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K M Connolly

Publications and source records attributed to K M Connolly.

At least 37 records · Page 2Linked to original sources
PubMed1988

Alteration of interleukin-1 activity and the acute phase response in adjuvant arthritic rats treated with disease modifying antirheumatic drugs.

Interleukin-1 (IL-1) activity and the acute phase response, as measured by plasma CRP and iron, were used to determine if the standard disease modifying antirheumatic drugs (DMARDs), gold, chloroquine and D-penicillamine had a common profile of activity in the adjuvant arthritic (AA) rat. All drugs were tested at a dose which significantly reduced noninjected paw swelling in AA rats. Inhibition of paw edema ranged from 37% for D-penicillamine (100 mg/kg) to 69% for auranofin (10 mg/kg). Two week medication of AA rats with gold sodium thiomalate (GST, 10 mg/kg, i.m.) or auranofin (10 mg/kg, p.o.) resulted in a significant decrease in splenic IL-1 activity, as measured in the standard lymphocyte activating factor (LAF) assay. The acute phase response, often associated with elevated IL-1 activity, was also significantly reduced following treatment of AA rats with 10 mg/kg of GST or auranofin (oral gold). Inhibition of the acute phase response by gold was determined by a significant reduction of plasma CRP levels (56-71% reduction) and enhancement of plasma iron levels (27-52% enhancement). In contrast to the effect of GST and auranofin on IL-1, CRP and iron, treatment with chloroquine (20, 30 and 35 mg/kg) and D-penicillamine (55 and 100 mg/kg) failed to reduce the acute phase response (as measured by plasma CRP and iron) or alter LAF activity from AA rat spleen cell supernatants. Based on its ability to reduce LAF activity in spleen cell supernatants and reduce the acute phase response, it is possible that the activity of gold in the AA rat may in part be due to its ability to inhibit IL-1 production in vivo. The inability of chloroquine and D-penicillamine to alter LAF activity and the acute phase response in AA rats does not preclude their possession of an immunoregulatory mechanism of action, but it does indicate that their mechanism of action in the AA rat probably differs from that of GST and auranofin.

Acute-Phase Reaction↗
PubMed1988

The effect of danazol in the MRL/lpr mouse model of autoimmune disease.

The purpose of the study was to determine if danazol was efficacious in the treatment of lupus MRL/MpJ (lpr) mice, as measured by longevity, proteinuria and serum amyloid protein (SAP) levels. Danazol, administered at an oral dose of 100 mg/kg, significantly prolonged survival of female MRL/MpJ (lpr) mice but had no effect on the mortality of their male counterparts. Medication with danazol began 40 days after birth of the mice and resulted in a significant decrease in proteinuria in female but not male lupus mice. The concentration of SAP, an acute phase reactant, was significantly decreased in danazol-treated female lupus mice at 80, 100, 120, 140 and 160 days of age when compared to vehicle-treated control mice. SAP levels in male lupus mice treated with danazol were significantly lower than normal control levels only at the 120 and 160 day time points. Measurements of mortality, proteinuria and SAP concentration indicate that danazol at 100 mg/kg is orally active in the treatment of MRL/MpJ (lpr) female, but not male mice.

Amyloid↗
PubMed1988

Lymphocyte activating factor (LAF) and the acute-phase response in adjuvant arthritic rats.

