Differential effects of corticosteroids on rat peripheral blood T-lymphocyte mitogenesis in vivo and in vitro

1993 ◽  
Vol 265 (6) ◽  
pp. E825-E830 ◽  
Author(s):  
G. J. Wiegers ◽  
G. Croiset ◽  
J. M. Reul ◽  
F. Holsboer ◽  
E. R. de Kloet
Keyword(s):  
T Lymphocytes ◽  
T Lymphocyte ◽  
Peripheral Blood ◽  
Suppressive Effect ◽  
Ru 486 ◽  
T Lymphocyte Proliferation ◽  
Lymphocyte Mitogenesis ◽  
Opposing Effects

The effects of corticosteroids were studied on the concanavalin A (Con A)-induced mitogenesis of peripheral blood T-lymphocytes obtained from intact and adrenalectomized (ADX) Wistar rats. One week of adrenalectomy reduced the proliferative response of T-cells by 65% compared with sham-operated controls. Substitution of ADX rats with subcutaneously implanted 12.5-mg corticosterone (Cort) pellets, which resulted in low circulating Cort levels (17 +/- 3 nM), restored the reduced proliferative capacity to that of sham-ADX animals. In contrast, T-lymphocyte proliferation was nearly absent in ADX rats substituted with high circulating Cort levels (173 +/- 15 nM; 100-mg Cort pellet). In vitro, Cort suppressed the mitogenic response of T-lymphocytes from ADX and sham-ADX animals. The glucocorticoid antagonist RU-486 (500 nM) completely blocked this suppressive effect. However, a 10 times lower concentration of RU-486 reversed the effects of a low (10 nM) Cort concentration from suppression to stimulation. It is concluded that high Cort concentrations in vivo and in vitro suppressed T-lymphocyte mitogenesis but that low concentrations in vivo were stimulatory, whereas this stimulation in vitro occurred only in the presence of antiglucocorticoids. These opposing effects of Cort emphasize a bimodal regulatory role of this hormone in immune regulation that may be mediated by different corticosteroid receptors.

scholarly journals Kv1.3 Channel Up-Regulation in Peripheral Blood T Lymphocytes of Patients With Multiple Sclerosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Ioannis Markakis ◽  
Ioannis Charitakis ◽  
Christine Beeton ◽  
Melpomeni Galani ◽  
Elpida Repousi ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Lymphocytes ◽  
T Lymphocyte ◽  
Peripheral Blood ◽  
Calcium Influx ◽  
Lymphocyte Function ◽  
Kv1.3 Channel ◽  
Kv1.3 Channels

Voltage-gated Kv1.3 potassium channels are key regulators of T lymphocyte activation, proliferation and cytokine production, by providing the necessary membrane hyper-polarization for calcium influx following immune stimulation. It is noteworthy that an accumulating body of in vivo and in vitro evidence links these channels to multiple sclerosis pathophysiology. Here we studied the electrophysiological properties and the transcriptional and translational expression of T lymphocyte Kv1.3 channels in multiple sclerosis, by combining patch clamp recordings, reverse transcription polymerase chain reaction and flow cytometry on freshly isolated peripheral blood T lymphocytes from two patient cohorts with multiple sclerosis, as well as from healthy and disease controls. Our data demonstrate that T lymphocytes in MS, manifest a significant up-regulation of Kv1.3 mRNA, Kv1.3 membrane protein and Kv1.3 current density and therefore of functional membrane channel protein, compared to control groups (p < 0.001). Interestingly, patient sub-grouping shows that Kv1.3 channel density is significantly higher in secondary progressive, compared to relapsing-remitting multiple sclerosis (p < 0.001). Taking into account the tight connection between Kv1.3 channel activity and calcium-dependent processes, our data predict and could partly explain the reported alterations of T lymphocyte function in multiple sclerosis, while they highlight Kv1.3 channels as potential therapeutic targets and peripheral biomarkers for the disease.

scholarly journals Predicting therapeutic outcome in severe ulcerative colitis by measuring in vitro steroid sensitivity of proliferating peripheral blood lymphocytes

