Interleukin 2 enhancement of lymphokine secretion by established T cell clones.
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Clone Cells↗
Biomedical subjects
B A Torres
Publications and source records attributed to B A Torres.
Evidence for suppressor T-cell regulation of human gamma interferon production.
Human gamma interferon (IFN gamma) production by peripheral blood lymphocytes (PBL) appears to be regulated by a dynamic interaction between distinct regulatory T-cell subsets and IFN gamma-producing cells. Time-course kinetics of IFN gamma production in response to T-cell mitogens suggested that suppressor cells were being activated to control IFN gamma production at 6 to 8 days of culture. This was confirmed by cocultivation of preactivated (4 to 6 days with mitogen) suppressor cells and fresh lymphocytes with a resultant depressed IFN gamma response to stimulation with staphylococcal enterotoxin A. The appearance of suppressor cells in cultures preceded the decline in IFN gamma production, which is consistent with suppressor cell regulation of IFN gamma production. The suppressor cells were of the phenotype Leu 2+,3- as determined by "panning" with monoclonal antibodies. This phenotype corresponds to that reported for suppressor cells of the autologous mixed-lymphocyte reaction and for antibody production. Abrogation of suppressor cell activity by addition of interleukin 2 (IL 2) to cultures and the absorption of IL 2 from cultures by suppressor cells suggested that suppressor cells regulated IFN gamma production by sequestering IL 2 that is required for IFN gamma production. IFN gamma production by human PBL thus appears to be regulated by an interaction between IL 2 (from helper cells), suppressor cells (absorption of IL 2), and IFN gamma-producing cells.
Animals↗
Recombinant mouse interferon-gamma regulation of antibody production.
Interferon-gamma produced in monkey cells by transfection with mouse interferon-gamma cDNA suppressed the mouse in vitro antibody response in a manner similar to that of natural mouse interferon-gamma. Significant suppression was obtained with as little as 1 U of interferon. Recombinant human interferon-gamma produced by cloning in a similar fashion was not suppressive. Both the suppressive and the antiviral activities of recombinant interferon-gamma were neutralized by antibodies to mouse natural interferon-gamma. Thus, interferon-gamma was responsible for the immunosuppression. At the cellular level, the recombinant interferon-gamma was capable of activating macrophages to suppress antibody production. The data provide clear-cut evidence that interferon-gamma plays an important role in regulation of immunological processes.
Animals↗
Recombinant mouse gamma interferon induces the priming step in macrophage activation for tumor cell killing.
Mouse macrophages become activated to kill tumor cells by traversing a series of steps (1-3). The first of these does not cause the expression of cytolytic activity; instead, it primes macrophages to respond to a second signal(s) that then triggers the onset of killing (4-7). The mediator that is responsible for priming is contained, along with other lymphokines, in the culture supernatants of concanavalin A-stimulated spleen cells (5-7) cloned T lymphocytes (8), or some T cell hybridomas (9). Close association has been noted between macrophage priming activity and antiviral activity that is attributable to gamma interferon (10-12). However, unequivocal evidence that the two activities are products of the same molecule has not been available. We now how conclusively by using mouse gamma interferon (MulFN-gamma)3 produced by recombinant DNA technology that, in addition to antiviral activity, this lymphokine has the capacity to induce the priming step in the process of macrophage activation for tumor cell killing.
Animals↗
Characterization of immune type interferon (IFN gamma)-induced cytoplasmic protein kinase activity in mouse L cells.
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Animals↗
Regulation of the in vitro antibody response by neuroendocrine hormones.
Treatment of lymphocytes with inducers of interferon alpha (IFN-alpha) results in the production of corticotropin (ACTH) and endorphin-like activities. The pro-opiomelanocortin-derived hormones ACTH and alpha-, beta-, and gamma-endorphin and the structurally related hormones [Leu]- and [Met]enkephalin were therefore tested for their effects on the in vitro antibody response of mouse spleen cells. ACTH and alpha-endorphin were potent inhibitors (>/=80% suppression) of the antibody response to the T-cell-dependent antigen sheep erythrocytes at a concentration of 0.5 muM. [Met]- and [Leu]enkephalin were moderate inhibitors (approximately 60% suppression) at 0.2-2 muM, and beta- and gamma-endorphin were minimal inhibitors (approximately 20% suppression) at 5-6 muM. At higher concentrations ACTH also inhibited the antibody response to the T-cell-independent antigen dinitrophenyl-Ficoll, suggesting that T-cell function was more sensitive to blockage by these hormones than was B-cell function. ACTH and IFN had similar suppression properties; thus, the hormone-like activities associated with IFN-alpha may play a role in IFN-induced immunosuppression. alpha-Endorphin immunosuppression was blocked by naloxone, which suggested that alpha-endorphin exerted its effects through binding to opiate-like receptors on the spleen cells. The failure of beta-endorphin to suppress the immune response significantly was not due to its failure to bind to the opiate-like receptors because it blocked alpha-endorphin-induced suppression. Direct evidence for both opiate and ACTH receptors on the spleen cells was obtained in binding studies with labeled enkephalin and ACTH. Such studies revealed the presence of both high- and low-affinity receptors. The data show that neuroendocrine polypeptide hormones can regulate the immune response.
