis of synovial tissue showed that a significantly greater percentage of RA macrophages (50 +/- 8%) as compared to either OA macrophages (5 +/- 2) or normal macrophages (1 +/- 0.3) reacted with anti-MCP-1 antibodies. In addition, the synovial lining layer reacted with MCP-1 in both RA and OA synovial tissues. In contrast, only a minority of synovial fibroblasts (18 +/- 8%) from RA synovium were positive for immunolocalization of MCP-1. These results suggest that synovial production of MCP-1 may play an important role in the recruitment of mononuclear phagocytes during inflammation associated with RA and that synovial tissue macrophages are the dominant source of this cytokine.

Arthritis, Rheumatoid↗
PubMed1991

Gamma/delta T cell receptor positive T cells in the inflammatory joint: lack of association with response to soluble antigens.

In patients with inflammatory synovitis, the proliferative response by lymphocytes from synovial fluid to soluble mycobacterial antigens is enhanced relative to those from peripheral blood. Earlier studies suggested that gamma/delta T cell receptor positive (TCR+) T lymphocytes may significantly contribute to the mycobacterial-specific synovial fluid response. We therefore examined the relationship of the T cell proliferative response to Mycobacterium tuberculosis antigens and the presence of gamma/delta TCR+ T cells employing several monoclonal antibodies. No consistent increase of gamma/delta TCR+ T cells was noted in inflammatory synovial fluids or tissues. Nonetheless, lymphocytes from the majority of the synovial fluids proliferated vigorously in response to water-soluble M. tuberculosis antigens. There was no relationship between the percentage of gamma/delta TCR+ T lymphocytes and the intensity of the proliferative response. In contrast, stimulation with whole mycobacterial organisms was capable of enriching the gamma/delta TCR+ cell population obtained from the peripheral blood of tuberculosis skin test positive normal controls and from some inflammatory synovial fluids. These observations do not support a role for mycobacteria reactive gamma/delta TCR+ synovial T lymphocytes in response to soluble mycobacterial antigens or in the local pathogenesis of inflammatory synovitis.

Antigens, Bacterial↗
PubMed1991

Synovial tissue macrophage as a source of the chemotactic cytokine IL-8.

Cells of the synovial microenvironment may recruit neutrophils (PMN) and lymphocytes into synovial fluid, as well as lymphocytes into the synovial tissues, of arthritic patients. We have investigated the production of the chemotactic cytokine IL-8 by using sera, synovial fluid, synovial tissue, and macrophages and fibroblasts isolated from synovial tissues from 75 arthritic patients. IL-8 levels were higher in synovial fluid from rheumatoid (RA) patients (mean +/- SE, 14.37 +/- 5.8 ng/ml), compared with synovial fluid from osteoarthritis patients (0.135 +/- 17 ng/ml) (p less than 0.05) or from patients with other arthritides (5.52 +/- 5.11 ng/ml). IL-8 from RA sera was 8.44 +/- 2.33 ng/ml, compared with nondetectable levels found in normal sera. IL-8 levels from RA sera and synovial fluid were strongly positively correlated (r = 0.96, p less than 0.05). Moreover, RA synovial fluid chemotactic activity for PMN in these fluids was inhibited 40 +/- 5% upon incubation with neutralizing polyclonal antibody to IL-8. Synovial tissue fibroblasts released only small amounts of constitutive IL-8 but could be induced to produce IL-8 by stimulation with either IL-1 beta, TNF-alpha, or LPS. In contrast, unlike normal PBMC or alveolar macrophages, macrophages isolated from RA synovial tissue constitutively expressed both IL-8 mRNA and antigenic IL-8. RA synovial macrophage IL-8 expression was not augmented by incubation with either LPS, TNF-alpha, or IL-1 beta. Immunohistochemical analysis of synovial tissue showed that a greater percentage of RA macrophages than osteoarthritis macrophages reacted with anti-IL-8. Whereas macrophages were the predominant cell for immunolocalization of IL-8, less than 5% of synovial tissue fibroblasts were positive for immunolocalized IL-8. These results suggest that macrophage-derived IL-8 may play an important role in the recruitment of PMN in synovial inflammation associated with RA.

Animals↗
PubMed1991

T cell activation by mycobacterial antigens in inflammatory synovitis.