Gut ◽  
1999 ◽  
Vol 45 (3) ◽  
pp. 382-388 ◽  
Author(s):  
S D Hearing ◽  
M Norman ◽  
C S J Probert ◽  
N Haslam ◽  
C M Dayan
Keyword(s):  
Ulcerative Colitis ◽  
T Lymphocytes ◽  
Disease Severity ◽  
T Lymphocyte ◽  
Peripheral Blood ◽  
Steroid Treatment ◽  
Steroid Resistance ◽  
Severe Ulcerative Colitis ◽  
Steroid Sensitivity

BACKGROUNDUp to 29% of patients with severe ulcerative colitis (UC) fail to respond to steroid treatment and require surgery. Previous studies have failed to show a clear correlation between failure of steroid treatment in severe UC and measures of disease severity. The reasons for treatment failure therefore remain unknown.AIMTo investigate the hypothesis that patients with severe UC who fail to respond to steroid treatment have steroid resistant T lymphocytes.METHODSEighteen patients with severe UC were studied. After seven days’ treatment with high dose intravenous steroids they were classified as complete responders (CR), incomplete responders (IR), or treatment failures (TF). Within 48 hours of admission blood was taken and the antiproliferative effect of dexamethasone on phytohaemagglutinin stimulated peripheral blood T lymphocytes was measured. Maximum dexamethasone induced inhibition of proliferation (Imax) was measured.RESULTSIn vitro T lymphocyte steroid sensitivity of TF and IR patients was significantly less than that of CR patients. Both TF and 3/5 IR patients had an Imax of less than 60%; all CR patients had an Imax of greater than 60%. No significant correlation was seen between response to treatment and disease severity on admission. When in vitro T lymphocyte steroid sensitivity was remeasured three months later, there was no difference between the groups.CONCLUSIONSResults suggest that T lymphocyte steroid resistance is an important factor in determining response to steroid treatment in patients with severe UC and may be more predictive of outcome than disease severity.

scholarly journals Interleukin-1 receptor antagonist blocks chemokine production in the mixed lymphocyte reaction

Blood ◽  
1993 ◽  
Vol 82 (12) ◽  
pp. 3668-3674 ◽  
Author(s):  
NW Lukacs ◽  
SL Kunkel ◽  
MD Burdick ◽  
PM Lincoln ◽  
RM Strieter
Keyword(s):  
Receptor Antagonist ◽  
T Lymphocyte ◽  
Mixed Lymphocyte Reaction ◽  
Interleukin 1 ◽  
Lymphocyte Activation ◽  
Chemokine Production ◽  
Cytokine Activation ◽  
T Lymphocyte Proliferation

Abstract The mixed lymphocyte reaction (MLR) has previously been used to elucidate pathways of cytokine activation and T-lymphocyte proliferation and is regarded as a model that simulates responses in allograft rejection. Studies have indicated that interleukin-1 (IL-1), a potent inflammatory cytokine, may have an important activating role in the MLR response. The discovery of a naturally occurring IL-1 receptor antagonist protein (IRAP) has renewed interest in control of IL-1--dependent responses both in vitro and in vivo. MLR cultures were used to study the role of IL-1 and IRAP in the regulation of subsequent cytokines during a T-lymphocyte-mediated alloantigen response. The temporal expression of IL-1 and IRAP during 5-day one-way MLR assays suggested antagonistic production of the two cytokines. IL-1 was produced early in the response, peaking at 4 hours through day 2, subsequently declining to near-background levels on day 5 of culture. In contrast, production of IRAP was delayed until day 2, steadily increased on days 3 and 4, and peaked on day 5 of culture, which correlated with the declining levels of IL-1. The addition of graded doses of IRAP (25 to 1,000 ng/mL) to MLR cultures decreased IL-1 production but had no effect on T-lymphocyte proliferative response. In addition, IRAP had little effect on the production of either IL-2 or tumor necrosis factor. The addition of 25 ng/mL of IRAP to MLR assays showed significantly decreased levels of two potent chemotactic cytokines, IL-8 and macrophage inflammatory protein-1 alpha (MIP-1 alpha), at peak chemokine production on day 5 of culture. The levels of IL-8 and MIP-1 alpha could be restored by the addition of IL-1 to the IRAP-treated cultures. IL-8 and MIP-1 alpha represent the two different families of chemotactic cytokines, C-X-C (IL-8) and C-C (MIP-1 alpha), and potentially play important roles in the recruitment of leukocytes to a site of immune allogeneic response. These studies indicate that regulation of IL-1 by IRAP does not significantly reduce T-lymphocyte activation but can regulate the production of chemokines involved in leukocyte recruitment.

