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J Goronzy

Publications and source records attributed to J Goronzy.

29 records · Page 2Linked to original sources
PubMed1985

Human T cell clones express functional homing receptors required for normal lymphocyte trafficking.

To function efficiently in vivo, lymphocytes must circulate from the blood into lymphoid tissues and other sites of immune reaction. Herein, we show that human cytotoxic and helper T cell clones and lines, maintained in vitro with IL-2, express the functional capacity to recognize and bind to high endothelial venules (HEV), a capacity essential for lymphocyte exit from the blood, and hence for normal lymphocyte trafficking. The expression of functional homing receptors distinguishes human T cell clones from their murine counterparts, which uniformly lack receptors for HEV and are unable to migrate normally from the blood in vivo. The results raise the possibility that human T cell clones may be more effective in mediating in vivo immune responses than is suggested by murine models.

Appendix↗
PubMed1985

T cell subpopulations in inflammatory bowel disease: evidence for a defective induction of T8+ suppressor/cytotoxic T lymphocytes.

Abnormal immune responses associated with inflammatory bowel disease may reflect a defect in immunoregulatory functions. To analyse T-T cell cooperation, we examined the influence of polyclonal activation with the mitogen phytohaemagglutinin on the distribution of the T4+ helper/inducer and the T8+ cytotoxic/suppressor T cell subset. Compared to controls, lymphocytes from patients with Crohn's disease displayed a slight reduction in T3+ cells; neither in patients with ulcerative colitis nor in patients with Crohn's disease a significant difference in T4+ and T8+ cells and the T4/T8 ratio was observed. Phytohaemagglutinin stimulation of normal lymphocytes resulted in a decrease of the T4 subset and a clear increase of the T8 subpopulation. In contrast, the subset distribution pattern was not changed by the mitogenic stimulation in any of the patients. This abnormal reaction pattern could not be influenced by the addition of interleukin-2. Small numbers of normal lymphocytes, however, were able to restore the predominant proliferation of T8+ cells. Thus, the reduced response of T8+ lymphocytes cannot be attributed to an altered composition of this subset in patient with inflammatory bowel disease; our results provide evidence for a defective induction of T8+ suppressor/cytotoxic T cells, which is independent from disease activity.

Adolescent↗
PubMed1985

T cell activation: differences in the signals required for IL 2 production by nonactivated and activated T cells.

Soluble antibodies against the T3/antigen receptor complex alone are not sufficient to induce proliferation and interleukin 2 expression by T lymphocytes. An additional requirement is the presence of accessory cells (AC). In this model, AC provide at least two functions required for T cell activation: 1) the surface interaction of T3 antibodies with Fc receptors on the AC surface and 2) the production of soluble mediators such as interleukin 1 (IL 1). In the experiments reported here, these stimuli are represented by T3 antibodies immobilized onto Sepharose beads and by recombinant IL 1. In this study we investigated differences in activation requirements in resting and activated T cells. Resting T cells were represented by AC-depleted peripheral blood mononuclear cells (PBMC) or the T cell line Jurkat, which phenotypically resembles a resting T cell. Activated T cells were represented by T cell clones and the T cell line HUT 78, which express the activation molecules Ia and the IL 2 receptor (Tac). In resting cells, activation required the presence of three different signals: perturbation of the T3/antigen receptor complex by T3 antibodies, surface redistribution of T3/antigen receptor complexes, and presence of IL 1. In contrast, activated T cells require only perturbation and redistribution of T3/antigen receptor complexes and not IL 1 for the induction of proliferation or IL 2 production. Possible mechanisms of intracellular signaling for these stimuli are discussed.

Antibodies, Monoclonal↗
PubMed1982

Pharmacokinetics of 3H-phenylephrine in man.

7-3H-phenylephrine was given to 15 volunteers by a short-infusion n = 4) or p.o. (10 volunteers, 1 patient with porto-caval anastomosis). Analysis of serum for free 3H-phenylephrine and fractionation of urinary radioactivity was performed by ion-exchange and thin-layer chromatography. As almost the same 3H-activity was excreted in urine after i.v. and p.o. administration, 86% and 80% of the dose respectively, complete enteral absorption can be assumed. A considerable difference was seen in the fraction of free phenylephrine, i.v. 16% of the dose versus p.o. 2.6%, which suggested reduced bioavailability. This was confirmed by comparison of the areas under the serum curve, which showed a bioavailability factor of 0.38. The result for the patient with porto-caval anastomosis was comparable to that in the normal volunteers. The biological half-life of 2 to 3h was comparable to that of structurally related amines, as were the total clearance of 2 l/h, and the volume of distribution of 340 l. Metabolism to phenolic conjugates mainly after oral ingestion, and to m-hydroxymandelic acid after i.v. injection, again demonstrated that m-hydroxylated amines are predominantly conjugated during the "first-pass" metabolism.

Administration, Oral↗
PubMed1981

Recognition of polymorphic H-2 domains by T lymphocytes. I. Functional role of different H-2 domains for the generation of alloreactive cytotoxic T lymphocytes and determination of precursor frequencies.