The purpose of the study was to determine the temporal relationship between lymphocyte activating factor (LAF) activity and the acute-phase response, as measured by plasma fibronectin (Fn), C-reactive protein (CRP), and albumin levels in adjuvant arthritic rats. LAF activity as measured in the thymocyte costimulator assay, and plasma Fn, CRP, and albumin levels were measured during the acute (Day 3), intermediate (Day 10), and systemic (Day 17) phases of arthritic disease. On Day 3, supernatants from whole spleen cells of adjuvant-injected rats did not exhibit abnormal LAF activity. By Day 10, LAF activity in splenic supernatants from arthritics was significantly (P less than or equal to 0.05) higher than normal, although the increase was no greater than 60%. On Day 17 the LAF activity from arthritic rats had increased an average 300% compared to normals. In contrast to the time course of IL-1 activity, Fn and CRP levels in the arthritic rat were significantly higher than normal at all three time points, although there was a transient fall in Fn and CRP concentrations on Day 10. Plasma albumin levels in arthritic rats were subnormal (P less than or equal to 0.01) on Days 3, 10, and 17, although the concentration of plasma albumin on Day 10 was significantly higher than that measured on Day 3. The acute, intermediate, and systemic phases of adjuvant arthritic paw inflammation paralleled the abnormal profile of Fn, CRP, and albumin concentrations over time. However, LAF activity from arthritic rat spleen cells increased gradually and more closely coincided with the systemic appearance of the disease. Since the appearance of abnormal plasma protein levels in arthritic rats preceded the appearance of increased splenic LAF activity, it appears that there is no causal relationship between enhanced splenic LAF activity and early alteration of plasma Fn, CRP, and albumin levels.

Acute-Phase Reaction↗
PubMed1988

Elevation of plasma fibronectin and serum amyloid P in autoimmune NZB, B/W, and MRL/1pr mice.

The acute-phase proteins, fibronectin (Fn) and serum amyloid P (SAP), are opsonins which by virtue of their adhesive properties may be involved in the glomerular nephritis associated with splenic lupus erythematosus (SLE). Because of their possible involvement in the pathophysiology of lupus, plasma Fn and SAP levels from three strains of autoimmune mice were measured over time to determine if Fn and SAP rose as the mice sickened and renal function degenerated. Baseline levels of Fn and SAP were measured when the mice were between 1.5 and 3 months of age. The characteristic rapid onset of autoimmune disease in MRL/1pr mice was accompanied by a two- to threefold increase in plasma Fn and SAP by Day 100. The B/W mice, which develop autoimmune disease more slowly, did not have a significant increase in plasma Fn and SAP until Day 240. The NZB mice, with the most delayed onset of disease, exhibited a modest but significant elevation of plasma Fn and SAP by Day 360. Histologic examination of the kidneys of B/W and NZB mice indicated that pathological abnormality of the glomeruli and tubules coincided with the elevation of plasma Fn and SAP levels. In contrast, blood samples taken over time from normal BALB/c mice did not possess abnormal levels of Fn or SAP. It appears that elevation of plasma Fn and SAP in the MRL/1 pr, B/W, and NZB mice is related to the onset and severity of autoimmune disease and the subsequent loss of renal function.

Age Factors↗
PubMed1988

Alteration of interleukin-1 production and the acute phase response following medication of adjuvant arthritic rats with cyclosporin-A or methotrexate.

