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Biomedical subjects

D A Fox

Publications and source records attributed to D A Fox.

At least 109 records · Page 6Linked to original sources
PubMed1986

Regulation of the alternative pathway of T cell activation by anti-T3 monoclonal antibody.

T cell activation may be triggered either through the T3-Ti antigen receptor complex or via an alternative macrophage-independent pathway involving the 50KD T11 sheep erythrocyte-binding glycoprotein. Monoclonal antibodies anti-T11(2) and anti-T11(3), directed at distinct epitopes of the T11 molecule, trigger mature T cells to proliferate and express their functional programs, and induce expression of IL 2 receptors on both T3+ and T3- thymocytes. We now show that a non-mitogenic anti-T3 antibody blocks activation via the T11 pathway of not only peripheral blood T cells, but also T3+ thymocytes. Anti-T3 does not affect surface expression of T11 or the rapid augmentation of T11(3) expression after incubation of cells with anti-T11(2). However, anti-T3 inhibits generation of IL 2 receptors and production of IL 2 by T lineage cells cultured with anti-T11(2) plus anti-T11(3). In contrast, modulation of the T11 molecule by a non-mitogenic anti-T11 antibody does not inhibit activation of T cells by a mitogenic anti-T3 antibody. The ability of anti-T3 to block expression of IL 2 receptors on both thymocytes and mature T cells activated by the T11 pathway suggests that a regulatory interaction may be important during T cell ontogeny to provide a mechanism for inhibiting expansion of autoreactive clones.

Antibodies, Monoclonal↗
PubMed1986

Selective inhibition of interleukin 2 gene function following thymocyte antigen/major histocompatibility complex receptor crosslinking: possible thymic selection mechanism.

Considerable evidence now exists to support the notion that the 50-kDa sheep erythrocyte-binding protein, T11, represents an essential cell surface component of a human T-cell lineage activation pathway. Furthermore, it is known that the human T3-Ti T-cell antigen/major histocompatibility complex receptor complex is capable of regulating cell growth mediated by the T11 structure. Here we show that, within the T3+ thymocyte compartment, T3-Ti crosslinking rapidly inhibits T11-initiated interleukin 2 (IL-2) gene transcription and translation. This inhibition is restricted to the IL-2 gene (IL2) as transcription of both the IL-2-receptor gene (IL2R) and the Ti beta-chain gene (TCRB) are not affected (human gene designations are in parentheses). Perhaps more importantly, T3-Ti-mediated IL-2 inhibition of this type is not operational in peripheral T lymphocytes. The results imply that the majority of T3+ thymocytes are functionally distinct from peripheral T lymphocytes despite their T3+ phenotype and must possess a unique endogenous regulatory component for suppressing IL-2 gene activity. Moreover, since IL-2 is likely rate-limiting for growth within the thymus, the findings provide one plausible mechanism for thymic selection--namely, T3-Ti crosslinking of thymocytes upon interaction with self-major histocompatibility complex inhibits clonal expansion of high-affinity autoreactive cells.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1986

Evidence for oligoclonal B cell expansion in the peripheral blood of patients with rheumatoid arthritis.

Peripheral blood lymphocytes from patients with rheumatoid arthritis and osteoarthritis were examined for evidence of oligoclonal B cell expansion using the computer assisted flow cytometric technique of kappa-lambda (kappa-lambda) analysis. Eleven of 29 patients with rheumatoid arthritis but only one of 16 with osteoarthritis gave abnormal results (p less than 0.025). Abnormal kappa-lambda determinations did not correlate with age, duration of disease, presence of rheumatoid factor, or other clinical and laboratory parameters. Therapy with oral or intramuscular gold compounds appeared to diminish the incidence of kappa-lambda abnormality. These findings may indicate defective control of clonal B cell proliferation in rheumatoid arthritis.

Adult↗
PubMed1986

Thrombotic thrombocytopenic purpura and systemic lupus erythematosus.

We report two patients with systemic lupus erythematosus who subsequently developed thrombotic thrombocytopenic purpura. In each case the coexistence of these two conditions was confirmed by pathological findings. Both patients responded to treatment, but one eventually died. A review of the literature suggests a possible relationship between the two disorders.

Adult↗
PubMed1986

Pharmacological characterization of rat jejunal contractility after chronic ablation of the myenteric plexus.