scholarly journals Preclinical study of a novel therapeutic vaccine for recurrent respiratory papillomatosis

npj Vaccines ◽  
2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Maxwell Y. Lee ◽  
Simon Metenou ◽  
Douglas E. Brough ◽  
Helen Sabzevari ◽  
Ke Bai ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
T Lymphocyte ◽  
Chronic Infection ◽  
Therapeutic Vaccine ◽  
Preclinical Study ◽  
Recurrent Respiratory Papillomatosis ◽  
Growth Delay ◽  
Lymphocyte Responses

AbstractActivation of antigen-specific T-lymphocyte responses may be needed to cure disorders caused by chronic infection with low-risk human papillomavirus (lrHPV). Safe and effective adjuvant therapies for such disorders are needed. The safety and efficacy of a novel gorilla adenovirus vaccine expressing a protein designed to elicit immune responses directed against HPV6 and HPV11, PRGN-2012, was studied using in vitro stimulation of T lymphocytes from patients with recurrent respiratory papillomatosis, in vivo vaccination studies, and therapeutic studies in mice bearing tumors expressing lrHPV antigen. PRGN-2012 treatment induces lrHPV antigen-specific responses in patient T lymphocytes. Vaccination of wild-type mice induces E6-specific T-lymphocyte responses without toxicity. In vivo therapeutic vaccination of mice bearing established HPV6 E6 expressing tumors results in HPV6 E6-specific CD8+ T-lymphocyte immunity of sufficient magnitude to induce tumor growth delay. The clinical study of PRGN-2012 in patients with disorders caused by chronic infection with lrHPV is warranted.

scholarly journals Protection against Lethal Encephalomyocarditis Virus Infection in the Absence of Serum-Neutralizing Antibodies

1998 ◽  
Vol 72 (10) ◽  
pp. 8052-8060 ◽  
Author(s):  
Zane C. Neal ◽  
Gary A. Splitter
Keyword(s):  
T Lymphocytes ◽  
T Lymphocyte ◽  
Neutralizing Antibodies ◽  
Cytotoxic T Lymphocyte ◽  
Encephalomyocarditis Virus ◽  
Cell Mediated Immunity ◽  
Lethal Challenge ◽  
Activation Markers

ABSTRACT Although the ability of serum-neutralizing antibodies to protect against picornavirus infection is well established, the contribution of cell-mediated immunity to protection is uncertain. Using major histocompatibility complex class II-deficient (RHAβ−/−) mice, which are unable to mediate CD4+ T-lymphocyte-dependent humoral responses, we demonstrated antibody-independent protection against lethal encephalomyocarditis virus (EMCV) infection in the natural host. The majority of RHAβ−/− mice inoculated with 104 PFU of attenuated Mengo virus (vMC24) resolved infection and were resistant to lethal challenge with the highly virulent, serotypically identical cardiovirus, EMCV. Protection in these mice was in the absence of detectable serum-neutralizing antibodies. Depletion of CD8+T lymphocytes prior to lethal EMCV challenge ablated protection in vMC24-immunized RHAβ−/− mice. The CD8+ T-lymphocyte-dependent protection observed in vivo may, in part, be the result of cytotoxic T-lymphocyte (CTL) activity, as CD8+ T splenocytes exhibited in vitro cytolysis of EMCV-infected targets. The existence of virus-specific CD8+T-lymphocyte memory in these mice was demonstrated by increased expression of cell surface activation markers CD25, CD69, CD71, and CTLA-4 following antigen-specific reactivation in vitro. Although recall response in vMC24-immunized RHAβ−/− mice was intact and effectual shortly after immunization, protection abated over time, as only 3 of 10 vMC24-immunized RHAβ−/− mice survived when rechallenged 90 days later. The present study demonstrating CD8+ T-lymphocyte-dependent protection in the absence of serum-neutralizing antibodies, coupled with our previous results indicating that vMC24-specific CD4+ T lymphocytes confer protection against lethal EMCV in the absence of prophylactic antibodies, suggests the existence of nonhumoral protective mechanisms against picornavirus infections.

