Mycophenolate mofetil: an update on its mechanism of action and effect on lymphoid tissue.

Introduction: Mycophenolate mofetil (MMF) is an immunosuppressive drug administered in the management of both autoimmune diseases and organ transplantation. The main aims of the study were: (a) to obtain information regarding the safety of using MMF in respect of its effect on normal T and B cells in lymphoid tissues; (b) to investigate whether the generation of inducible Foxp3-expressing regulatory T cells (Treg) might constitute additional mechanisms underlying the immunosuppressive properties of MMF.

Methods: The effect of MMF ( studies) and its active metabolite, mycophenolic acid, ( studies) on murine CD4 and CD8 T cells as well as B cells was determined, regarding: (a) absolute count, proliferation and apoptosis of these cells ( studies); (b) absolute count of these cells in the head and neck lymph nodes, mesenteric lymph nodes and the spleen ( studies).

Mycophenolate Mofetil, an Inhibitor of Inosine Monophosphate Dehydrogenase, and Tofacitinib, a Janus Kinase Inhibitor, Attenuate Airway Inflammation and Hyperresponsiveness in a Mouse Model of Allergic Asthma.

Treatment-resistant asthma remains an unresolved clinical problem and a challenge for current medical science. Consequently, there is a growing and urgent need to develop novel or alternative therapeutic options for the treatment of asthma. The research problem raised in this study was to assess and compare mycophenolate mofetil (MMF), an inhibitor of inosine monophosphate dehydrogenase, and tofacitinib (TFB), a Janus kinase inhibitor, for anti-asthmatic properties, and consequently to determine whether these agents may have potential as alternative options for treatment of allergic asthma.

Teriflunomide induces Foxp3 expression in murine CD8 + T cells while IL-27 and retinoic acid exert a synergistic effect on the induction of CD39 expression on these cells.

The purpose of this study was to verify the possibility of pharmacological induction of Foxp3 +CD25 +CD8 + and Foxp3 -CD103 +CD8 + T regulatory cells 'armed' with immunosuppressive molecules, i.e. CD39 and IL-10.

Depletion of T and B cells in lymphoid tissues of mice induced by oclacitinib, a Janus kinase inhibitor.

The main purpose of the study was to determine the safety of oclacitinib (OCL), a Janus kinase inhibitor, with respect of its effect on CD4 + and CD8 + T cells as well as B cells in the lymphoid tissue. The mice were treated orally with OCL at a dose of 2.7 mg/kg for 14 days and peripheral blood, head and neck lymph nodes (HNLNs), mediastinal lymph nodes (MLNs) and spleen were collected.

Effect of IL-27, Teriflunomide and Retinoic Acid and Their Combinations on CD4 T Regulatory T Cells-An In Vitro Study.

The principal goal of the study was to verify the concept of pharmacological induction of Foxp3CD25CD4 T regulatory (Treg) cells which will additionally be characterized by a highly suppressive phenotype, i.e., by extensive CD25 and CD39 expression and IL-10 and TGF-β production.

Oclacitinib, a Janus Kinase Inhibitor, Reduces the Frequency of IL-4- and IL-10-, but Not IFN-γ-, Producing Murine CD4 and CD8 T Cells and Counteracts the Induction of Type 1 Regulatory T Cells.

The purpose of the present study was to broaden the knowledge and understanding of the effects of oclacitinib (OCL), a Janus kinase inhibitor, on T cells in the context of both the immune mechanisms underlying anti-inflammatory and anti-allergic properties of the drug and its safety. The results indicate that beneficial effects of OCL in the treatment of skin allergic diseases may be partially mediated by the inhibition of IL-4 production in CD4 and CD8 T cells. To a certain extent, the antiproliferative effect of OCL on CD8 T cells may also contribute to its therapeutic effect.

Blockade of NF-κB Translocation and of RANKL/RANK Interaction Decreases the Frequency of Th2 and Th17 Cells Capable of IL-4 and IL-17 Production, Respectively, in a Mouse Model of Allergic Asthma.