The authors have pharmacologically characterized longitudinal muscle contractility of the isolated rat jejunum chronically devoid of myenteric neurons. The myenteric plexus of a 3- to 4-cm segment of rat jejunum was ablated by serosal application of the cationic surfactant benzalkonium chloride (BAC). Fifteen days after treatment, both BAC-treated and untreated control jejunal segments were removed from each animal for pharmacological studies. BAC-treated tissues did not respond to the ganglionic stimulants nicotine, 1,1-dimethyl-4-phenylpiperazinium iodide and McN-A-343 or to the acetylcholinesterase inhibitor physostigmine. Short-pulse duration transmural electrical stimulation (0.1 msec) caused a frequency-dependent, tetrodotoxin-sensitive contraction in control but not BAC-treated tissues. Long-pulse duration transmural electrical stimulation (5.0 msec) contracted both control and BAC-treated jejunum. These contractions were partially reduced but not completely blocked by tetrodotoxin. To assess smooth muscle function, the mechanical responses to the muscarinic receptor agonist carbachol were examined. Carbachol contracted both control and BAC-treated tissues with maximal responses and ED50 values that were not significantly different. In addition, the maximal tension development produced by 10(-2) M barium chloride in similar lengths of control and BAC-treated jejunal segments was not significantly different. These studies demonstrate that chronic ablation of the myenteric plexus by serosal application of BAC essentially eliminates neuronally mediated responses without a concomitant alteration in longitudinal muscle contractility. Because nerve-mediated longitudinal muscle responses are lost despite the presence of an intact submucosal plexus in the BAC-treated jejunum, our data suggest that the motor neurons innervating the rat jejunal longitudinal muscle are located in the myenteric plexus.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMed1986

Ablation of the myenteric plexus impairs alpha but not beta adrenergic receptor-mediated mechanical responses of rat jejunal longitudinal muscle.

The mechanical responses produced by alpha and beta adrenergic receptor agonists were evaluated in control and myenteric neuron-ablated rat jejunal longitudinal muscle. The myenteric plexus of the jejunum was destroyed by serosal application of benzalkonium chloride (BAC). The beta adrenergic receptor agonists isoproterenol and sulfonterol produced a concentration-dependent relaxation of both control and BAC-treated jejunum. Dose-response curves obtained in control and BAC-treated jejunum were nearly superimposable regardless of the beta agonist used. Isoproterenol-induced relaxation was antagonized by the beta receptor antagonists propranolol and practolol but not by butoxamine. The alpha-1 selective agonists phenylephrine and methoxamine were more potent and efficacious in producing relaxation of control than BAC-treated jejunum. The relaxant responses of methoxamine and phenylephrine in control jejunum were blocked by prazosin but not by yohimbine. The supposed alpha-2 selective agonist clonidine also produced a concentration-dependent, prazosin-sensitive, yohimbine-resistant relaxation which was markedly greater in control than BAC-treated jejunum, consistent with alpha-1 receptor stimulation. Clonidine tested in the presence of prazosin and the alpha-2 selective receptor agonists UK-14,304, M-7 and B-HT 920 all produced a concentration-dependent contraction of control but not BAC-treated jejunum. The contractile response produced by UK-14,304 was antagonized by yohimbine but not by atropine. Our results suggest that in rat jejunal longitudinal muscle: beta adrenergic receptors mediate relaxation and are located on the smooth muscle; alpha-1 adrenergic receptors mediate relaxation and are located on both the smooth muscle and myenteric plexus.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗
PubMed1985

In vivo activated T lymphocytes in the peripheral blood and cerebrospinal fluid of patients with multiple sclerosis.