To define which mycobacterial antigens were responsible for the activation of synovial fluid T lymphocytes, acetone-precipitated Mycobacterium tuberculosis (AP-MT) antigens were separated into five fractions following polyacrylamide gel electrophoresis and added to the mononuclear cell cultures of patients with inflammatory synovitis. Fractions 2 (50 to 70 kDa) and 5 (less than 28 kDa) resulted in significantly more proliferation than that of fractions 1, 3, and 4. The response to a purified mycobacterial 65-kDa heat shock protein (hsp), which migrated in fraction 2, was highly correlated (r = 0.89, P less than 0.001) with the response to the crude AP-MT. The proliferative response to a different hsp. the Escherichia coli DnaK, by synovial fluid lymphocytes was marginal. Analysis of the synovial fluid T cell response to mycobacterial culture filtrates by T cell Western blotting revealed dominant responses to antigen(s) in the range of 31 to 21 kDa in each responding patient, although no other consistent pattern of T cell activation was noted. Three lines of evidence suggested that the response to the low molecular weight fractions was directed against degradation fragments of the 65-kDa protein. These observations suggest that the activation of T lymphocytes obtained from inflammatory synovial fluids by crude mycobacterial antigens was due in large part to recognition of the 65-kDa mycobacterial hsp.

Antigens, Bacterial↗
PubMed1991

Identification of a population of large granular lymphocytes obtained from the rheumatoid joint coexpressing the CD3 and CD16 antigens.

In this study, we phenotypically characterized large granular lymphocytes (LGL) among the synovial fluid mononuclear cells obtained from rheumatoid arthritis (RA) patients. Cytochemical and flow cytometric studies revealed an increased percentage of LGL in the synovial fluid mononuclear cells obtained from patients with RA compared to those without RA. Flow cytometric analysis revealed an expanded population of cells expressing a rare phenotype: CD3 +/CD16+. While these cells are seen in very low percentages in normal individuals (less than 2%) and have been reported in T cell lymphoproliferative disorders. In 20/30 RA patients studied, these cells constituted from 20 to 80% of the total synovial fluid mononuclear cells. Furthermore, studies of synovial fluids with greater than 20% CD3 +/CD16+ cells failed to show significant cytolytic activity even after incubation with recombinant interleukin-2, while fluids with less than 20% CD3 +/CD16+ cells possessed normal cytolytic activity. Studies of matched blood and fluid in eight patients with RA demonstrated a significantly increased percentage of CD3 +/CD16+ cells in synovial fluid compared to peripheral blood. Modulation and adsorption studies did not provide evidence that the CD16 antigen present on these CD3 cells was due to passive adsorption of soluble CD16 antigens. Thus, while the relevance of these cells in the pathogenesis of RA is not clear, this report identifies CD3 +/CD16+ cells in a disease state other than T cell lymphoproliferative disorders.

Antigens, Differentiation↗
PubMed1991

Mechanism of T-cell activation by mycobacterial antigens in inflammatory synovitis.

Earlier studies demonstrated enhanced proliferative responses to an acetone precipitable Mycobacterium tuberculosis (AP-MT) antigenic complex by T lymphocytes from the synovial fluid, compared with the peripheral blood, of patients with inflammatory synovitis, including rheumatoid arthritis. In contrast, decreased proliferation and interleukin 2 (IL-2) production in response to mitogens by synovial fluid lymphocytes from patients with rheumatoid arthritis has been demonstrated. In order to determine if IL-2 was produced in response to AP-MT, the peripheral blood and synovial fluid of patients with inflammatory arthritis were analysed by measuring proliferation and IL-2 production in response to AP-MT and tetanus toxoid. A reduction of IL-2 production relative to proliferation was observed in some, but not all, synovial fluids of patients who responded to the AP-MT. Nevertheless, antibodies to IL-2 as well as interleukin 4 (IL-4), significantly inhibited proliferation of synovial fluid lymphocytes by AP-MT. There was no inhibition by antibodies to interleukin 6 (IL-6). We conclude that AP-MT induced proliferation by synovial fluid lymphocytes is mediated by both IL-2 and IL-4.

Antigens, Bacterial↗
PubMed1991

Amenorrhoea in women with non-alcoholic chronic liver disease.