The main purpose of this study was to investigate whether the blockade of the interaction between the receptor activator of nuclear factor-κB (NF-ĸB) ligand (RANKL) and its receptor RANK as well as the blockade of NF-κB inhibitor kinase (IKK) and of NF-κB translocation have the potential to suppress the pathogenesis of allergic asthma by inhibition and/or enhancement of the production by CD4 and CD8 T cells of important cytokines promoting (i.e., IL-4 and IL-17) and/or inhibiting (i.

CD4- and CD8-expressing cells in the chambers of normal, cataract and uveitic eyes: A comparative study in dogs.

The main aims of this study were to determine whether CD4 and CD8 cells are present in the normal chambers of the eye in dogs and to verify the hypothesis that uncomplicated cataract may be associated with the local recruitment of CD4 and CD8 cells. The presence of CD4 and CD8 cells was detected in aqueous humor (AH) of normal and cataract eyes. The study did not reveal differences in the percentage and absolute number of CD4 cells between normal and cataract eyes.

Nasal vaccination of β7 integrin-deficient mice retains elevated IgA immunity.

Understanding the migration of lymphocytes to nonintestinal mucosal sites is fundamental to developing mucosal vaccination strategies. Studies have shown that nasal and oral immunization with cholera toxin (CT) stimulates, in addition to α4β7 , the induction of αE (CD103)β7 B cells. To determine the extent to which αE-associated β7 contributes to antigen (Ag)-specific immunoglobulin (Ig)A responses in the upper respiratory tract, nasal CT vaccination was performed in wild-type (wt) and β7 mice.

Blockade of RANKL/RANK and NF-ĸB signalling pathways as novel therapeutic strategies for allergic asthma: A comparative study in a mouse model of allergic airway inflammation.

The main aims of this study were: (1) to investigate whether a blockade of the interaction between the receptor activator of nuclear factor-κB (NF-ĸB) ligand (RANKL) and its receptor RANK may have potential as a novel therapeutic strategy for allergic asthma; (2) to compare the efficacies of the blockade of RANKL/RANK interaction as well as the blockade of NF-κB inhibitor kinase (IKK) and of NF-κB translocation to the nucleus, also in comparison with glucocorticosteroid treatment, in terms of the development of a mouse model of allergic airway inflammation (AAI) and accompanying immune response. The blockade of each of the targets fully prevented the development of AAI. All the tested therapeutic strategies seemed to have a certain advantage over glucocorticosteroids with regard to counteracting the development of AAI.

Effect of selected non-steroidal anti-inflammatory drugs on activation-induced CD25 expression on murine CD4 and CD8 T cells: an study.

The main aim of this study has been to determine the effect of selected non-steroidal anti-inflammatory drugs (NSAIDs) - depending on their selectivity to cyclooxygenase (COX) 1 and 2 - on the activation-induced CD25 expression on CD4 and CD8 T cells. Lymphocytes obtained from lymph nodes of mice were treated with acetylsalicylic acid (ASA; a preferential COX-1 inhibitor), ketoprofen (KET; a non-selective COX inhibitor) and robenacoxib (ROB; a selective COX-2 inhibitor) in concentrations reflecting their plasma levels achieved in vivo at therapeutic doses and in ten-fold lower concentrations. The cells were activated with concanavalin A.

Hard water may increase the inhibitory effect of feed on the oral bioavailability of oxytetracycline in broiler chickens.

The aim of this study was to determine to what extent the ions present in hard water (125 mg/L of MgCl2 and 500 mg/L of CaCl2) may intensify the feed-induced decrease in oxytetracycline (OTC) absorption rate in broiler chickens after single oral administration at a dose of 15 mg/kg. Drug concentrations in plasma were determined by liquid chromatography-tandem mass spectrometry and combined, compartmental and non-compartmental approach was used to assess OTC pharmacokinetics. The administration of feed decreased the absolute bioavailability (F) of OTC from 12.

Beneficial effects of rosiglitazone, a peroxisome proliferator-activated receptor-γ agonist, in a mouse allergic asthma model is not associated with the recruitment or generation of Foxp3-expressing CD4 regulatory T cells.