We found an increase in peripheral-blood lymphocytes bearing the T-cell-specific activation antigen Ta1 in 20 of 35 patients with progressive multiple sclerosis, 4 of 18 patients with stable or improving multiple sclerosis, 1 of 17 patients with other neurologic diseases, and 1 of 14 normal controls (P less than 0.0002, Fisher's exact test). No increases in two other markers of T-cell activation, T113 and the interleukin-2 receptor, were found. In the cerebrospinal fluid, patients with progressive multiple sclerosis (pleocytosis, 3.9 +/- 1.6 cells per cubic millimeter) had 42 +/- 3.0 per cent Ta1+ cells. In contrast, patients with other inflammatory central nervous system diseases (36 +/- 13 cells per cubic millimeter) had 9.6 +/- 1.8 per cent Ta1+ cells (P less than 0.01). In patients with other neurologic diseases without inflammation (0.7 +/- 0.16 cells per cubic millimeter), the percentage of Ta1+ cells was equivalent to that in patients with multiple sclerosis (39 +/- 5.4 per cent), although the absolute number was lower. There was a positive correlation between the presence of Ta1+ cells in the spinal fluid and blood of patients with other neurologic diseases, but not patients with multiple sclerosis. Less than 1 per cent of lymphocytes from the spinal fluid of patients with multiple sclerosis expressed interleukin-2 receptors, as compared with 9.8 per cent of cells from subjects with other inflammatory neurologic diseases (P less than 0.01). These results suggest that the T cells in the spinal fluid of patients with multiple sclerosis may be activated by a different mechanism or in a different temporal sequence from that in patients with other nervous system diseases. Furthermore, the increase in Ta1+ cells in the peripheral blood of patients with multiple sclerosis demonstrates systemic immune activation in the disease; monitoring such cells may provide an objective measure of abnormal immunologic activity.

Adolescent↗
PubMed1985

Efficacy of low-dose methotrexate in rheumatoid arthritis.

Twenty-eight patients with refractory rheumatoid arthritis completed a randomized 24-week double-blind crossover trial comparing oral methotrexate (2.5 to 5 mg every 12 hours for three doses weekly) with placebo. The methotrexate group had significant reductions (P less than 0.01 as compared with the placebo group) in the number of tender or painful joints, the duration of morning stiffness, and disease activity according to physician and patient assessments at the 12-week crossover visit; reductions in the number of swollen joints (P less than 0.05) and 15-m walking time (P less than 0.03) also occurred. These variables, as well as the grip strength and erythrocyte sedimentation rate, showed significant (P less than 0.01) improvement at 24 weeks in the population crossed over to methotrexate. A significantly increased frequency (P less than 0.03) of the HLA-DR2 haplotype occurred in the eight patients with the most substantial response to methotrexate. Adverse reactions during methotrexate therapy included transaminase elevation (21 per cent), nausea (18 per cent), and diarrhea (12 per cent); one patient was withdrawn from the trial because of diarrhea. One patient died while receiving the placebo. Methotrexate did not affect measures of humoral or cellular immunity. We conclude that this trial provides evidence of the short-term efficacy of methotrexate in rheumatoid arthritis, but the mechanism of action is unknown. Longer trials will be required to determine the ultimate safety and effectiveness of this drug.

Administration, Oral↗
PubMed1985

Use of gut cyclic motor activity to evaluate a stimulant (narcotic) and inhibitor (anticholinergic) of gastrointestinal-tract activity in the unanesthetized dog.

The use of gut cyclic motor activity to evaluate both a stimulant and inhibitor of gastrointestinal contractile activity in the unanesthetized dog is described. In the interdigestive (fasted) state, there is a cyclic alternation of intense periods of contractions (burst) with quiescent periods (basal). Codeine phosphate, a narcotic agent, caused a dose-dependent increase in the number and duration of circular muscle contractions when administered in the basal phase. Hyoscine N-butyl-bromide, an anticholinergic drug, caused a dose-dependent reduction in both amplitude and frequency of burst-phase contractions. When a combination of codeine phosphate and hyoscine N-butylbromide was administered simultaneously in the basal or burst phase, the hyoscine N-butylbromide prevailed and had the dominant effect. This is a useful in vivo model to evaluate the effects of drugs on the gastrointestinal tract.

Animals↗
PubMed1985

Activation of human thymocytes via the 50KD T11 sheep erythrocyte binding protein induces the expression of interleukin 2 receptors on both T3+ and T3- populations.