The purpose of the paper was to determine whether two clinically active antirheumatic compounds, cyclosporin-A (CS-A) and methotrexate (MTX) were efficacious in the treatment of adjuvant arthritis (AA) in rats, as measured by reduction of paw inflammation, lymphocyte activating factor (LAF) activity and the acute phase response. Parameters of the acute phase response consisted of plasma fibronectin (Fn), C-reactive protein (CRP), albumin and iron. Rats injected with Freund's complete adjuvant on day 1, developed systemic arthritis, which was quantitated by measuring non-injected paw swelling on day 17. When compared to normal animals, AA rats had significantly (P less than or equal to 0.01) increased: (1) splenic LAF activity (100% increase), (2) plasma Fn (58%), and (3) CRP (122%), as well as abnormally reduced levels of: (1) plasma albumin (53% reduction), and (2) iron (54%). Orally dosing AA rats from days 3 to 17 with the immunoregulatory drugs, CS-A (3 and 5 mg/kg) or MTX (0.5 and 1 mg/kg), significantly (P less than or equal to 0.01) reduced paw inflammation (100% reduction), increased final body wt 40-50 g over arthritic controls and decreased LAF activity from splenic leukocytes. The acute phase response, often associated with a high degree of LAF activity, was significantly (P less than or equal to 0.01) decreased by dosing with CS-A (3 and 5 mg/kg) and MTX (0.5 and 1 mg/kg). The inhibition of the acute phase response was measured by reduction of high plasma Fn levels (42-79% decrease) and CRP levels (57-100% decrease) as well as elevation of subnormal levels of plasma albumin (57-101% increase) and iron (40-114% increase). Dosing with the nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin (50 and 100 mg/kg) or phenylbutazone (10 and 30 mg/kg), significantly inhibited paw inflammation (29-85%), but did not decrease the high rate of splenic LAF activity, nor did aspirin (55, 100 and 200 mg/kg) or phenylbutazone (1, 10 and 30 mg/kg) alter the acute phase response in AA rats, as measured by levels of plasma Fn, CRP, albumin and iron. Since CS-A and MTX have been reported to be effective in the treatment of RA, their activity in the LAF, Fn, CRP, albumin and iron assays of the AA rat suggests that these immunological and serological parameters may be useful in identifying potential antirheumatic drugs and distinguishing them from standard NSAIDs.

Acute-Phase Reaction↗
PubMed1988

Effect of auranofin on plasma fibronectin, C reactive protein, and albumin levels in arthritic rats.

Auranofin, a member of a class of compounds with disease modifying activity, was given to arthritic rats to determine if it could reverse the abnormal plasma concentrations of fibronectin (Fn), C reactive protein (CRP), and albumin, which were unaffected by treatment with non-steroidal anti-inflammatory drugs (NSAIDs). When auranofin was orally administered for two weeks to adjuvant induced arthritic rats it significantly inhibited swelling of the injected and non-injected paws at doses of 3 and 10 mg/kg. Rocket electroimmunoassay measurement of plasma proteins in normal, arthritic, and auranofin treated arthritic rats indicated that auranofin at 10 mg/kg significantly decreased (by 77%) the abnormally high concentration of arthritic rat plasma Fn, though it had no effect on Fn concentrations when administered to normal rats. CRP, which was raised approximately twofold above normal in arthritic rats, was reduced by 56% after treatment of arthritic rats with auranofin at 10 mg/kg, though CRP concentrations in normal rats were unaffected by auranofin treatment. Depressed albumin concentrations in arthritic rats were significantly enhanced (by 30%) by dosing with 10 mg/kg of auranofin. At the 3 mg/kg dose, auranofin did not significantly change plasma concentrations of Fn, CRP, and albumin in arthritic rats. At a dose of 10 mg/kg, however, auranofin, in addition to inhibiting chronic systemic paw inflammation, also altered abnormal concentrations of plasma Fn, CRP, and albumin in the adjuvant arthritic rat, thus distinguishing auranofin from standard NSAIDs we have previously tested.

Animals↗
PubMed1988

Examination of interleukin-1 activity, the acute phase response, and leukocyte subpopulations in rats with adjuvant-induced arthritis.