scholarly journals T-lymphocyte killing by T101-ricin A-chain immunotoxin: pH-dependent potentiation with lysosomotropic amines

Blood ◽  
1988 ◽  
Vol 72 (4) ◽  
pp. 1197-1202
Author(s):  
P Casellas ◽  
S Ravel ◽  
BJ Bourrie ◽  
JM Derocq ◽  
FK Jansen ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
T Lymphocyte ◽  
Peripheral Blood ◽  
Peripheral Blood Cell ◽  
T Cell Response ◽  
Ricin A Chain ◽  
Macrophage Colony ◽  
A Chain ◽  
Ricin A

To maximize T-lymphocyte killing with anti-pan-T-lymphocyte immunotoxin (IT), prepared by linking ricin A-chain to monoclonal antibody (MoAb) T101 (T101-RTA IT), we have established the nature and the extent of parameters that influence the sensitivity of T lymphocytes to the IT. We showed that peripheral blood T lymphocytes, which are much less susceptible than malignant T cells to the T101-RTA IT, could become highly sensitive to the IT when used in conjunction with NH4Cl. However, enhancement of the IT by NH4Cl only occurred when the pH rose above neutrality. This pH-sensitive process of IT activation by NH4Cl, which led to an all-or-nothing effect within an extremely narrow pH window of 0.7 pH unit width, is due to the fact that NH3 is the effective enhancing component of NH4Cl. We also showed that F(ab')2 or Fab containing IT were much more effective than those produced using the whole IgG counterpart. From these data, we defined a procedure for an optimal and specific elimination of T lymphocytes in vitro by treating them with (Fab)T101-RTA at 10(-8) mol/L at pH 7.8 in the presence of NH4Cl for two hours. This peripheral blood cell processing elicited an abrogation of three logs of functional T-cell response. Under the same conditions, there was no reduction in the number of marrow hematopoietic precursor granulocyte-macrophage colony-forming units (CFU-GM).

scholarly journals Growth hormone stimulation of normal and leukemic human T-lymphocyte proliferation in vitro

Blood ◽  
1981 ◽  
Vol 58 (2) ◽  
pp. 337-340 ◽  
Author(s):  
KE Mercola ◽  
MJ Cline ◽  
DW Golde
Keyword(s):  
Growth Hormone ◽  
T Cell ◽  
T Lymphocytes ◽  
Human Growth Hormone ◽  
T Lymphocyte ◽  
Human Peripheral Blood ◽  
Gradient Centrifugation ◽  
Human Growth ◽  
T Lymphocyte Proliferation

Abstract In order to investigate the effect of human growth hormone on T lymphocytes, we utilized a clonogenic assay for mitogen-responsive human peripheral blood T lymphocytes. Lymphocytes were purified by density gradient centrifugation and incubated in the presence of phytohemagglutinin using a two-layer agar technique for CFU- T- lymphocyte culture. Nanogram concentrations of human growth hormone, ovine prolactin, human chorionic somatomammotropin, or growth hormone fragment were added to cell cultures. Growth hormone potentiated normal T-cell colony formation in a species-specific manner. Cells from a homogeneous T-lymphoblast line derived from a patient with a T-cell variant of hairy cell leukemia also showed augmentation of colony growth in the presence of human growth hormone. These studies provide evidence for a direct effect of growth hormone on normal and some neoplastic human T cells.

Continuous in vivo treatment with catecholamines suppresses in vitro reactivity of rat peripheral blood T-lymphocytes via α-mediated mechanisms

1992 ◽  
Vol 37 (1-2) ◽  
pp. 47-57 ◽  
Author(s):  
P. Felsner ◽  
D. Hofer ◽  
I. Rinner ◽  
H. Mangge ◽  
M. Gruber ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Peripheral Blood ◽  
In Vivo Treatment
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