Recent studies have demonstrated that the 50KD T11 molecule is a surface component of a macrophage-independent alternative pathway of human T cell activation that is unrelated to the T3/Ti antigen-MHC receptor complex. Given the expression of T11 on all human thymocytes, it was of interest to determine whether they could be activated via this pathway. The triggering of T11 by monoclonal antibodies anti-T112 and anti-T113, directed at two unique epitopes on the molecule, induced IL 2 receptor expression on both T3+ and T3- thymocytes but did not induce IL 2 production. Consequently, in contrast to peripheral blood T cells, thymocytes did not proliferate in response to anti-T112 and anti-T113 in the absence of exogenous IL 2. These studies suggest that IL 2 receptor gene activation precedes IL 2 gene activation in T cell development. The ability of the alternative pathway of T cell activation to induce IL 2 receptor expression on T3- thymocytes implies that the T11 molecule may have an important role in early thymocyte ontogeny.

Antibodies, Monoclonal↗
PubMed1985

Structural and functional characterization of IL 2 receptors on activated human B cells.

After activation, B cells express the IL 2 receptor as determined by their reactivity with monoclonal anti-IL 2 receptor antibodies. In this report we show that anti-IL 2 receptor antibodies precipitated comparable 60,000 to 65,000 dalton proteins from highly purified B and T cells. Limited peptide mapping suggested that the receptors on B and T cells were identical. Moreover, activated B cells could be induced to proliferate by IL 2, but not to secrete Ig. Anti-IL 2R antibody blocked the effect of IL 2 but not the proliferative response induced by B cell growth factor (BCGF), suggesting independent growth factor receptors. Investigation of the kinetics of the B cell response to growth factor indicated that BCGF acts within 24 hr, whereas IL 2 was virtually devoid of activity for 48 hr. Nevertheless, after 72 to 96 hr, the effect of IL 2 was equal to or greater than that obtained with BCGF. These studies suggest that the initial stages of B cell proliferation involves a sequential interaction of BCGF and IL 2 with their respective receptors.

Antibodies, Monoclonal↗
PubMed1985

The role of interleukin 2 and T11 E rosette antigen in activation and proliferation of human NK clones.

Although considerable data have recently been accumulated regarding the functional role of natural killer (NK) cells, relatively little is known about the factors that regulate NK cell activity. In these studies, we evaluated the role of interleukin 2 (IL 2) and the expression of the IL 2 receptor in the activation and proliferation of human NK cloned cell lines. By using a series of cloned cell lines, we were able to analyze homogeneous populations of NK cells that ordinarily comprise only a small fraction of peripheral blood lymphocytes and are extremely heterogeneous with respect to phenotypes and cytotoxic specificities. In comparison with several T cell clones, we found a much lower density of IL 2 receptors on NK clones, regardless of whether or not these cloned cells had a mature T cell phenotype. Correspondingly, NK clones needed a 10-fold higher concentration of recombinant IL 2 for maximal proliferation. Moreover, blocking studies with specific monoclonal IL 2 receptor antibodies indicated that IL 2 is both necessary and sufficient to induce the proliferation of NK clones. Because the majority of peripheral blood NK cells and NK clones express the T11 E rosette receptor antigen, which has been shown to be an antigen-independent activation pathway for T cells, we were able to study the role of monoclonal anti-T11 antibodies in the activation of various NK clones for which a specific target antigen is not known. In contrast to T cell clones, the induction of IL 2 receptor expression after T11 activation was possible only for some NK clones such as JT10 and JT3, but not for CNK5. Before activation, the IL 2 receptor expression of NK clones was confined to cells in the G2 - M phase, but after T11 activation the more pronounced IL 2 receptor expression became independent of the cell cycle. With respect to the direct proliferative effect of anti-T11 activation that has been noted with T cell clones, only the T3+ (JT10) and not the T3- NK clones could be directly stimulated. Nevertheless, IL 2 receptor expression could be triggered on some T3- clones such as JT3. Because T11-induced proliferation of T cells has been shown to be dependent on both the expression of the IL 2 receptor and on the interaction of this receptor with IL 2, it is proposed that the different responses of NK cells to T11 activation may reflect the ability of the individual clone to produce endogenous IL 2, as well as its ability to express the IL 2 receptor.

Antibodies, Monoclonal↗
PubMed1984

Nonsteroidal anti-inflammatory drugs and renal disease.