Amenorrhoea is common in women with non-alcoholic chronic liver disease, but little is known about its causes or consequences. We investigated 12 young women with non-alcoholic chronic liver disease and amenorrhoea and compared them with 11 healthy age matched controls studied in the follicular phase of the menstrual cycle. None of the patients had raised serum concentrations of follicle stimulating hormone suggesting primary gonadal failure, but the variance in serum concentrations of testosterone, oestradiol, prolactin, and luteinising hormone were significantly greater in chronic liver disease patients than control subjects (p less than 0.01). Seven of the 12 chronic liver disease patients had low serum luteinising hormone concentrations, and compared with controls these patients also had significantly reduced median values of oestradiol (64 pmol/l), testosterone (1.1 nmol/l), and follicle stimulating hormone, and were significantly underweight as assessed by skinfold thickness measurements (all comparisons p less than 0.025). In the group with chronic liver disease skinfold thickness was significantly correlated with serum luteinising hormone (p less than 0.02). The five patients with normal serum luteinising hormone had higher median values of both oestradiol (237 pmol/l) and testosterone (3.0 nmol/l) than the control subjects (oestradiol: 113 pmol/l, testosterone: 1.9 nmol/l) but were not more obese or hirsute. Amenorrhoea was unrelated to the duration or severity of liver disease. The metacarpal cortical bone area (an index of bone density) was inversely related to the duration of amenorrhoea (p less than 0.02). We conclude that amenorrhoea in women with non-alcoholic chronic liver disease arises from hypothalamic-pituitary dysfunction and can occur at any stage. The hormonal findings in amenorrhoeic chronic live disease patients are not uniform. In some, hypogonadotrophic hypogonadism is related to undernutrition whereas others have normal to high values of luteinising hormone and sex steroids. Prolonged oestrogen deficiency can be a risk factor for osteoporosis in women with chronic liver disease.

Adult↗
PubMed1990

Distribution of CD45RA and CD45RO T-lymphocyte subsets in rheumatoid arthritis synovial tissue.

We have characterized the lymphocytes in the synovium of patients with rheumatoid arthritis (RA) by immunohistochemistry using monoclonal antibodies directed against B lymphocytes, T lymphocytes, and antibodies directed against CD45RA and CD45RO, which define T-cell subsets. Both CD45RA+ and CD45RO+ T lymphocytes were detected in the perivascular regions. CD45RA+ lymphocytes were present primarily in perivascular areas of moderate to large lymphocytic infiltration. Some synovial perivascular lymphocytic aggregates were organized into focal areas of CD45RA+ B lymphocytes surrounded by CD45RO+ T lymphocytes. In areas of diffuse lymphocytic infiltration, the T lymphocytes were CD45RO+. These data suggest that both CD45RO+ and CD45RA+ T lymphocytes enter the RA synovial tissue via the synovial vasculature and that, once in the tissue, the CD45RA+ T lymphocytes may undergo activation/maturation and acquire the CD45RO phenotype.

Antigens, Differentiation↗
PubMed1990

Enhanced cytotoxicity in the rheumatoid joint.

The cytotoxic cytokines, tumor necrosis factor-alpha or cachectin and lymphotoxin (LT), are mediators of bone resorption and of inflammation and may have relevance in rheumatoid arthritis. Using mononuclear cells (MC) isolated from matched peripheral blood (PB) and synovial fluid (SF) of 13 patients with rheumatoid arthritis, we examined the generation of cytotoxic activity in a bioassay capable of detecting both TNF and LT. Synovial fluid mononuclear cells (MC) released significantly more cytotoxic activity than did matched PBMC, both spontaneously and following activation with phytohemagglutinin P (PHA). When PB and SFMC were stimulated with the combination of PHA plus phorbol-12-myristate acetate (PMA), the resulting culture supernatants possessed comparable cytotoxic activity. Neutralization studies employing anti-cytokine antibodies indicated that TNF represented 43 and 59% of the cytotoxic activity in the PHA plus PMA-induced culture supernatants from PB and SF, respectively. Since no inhibition was noted with antibodies to LT, the nature of the remaining approximately 50% of the cytotoxic activity was not determined. In PB and SF culture supernatants, obtained both spontaneously and following PHA activation, the concentration of TNF measured by ELISA significantly correlated with the level of cytotoxicity. As with the cytotoxic activity, the concentration of TNF was greater in the PHA-stimulated supernatants from SF than from PB. These observations suggest that TNF in the SF may contribute to the inflammation and bone destruction observed in rheumatoid arthritis.