Rats with adjuvant-induced arthritis (AA) were used to determine whether chronic systemic paw inflammation was accompanied by appearance of the acute phase response, an increase in splenic interleukin-1 (IL-1) production, and a reduction of nonhelper T cells in the spleen and peripheral blood. Two weeks after injection of adjuvant, the rats developed significant (P less than or equal to 0.01) swelling of the noninjected paw indicative of systemic inflammation. The rats with AA also exhibited signs of the acute phase response, as measured by a significant increase in plasma C-reactive protein (138% above normal) and a significant decrease in plasma albumin (47% below normal), zinc (30% below normal), and iron (58% below normal). IL-1 production from spleen cells of rats with AA was increased 115% compared with normals. Results from immunofluorescence studies with W3/25 and OX8 antibodies to distinguish rat T-helper-inducer (TH) spleen cells from suppressor-cytotoxic (nonhelper T) spleen cells indicated no significant difference between the percentage of OX8+ cells in spleens of arthritic rats compared with OX8+ cells in spleens of normal rats. The W3/25+-to-OX8+ ratio of 1.6 +/- 0.2 for normal rat spleen cells (33% to 21%) was not significantly different from the arthritic rat ratio of 1.9 +/- 0.1 (36% to 19%). When the phenotypes of peripheral blood mononuclear cells were analyzed, the normal animals possessed a greater percentage of W3/25+(TH) cells than did rats with AA. Normal blood mononuclear cell samples were composed of 51% +/- 3% W3/25+ cells and 22% +/- 2% OX8+ cells, and the samples from rats with AA contained 43% +/- 4% W3/25+ cells and 24% +/- 3% OX8+ cells. Thus, the helper-to-nonhelper ratio was higher for normal rats (2.3 +/- 0.1) than for arthritic rats (1.8 +/- 0.2). The data indicated that the appearance of the acute phase response and the abnormally high rate of splenic IL-1 production in the rats with AA did not stem from a subnormal percentage of OX8+ nonhelper T cells in the spleen or peripheral blood.

Acute-Phase Reaction↗
PubMed1986

The effect of glucocorticoids on plasma fibronectin levels in normal and arthritic rats.

In vivo studies with normal and adjuvant-induced arthritic rats were undertaken in order to measure the effects of glucocorticoids on paw inflammation and plasma fibronectin (Fn) levels. Dexamethasone, methylprednisolone, and corticosterone all enhanced plasma Fn levels in normal animals. All drugs also significantly decreased inflammation in arthritic rats as measured by paw swelling. Of the three glucocorticoids, only corticosterone did not significantly enhance Fn levels in arthritic rats, possibly due to its lesser potency and narrow therapeutic window.

Adrenal Glands↗
PubMed1984

In vivo assessment of tumor-induced nonspecific suppression of contact sensitivity. II. Regulation by cytokines and T cells via adoptive transfer.

Normal BALB/c mice were assessed for 2,4-dinitrofluorobenzene (DNFB)-induced contact sensitivity following adoptive transfer of macrophages (Mo). T cells, or their derived products, from normal or tumor-bearing hosts (TBH). Contact sensitivity (CS) was measured by a quantitative radioisotopic ear assay, a total in vivo system based on localization of IP-injected iodinated human serum albumin [( 125I]HSA) in the DNFB-challenged ear. Adoptive transfer of low or high doses of TBH T cells or their derived supernatants into normal recipients suppressed their responsiveness, while Mo supernatants enhanced it. Moreover, in all cases adoptive transfer of TBH cells or supernatants resulted in a lower CS response than did their normal counterparts. These results further corroborate our previous in vitro data indicating that T cells, or Mo and T cell soluble products, possess immunoregulatory capabilities in vivo.

Animals↗
PubMed1983

Mechanism of cytotoxic activity of 5'-deoxy-5-fluorouridine.

The purpose of these studies was to characterize the effect of the new fluoropyrimidine nucleoside 5'-deoxy-5-fluorouridine (5'dFUrd) on macromolecular processes in correlation with its cytotoxicity in Ehrlich ascites tumor cells. Following a 2-h exposure, 5'-dFUrd exhibited an LD50 (as determined by clonogenicity) of 48 microM. In cells supplemented with 10 microM dThd, the LD50 for 5'-dFUrd increased to 660 microM. DNA synthesis was markedly and rapidly suppressed by all cytotoxic concentrations of 5'-dFUrd. There was no apparent direct measurable effect of 5'-dFUrd on either RNA or protein synthesis, although both were suppressed 24 h after the drug exposure. Thymidylate synthetase activity was completely inhibited by all cytotoxic concentrations of 5'-dFUrd. FUra incorporation into RNA was also measured and appeared to correlate with the dThd-nonreversible toxicity of 5'-dFUrd. These studies indicate that the mechanism of 5'-dFUrd cytotoxicity is directly analogous to that reported for 5-fluorouracil. The inhibition of thymidylate synthetase leading to an inhibition of DNA synthesis was the most potent cytotoxic mechanism (i.e., dThd-reversible) for 5'-dFUrd, and was found to be highly time-dependent. Higher concentrations of 5'-dFUrd resulted in dThd-nonreversible toxicity, which appeared to be related to the incorporation of FUra into RNA.