Adrenocorticotropic Hormone↗
Cellular regulation of gamma interferon production: Lyt phenotype of the suppressor cell.
Suppressor cell activity for in vitro gamma interferon (IFNgamma) production can be induced in C57BL/6 mice with the T-cell mitogens staphylococcal enterotoxin A and concanavalin A. The suppressor cell lacked mitogen specificity in that injection of mice with either staphylococcal enterotoxin A or concanavalin A induced potent suppressor cell activity that inhibited the in vitro induction of IFNgamma by either mitogen. The suppressor cell is a T cell with a relatively high density of Thy 1 antigen. The IFNgamma-producing cell has a low density of Thy 1 and appears to have evolved from cells with a high density of Thy 1.2 or to have required such cells as helpers in the production of IFNgamma. Monoclonal anti-Lyt 2.2 antibody completely eliminated the suppressor cell activity, whereas anti-Lyt 1.2 partially, but significantly, reduced the suppressor cell activity. The suppressor cell, then, may be or may require a Lyt 1,2,3(+) cell with a relatively low density of the Lyt 1 antigen for activity. The Lyt phenotype of the IFNgamma- producing cells was examined for both virgin and suppressor cell populations. Treatment of cells with either anti-Lyt 1.2 or anti-Lyt 2.2 completely eliminated IFNgamma production in both virgin and suppressor cell cultures. Cocultivation of Lyt 1(+) and Lyt 2(+) cells in both virgin and suppressor cell cultures significantly restored the ability to produce IFNgamma when cells were stimulated with staphylococcal enterotoxin A. For the virgin cells, this seems to indicate clearly that both Lyt 1(+) and Lyt 2(+) cells are required for IFN production, but that Lyt 1,2,3(+) cells are not required. For the suppressor cell population this type of treatment resulted in IFNgamma production comparable to that of the virgin cell population. The treatment eliminated or depleted Lyt 1,2,3(+) cells from the suppressor cell population, thus providing additional evidence that a Lyt 1,2,3(+) cell is required for suppressor cell activity. Treatment of spleen cells with anti-Lyt antibodies at the time that they were involved in ongoing IFNgamma production showed that the IFNgamma-producing cell is Lyt 2(+). At least a 1:1 ratio of virgin to suppressor cells was required for optimal suppression of IFNgamma production by virgin spleen cells. This suggests that suppression involved cell-to-cell contact. Preliminary data showed that the suppressor cell activity could also be induced in in vitro cultures incubated with mitogen for 4 days. This is evidence that the suppressor cell is inducible and not necessarily recruited to the spleen from other lymphoid organs.
Animals↗
Phorbol ester replacement of helper cell and interleukin 2 requirements in gamma interferon production.
Immune interferon (IFN-gamma) production by mitogen-stimulated C57BL/6 mouse spleen cells required both Lyt 1+,2- and Lyt 1-,2+ lymphocytes. The Lyt 1-,2+ cells were the IFN-gamma producers, whereas the Lyt 1+,2- cells were the helpers. Interleukin 2 mediated the Lyt 1+,2- cell help. Phorbol myristic acetate (10 ng/ml) completely replaced Lyt 1+,2- helper cell or interleukin 2 requirements in IFN-gamma production. The phorbol ester exerted its helper effects by direct interaction with IFN-gamma-producing Lyt 1-,2+ cells and not through stimulation of production of interleukin 2 by Lyt 1+, 2- cells. Suppressor cell effects in IFN-gamma production were also completely abrogated by phorbol myristic acetate. The data suggest a mechanism for phorbol myristic acetate regulation of IFN-gamma production at the cellular level.
Animals↗
Interleukin 2 regulates immune interferon (IFN gamma) production by normal and suppressor cell cultures.