The relationship between nonsteroidal anti-inflammatory drugs (NSAIDs) and deterioration of renal function was examined in a large group of hospitalized patients carefully monitored for adverse drug effects and in a large group of outpatients whose discharge diagnoses after subsequent hospital admission were recorded. In the in-hospital study, no association between the use of NSAIDs and drug-attributed elevation of serum urea nitrogen levels diagnosed during hospitalization was present. In the outpatient study, none of the patients who used NSAIDs was hospitalized for acute renal disease. The majority of the available data related to indomethacin, ibuprofen, and phenylbutazone.

Anti-Inflammatory Agents↗
PubMed1984

Ta1, a novel 105 KD human T cell activation antigen defined by a monoclonal antibody.

By using a murine monoclonal antibody produced against an IL 2-dependent human T cell line, we defined a T lineage-specific molecule, termed Ta1, that is expressed strongly on activated T lymphocytes of both the T4 and T8 subsets, as well as on T cell lines and clones, but only weakly on a fraction of resting T cells. SDS-PAGE analysis of immunoprecipitates from 125I-labeled, activated T cells demonstrates a single major band of apparent m.w. 105 KD under both reducing and nonreducing conditions. Unlike anti-IL 2 receptor antibodies, anti-Ta1 does not inhibit T cell proliferative responses to mitogen, antigen, or IL 2-containing medium. Moreover, anti-Ta1 has no effect on T cell-mediated cytotoxicity. Ta1 appears to be a novel human T cell-specific activation antigen that may serve as a useful marker of T cell activation in human disease.

Animals↗
PubMed1984

Selective myenteric neuronal denervation of the rat jejunum. Differential control of the propagation of migrating myoelectric complex and basic electric rhythm.

Serosal application of benzalkonium chloride (BAC), a cationic surfactant, was used to selectively ablate the myenteric neurons of the rat jejunum. The myoelectric activity of the BAC-treated area and the areas both orad and caudad to it were assessed. In the jejunal segment devoid of myenteric neurons, the basic electric rhythm (BER) pattern was erratic and the amplitude of the BER was attenuated. The BER frequency of the jejunal area caudad to the BAC-treated area was 30.7 +/- 0.73 cycles/min, which was significantly reduced from the normal BER frequency (37.7 +/- 0.64 cycles/min). Spike activity was normal in areas both orad and caudad to the treated area, existing in regular cycling bursts (migrating myoelectric complex). Spiking in the treated area did not appear until approximately 13-17 days after BAC treatment. These spikes, though of greater duration and lower frequency than the adjacent areas, always appeared after an orad burst and were followed by a caudad burst. In addition, the following motility parameters of the regions orad and caudad to the treated area were not significantly different from control animals: burst duration, period, and burst propagation velocity. In conclusion, the present investigation has demonstrated that BAC-induced ablation of the myenteric neurons in the rat jejunum disrupts the BER but not the migrating myoelectric complex propagation. This suggests that the myenteric neurons play a modulatory role in the generation and propagation of the BER, whereas humoral factors or the submucosal neurons may be more important in the control of the migrating myoelectric complex.

Action Potentials↗
PubMed1983

A selective decrease of cholinergic muscarinic receptors in the visual cortex of adult rats following developmental lead exposure.

The effects of low-level developmental lead (Pb) exposure (postnatal days 0-21) on the binding of [3H]quinuclidinylbenzilate (QNB) and on acetylcholinesterase (AChE) activity in the retina, superior colliculus, lateral geniculate nucleus and visual cortex (VC) were studied in the adult rat. Maximal blood and tissue Pb concentrations (50-60 micrograms %) were reached on day 21 and decreased to control levels (4-5 micrograms %), except in the retina (12 micrograms %) and VC (18 micrograms %; 0.87 microM), by day 90. A large decrease in [3H]QNB binding (-38%) and AChE activity (-29%) was found only in the VC of Pb-exposed rats. Scatchard plots of saturation binding data revealed a decrease in the density (Bmax), but not in the affinity (Kd), of the muscarinic receptors. Pb (10(-4)-10(-9)M) had no effect on [3H]QNB binding or AChE activity in VC membrane preparations from control rats. The mechanism accounting for this selective decrease of cholinergic muscarinic receptors in the VC is presently unknown. These results, in combination with those from our psychophysical and pharmacological studies demonstrating a scopolamine supersensitivity in Pb-exposed rats, suggest that the long-term effects of developmental Pb exposure are due to a direct action of Pb on visual cortex cholinergic neurons.

Acetylcholinesterase↗