Animals↗
PubMed1983

Immunoregulation of the mixed lymphocyte reaction by macrophage-derived factors: functional and biochemical separation of enhancing and inhibitory factors.

Positive and negative immunoregulation of the mixed lymphocyte reaction (MLR) occurred through release of macrophage(MO)-derived, soluble enhancing and inhibitory factors. Macrophages, sonicated or cultured in low concentrations, produced nondialyzable, soluble factor(s) capable of enhancing the MLR; but the culture supernatant had no biologically detectable levels of Interleukin 1, Interleukin 2, or interferon. Production of enhancing supernatants was not affected by pretreatment of MO with trypsin or anti-Thy 1 antibody plus complement. In contrast, MO cultured in high concentrations yielded an inhibitory supernatant factor(s) which suppressed MLR reactivity even when MO were cultured in the presence of indomethacin. Culturing MO with proteolytic enzyme inhibitors increased the yields of the inhibitory and enhancing factors. Both factors were precipitable with ammonium sulfate and could be separated into several biologically active fractions using anion exchange chromatography.

Animals↗
PubMed1983

Decreased immunosuppression associated with antitumor activity of 5-deoxy-5-fluorouridine compared to 5-fluorouracil and 5-fluorouridine.

5-Fluorouracil (5-FUra), 5-deoxy-5-fluorouridine (5'dFUrd), and 5-fluorouridine were compared for their relative antitumor activity, their capacity to inhibit leukocyte exudation and macrophage (macrophage) killing of tumor cells in vivo and in vitro, and their ability to induce leukopenia and monocytopenia. 5'dFUrd was less toxic than 5-FUra and exhibited anti-Ehrlich ascites activity over a wider range of drug doses. Inflammatory exudates induced by thioglycollate or pyran were inhibited up to 91% by prior 5-FUra injection but were inhibited not more than 62% by 5'dFUrd. Pyran-induced macrophage inhibition of Ehrlich ascites proliferation in vivo was diminished up to 5-fold by 5-FUra but was never diminished more than 2-fold by 5'dFUrd, while neither agent suppressed in vitro macrophage cytotoxicity of in vivo pyran-activated macrophage. At high doses, 5-FUra reduced white blood cell counts 73%, in contrast to the 8% reduction caused by 5'dFUrd, while at their optimal anti-Ehrlich ascites doses, 5-FUra and 5'dFUrd both lowered white blood cell counts by only 20%. However, 5-FUra caused a severe monocytopenia not seen in animals given injections of comparable doses of 5'dFUrd. Therefore, 5-FUra appeared to inhibit the inflammatory response and antitumor activity by inhibiting the influx of immature macrophage into the peritoneal cavity, not by inhibiting the function of mature effector cells.

Animals↗
PubMed1980

Enhancement of T cell MLR reactivity by addition of macrophage supernatants from tumor-bearing mice.

One-way mixed lymphocyte reactions (MLR) were used to establish a correlation between loss of in vitro T cell reactivity and in vivo tumor growth. Though supernatants from anti-Thy 1 treated macrophages (M phi) greatly enhanced MLR activity in normal T cells, such addition had little effect in reversing the inability of T cells from 2-week palpable tumor-bearing mice (TBM) to recognize in vitro foreign histocompatibility antigens. Since normal T cells, exposed to TBM M phi supernatants, exhibited no decrease in proliferative response, TBM T cell loss of MLR reactivity could not be ascribed to tumor-induced suppressor M phi.

Animals↗