In the present communication, the repertoire of alloreactive cytotoxic T lymphocytes (CTL) clones was quantitatively investigated by limiting dilution analysis and by target inhibition with a panel of monoclonal antibodies (mAb). These mAb have previously been shown to define two distinct alloantigenic domains, A and B, on the H-2Kk molecule. The Poisson distribution analysis of H-2Kk-specific CTL clones generated in a limiting dilution system revealed three CTL populations with different precursor frequencies. The high frequent population is suppressed by an unknown suppressive mechanism that allows less frequent CTL populations to become visible. Target inhibition studies with a panel of Kk-specific mAb showed that these CTL populations differ not only in their precursor frequency but also in their specificity for different H-2 epitopes on the Kk molecule. Thus clones of the high frequency population are almost exclusively specific for determinants within domain A. In contrast, the low frequency population displays predominant specificity for determinants of domain B, while the population with medium frequency is blocked equally well by mAb against either domains A or B. Each mAb blocked only a fraction of clones indicating that each CTL subpopulation may consist of a large number of clonotypes with specificity for different H-2 epitopes. The data suggest that CTL recognize basically the same polymorphic domains on the H-2Kk molecule defined by antibodies, and they show that regulatory mechanisms determine the expressed repertoire in CTL populations.

Animals↗
PubMed1981

Recognition of H-2 domains by cytotoxic T lymphocytes.

The polymorphic major histocompatibility antigens (H-2) have a crucial role in the activation of antigen-specific T lymphocytes. Thus, H-2 antigens are not only recognized by allogenic lymphocytes leading to generation of cytotoxic T lymphocytes (CTLs), but it has also been demonstrated that in syngeneic systems most T cells are only able to recognize foreign antigens in conjunction with their own MHC (major histocompatibility complex) antigens. This phenomenon, termed H-2 restriction, may be the key to our understanding to the biological function of MHC antigens. It is not clear whether recognition by T cells of H-2 on a molecular level is confined to particular domains on the H-2 molecule, nor whether the same polymorphic H-2 sites, which are characterized by antibodies, are recognized by allogeneic as well as by H-2 restricted syngeneic CTLs. Previous findings indicate the existence of at least two major polymorphic domains on the H-2Kk molecule as defined by antibodies. Here we show the existence of CTLs with specifity for these polymorphic domains, and the preferential recognition of a particular domain by both alloreactive as well as H-2 restricted CTLs.

Animals↗
PubMed1981

Quantitative studies on T cell diversity. II. Determination of the frequencies and Lyt phenotypes of two types of precursor cells for alloreactive cytotoxic T cells in polyclonally and specifically activated splenic T cells.

Two different limiting dilution systems have been applied to compare precursor frequencies of alloreactive cytotoxic T cells (CTL-P) in the polyclonally and specifically activated lymphocyte populations and in selected Lyt T cell subsets. Both systems make use of T cell growth factor for T cell expansion but differ with respect to the activation step in that lymphocytes are either activated directly with allogenetic stimulator cells or are sensitized polyclonally with concanavalin A (Con A) in bulk culture before their expansion under limiting dilution conditions. In polyclonally activated C57BL/6 lymphocyte populations, two types of CTL-P specific for H-2d alloantigens could be identified: a frequent set with a frequency of 1/100-1/300, and a rare set with a frequency of 1/2,000-1/8,000. In contrast, only a single CTL-P set was found in specifically activated populations with a frequency similar to that of the frequent CTL-P found on Con A blasts. In Con A blasts, the frequent at higher cell concentrations by suppressor T cells, whereas rare CTL-P were insensitive to this suppressive mechanism. Whereas in specifically activated T cells, the predominant CTL-P phenotype was Lyt-123, the predominant Lyt phenotypes for the frequent and the rare CTL-P found in Con A blasts were Lyt-123 and Lyt-123, respectively, which suggests that they represent primary and secondary CTL-P, respectively. The results are discussed with respect to previous reports on the involvement of Lyt T cell subsets in the generation of cytotoxic responses and their regulation by T suppressor cells.

Animals↗
PubMed1980

[Enteral resorption and bioavailability of norfenefrine].

Four volunteers received orally an aqueous solution of 4.5 mg of 14C norfenefrine. Urine was collected for the following 24 h and assayed for unchanged drug and metabolites. Blood was drawn for the determination of free norfenefrine at frequent intervals over an 8-h period. The highest serum levels of free norfenefrine were seen 30-60 min after ingestion with an average of 2 ng/ml. The half-lives ranged from 163-402 min. The cumulative urinary excretion of 14C radioactivity exceeded 90% of the dose, more than 50% being conjugated norfenefrine. As result of the area under the plasma level curve bioavailability has to be set at 20% when compared to other sympathomimetic amines. The result in our patient with porto-caval anastomosis did not differ from normal. Thus, the significance of the gut wall as the site of conjugation during the first-pass is demonstrated.

2-Hydroxyphenethylamine↗
PubMedDate not supplied

Single-channel and whole-cell recordings of mitogen-regulated inward currents in human cloned helper T lymphocytes.

Cytoplasmic free Ca2+ [( Ca2+]i) appears to be an important signal for DNA synthesis in early stages of lymphocyte activation. In spite of many experimental studies which employ fluorescent Ca2+ indicator dye to demonstrate an early increase of [Ca2+]i in T-lymphocytes after stimulation with lectins, specific antigens, and monoclonal antibodies to T-lymphocyte receptors, the mechanism responsible for the rise of [Ca2+]i is unknown. We have used the extracellular patch clamp technique to investigate this mechanism. Unitary inward currents, mediated by Ca2+ or Ba2+, were recorded in the membrane of T-lymphocytes. The inward current channel was characterized by a conductance of 7 pS and extrapolated reversal potential (Erev) 110 mV positive to resting potential (Vr). While gating kinetic parameters were not affected by membrane potential changes, the probability of channel opening markedly increased upon activation of the T-lymphocyte by the mitogenic lectin, phytohaemagglutinin (PHA). PHA also evoked a cadmium-sensitive, inward Ba2+ current on whole-cell clamp. We suggest that this mitogen-regulated channel introduces Ca2+ into the cytoplasm upon activation and represents a new class of voltage-independent Ca2+ channels.

Calcium↗