Adult↗
PubMed1990

Immunoregulatory mechanisms present in the maternal circulation during pregnancy.

Systemic alterations of the maternal inflammatory and immune system occur during pregnancy. These changes alone are unlikely to be responsible for the acceptance of the fetal semiallograft. Numerous local events at the maternal-fetal interface appear to be more important. The alterations of the maternal inflammatory and immune systems are subtle enough for no significant increase of infections or malignancy to be apparent. However, 75% of women with rheumatoid arthritis are clinically improved during pregnancy. The effects of pregnancy on polymorphonuclear cells are not likely to be responsible because cell function actually appears enhanced in vivo, despite the fact that pregnancy serum is suppressive in vitro. There is no clear evidence for reduction of monocyte/macrophage function during pregnancy, either in vivo or in vitro. It is unlikely that modulation of B cell phenotype or function is responsible because no suppression is noted, either in vivo or in vitro. Selected products of B cells, immune complexes, appear to be reduced during pregnancy. In patients, the reduction in the concentration of complexes may be due to adsorption by the placenta. The importance of this reduction as a causative factor in the improvement of women with rheumatoid arthritis during pregnancy remains to be determined. Natural killer cell cytotoxicity is decreased during pregnancy. This may in part be due to the release of progesterone induced blocking factor. It is also possible that circulating factors, capable of inhibiting IL-2 release or IL-2 function in vivo, might be responsible. Natural killer cytotoxicity can be normalized by incubation with IL-2. It is unclear how the reduction of natural killer cell activity might systematically affect inflammation or immunity in vivo during pregnancy. In vivo delayed type hypersensitivity appears somewhat reduced during pregnancy. This observation appears consistent with the improvement of rheumatoid synovitis, which is also thought to be T cell mediated. T cell function, measured in vitro, generally appears normal. However, most recent studies have employed mitogens, such as PHA, which is not physiological. Subtle defects involving antigen processing or antigen presentation might be missed in this system. These observations suggest that circulating factors might be important in modulating the cell mediated immune system, in vivo, during pregnancy. While anti-HLA-DR antibodies eluted from the human placenta may be effective therapy in patients with rheumatoid arthritis, their occurrence is too infrequent to account for the improvement seen in afflicted patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Adjuvants, Immunologic↗
PubMed1990

Human abdominal aortic aneurysms. Immunophenotypic analysis suggesting an immune-mediated response.

Cellular immunity may play a role in the pathogenesis of atherosclerosis. In this report the potential role of these cells in the formation of abdominal aortic aneurysms by immunohistochemistry was investigated. Aortic tissues from 32 patients were examined: 4 normal aortas, 6 aortas with occlusive atherosclerotic disease, 17 abdominal aortic aneurysms, and 5 inflammatory abdominal aneurysms. Using monoclonal anti-CD3 (T cells), anti-CD19 (B cells), anti-CD11c (macrophages), anti-CD4 (T helper cells), and anti-CD8 (T suppressor cells), several distinctions among these groups were found. The amount of inflammatory cell infiltrate was as follows: inflammatory aneurysms more than abdominal aortic aneurysms more than occlusive aortas more than normal aortas. CD3-positive T lymphocytes rarely were found in the adventitia of normal or occlusive aortas. In contrast, abdominal aortic aneurysms and inflammatory aneurysms exhibited most of the CD3-positive infiltrates in the adventitia. CD19-positive B lymphocytes were present mainly in the adventitia of all pathologic tissues. The CD4-positive:CD8-positive ratio was greater in abdominal aortic aneurysms and inflammatory aneurysms than in the other groups, both in the adventitia and in the media of the aortas. CD11c-positive macrophages were present throughout the diseased tissues, often surrounded by lymphoid aggregates; the greatest numbers of macrophages were found in the inflammatory aneurysm group. Our data suggests that the aneurysmal disease may progress from occlusive disease and is accompanied by an increase in chronic inflammatory cells as well as a redistribution of these cell types. Therefore it is suggested that aneurysmal disease may represent an immune-mediated event.

Antibodies, Monoclonal↗