A Lyt-2+ lymphocyte is responsible for immune interferon (IFN gamma) production in mitogen-stimulated mouse spleen cell cultures. A Lyt-1+ helper cell is required for the induction of IFN gamma. Interleukin 2 (IL 2) can specifically replace the Lyt 1 cell requirement. IL 2 will also abrogate suppressor cell inhibition of IFN gamma production. IFN gamma production appears to be regulated by a dynamic interaction between helper cells (source of IL 2), suppressor cells (absorption of IL 2?) and IFN gammna-producer cells.
Animals↗
Vasopressin replacement of interleukin 2 requirement in gamma interferon production: lymphokine activity of a neuroendocrine hormone.
The neuroendocrine antidiuretic hormone arginine vasopressin (AVP) was capable of replacing the interleukin 2 (IL 2) requirement for gamma-interferon (IFN gamma) production by Lyt-2+ cells from C57BL/6 mouse spleen cells. The AVP replacement did not stimulate DNA synthesis in the target lymphocytes. This suggested that AVP was capable of replacing an IL 2 function that did not involve stimulation of cellular proliferation or DNA synthesis. This was confirmed by the demonstration that mitomycin C inhibition of IFN gamma production was reversed by IL 2 or AVP without concomitant reversal of blockage of DNA synthesis. Oxytocin, which is structurally related to AVP, was also capable of replacing IL 2 requirement for IFN gamma production, whereas insulin was ineffective. The data show that the neuroendocrine hormones AVP and oxytocin are capable of lymphokine-like activity. This activity may involve the induction of a second messenger such as cyclic GMP.
Animals↗
Cyclic GMP as the second messenger in helper cell requirement for gamma-interferon production.
Cyclic GMP and activators (acetylcholine, E. coli heat-stable toxin) of guanylate cyclase were capable of completely replacing the helper cell or interleukin 2 requirement for gamma-interferon (IFN gamma) production by Lyt-1-,2+ cells from C57BL/6 mouse spleen cells. The cyclic GMP help was independent of DNA synthesis or proliferation in the IFN gamma-producing cells, because cyclic GMP reversed mitomycin C blockage of IFN gamma production but did not reverse the inhibition of DNA synthesis. Thus, the findings presented here are unrelated to the question of the second messenger role of cyclic GMP in the activation of lymphocytes for DNA synthesis and cellular proliferation. The cyclic GMP help for IFN gamma production was antagonized by cyclic AMP and inducers (isoproterenol) of adenylate cyclase.
Animals↗
[Maternal prognosis in eclampsia].
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Adolescent↗
Pharmacokinetics of continuous infusion fentanyl in newborns.
Although fentanyl administration by continuous infusion in newborns during ventilatory support has increased, pharmacokinetic data are lacking. Our objective was to determine the pharmacokinetics of fentanyl continuous infusions for sedation/analgesia in newborns who had undergone mechanical ventilation. Fentanyl was administered per routine care in seven newborns who had undergone mechanical ventilation and had normal hepatic, renal, and cardiac function. Five blood samples were collected from each newborn's umbilical artery catheter. Sample 1 was obtained at > or = 36 hours after constant fentanyl was infused, and sample 2 was collected 12 hours later. Fentanyl was then discontinued and meperidine given. Additional samples were obtained 6, 12, and 24 hours after fentanyl was discontinued. Decanted plasma was stored at -20 degrees C until gas chromatography analysis was performed. Total body clearance (TBC), elimination half-life, and volume of distribution at steady state were determined. Patient weights were 1.88 +/- 1.12 kg (mean +/- SD) with postnatal age 16 +/- 9 days; the mean gestational age was 32 +/- 4 weeks. Mean final fentanyl dosage was 1.28 +/- 0.58 microgram/kg/hr (range 0.53 to 1.9 micrograms/kg/hr). Mean elimination half-life was 9.5 +/- 2.6 hours (range 5.7 to 12.7 hours), and volume of distribution at steady state was 17 +/- 9 L/kg (range 10.1 to 30.3 L/kg). Mean TBC was 1154 +/- 494 ml/kg/hr (range 565 to 2000 ml/kg/hr). Significant correlation between postnatal age and TBC occurred (r = 0.80; p = 0.03). Newborns were hemodynamically stable during the sampling period. We found an increased volume of distribution at steady state and prolonged elimination half-life compared with single-dose administration in newborns. TBC was similar to reported values for infants and young children but was higher than for older patients.
Anesthetics, Intravenous↗