The activation of peroxisome proliferator-activated receptor γ (PPAR-γ) has been shown to attenuate allergic airway inflammation (AAI). To gain better understanding of mechanisms underlying this effect, the impact of rosiglitazone (RSG), a PPAR-γ agonist, on CD4 effector (Teff) and Foxp3-expressing regulatory (Treg) T cells in a mouse model of allergic asthma was studied. Furthermore, we investigated whether the activation of PPAR-γ may directly affect IL-4, IL-10 and IL-17 production by CD4 T cells.

Effect of tigecycline on the production of selected cytokines and counts of murine CD4+ and CD8+ T cells - an in vitro study.

Due to the unrecognized effect of tigecycline (TIG) on CD4+ and CD8+ T cells, the present study has been undertaken in order to determine whether the drug can affect these cells in respect of their counts, and the production of IFN-γ, IL-17 (pro-inflammatory and immune-protective cytokines), IL-4 (anti-inflammatory and immune-protective cytokine), IL-10 and TGF-β (anti-inflammatory and immune-suppressive cytokines). Murine lymphocytes were treated with TIG for 48 and 96 h at concentrations reflecting its plasma levels obtained in vivo at therapeutic doses, and at 10-fold lower concentrations. It was found that TIG neither affected substantially the percentage and absolute counts of entire CD4+ and CD8+ T cell populations nor influenced the Foxp3+CD25+CD4+ regulatory/suppressive T cell subset.

Simvastatin Impairs the Inflammatory and Repair Phases of the Postinjury Skeletal Muscle Regeneration.

Background: Recent clinical data have suggested that the chronic use of high-lipophilic statins impairs the regenerative capacity of skeletal muscle. Because this activity of statins is poorly understood, we aimed to investigate the effect of simvastatin (SIM) on postinjury myofibre regeneration.

Methods: The porcine model was used in this study.

CD4- and CD8-expressing cells found in the bovine and porcine anterior chamber of the eye.

The aim of the present study was to investigate whether the anterior chamber constitutes part of the normal migratory pathway of CD4+ and CD8+ lymphocytes in cattle and swine. The cells obtained from aqueous humor of cows and pigs were stained for CD4 and CD8 receptors, and subsequently analyzed with flow cytometry. The mean percentage of CD4+CD8-, CD4-CD8+ and CD4+CD8+ cells within the total lymphocyte population of the bovine anterior chamber was, respectively, 17.

Oclacitinib depletes canine CD4 and CD8 T cells in vitro.

Oclacitinib (OCL) is a novel immunosuppressive agent approved for dogs that controls itch and inflammation in allergic disease via the inhibition of the JAK/STAT pathway. This paper investigates the in vitro effect of OCL, a novel Janus kinase inhibitor, on selected canine regulatory (Treg) and effector (Teff) CD4 and CD8 T cells. Exposure of peripheral blood lymphocytes to OCL did not affect the transcription factor Foxp3 (Forkhead Box P3 protein) expression in CD25CD4 and CD25CD8 T cells.

Significant expression of Foxp3 in murine extrathymic CD4+CD8+ double positive T cells.

Forkhead box protein 3 (Foxp3) is a specific marker and the key factor in the development and function of regulatory T (Treg) cells. The present study investigates Foxp3 expression in murine head and neck lymph node (HNLN) and peripheral blood (PB) CD4+CD8+ double positive (DP) T cells and compares it with that in CD4+ or CD8+ single positive (SP) T cells. Here we provide evidence that murine extrathymic DP cells express Foxp3.

Inhaled glucocorticoid treatment prevents the response of CD8 T cells in a mouse model of allergic asthma and causes their depletion outside the respiratory system.

The principal objective of this research has been to determine the safety of inhaled glucocorticoids (GCs) in respect of their effect on CD8 T cells within respiratory and extra-respiratory tissues, and to compare it with systemic GC treatment. Another purpose has been to identify whether inhaled and systemic GCs affect the CD8 T cell response in the mediastinal lymph nodes (MLNs) and lungs in a mouse model of ovalbumin (OVA)-induced asthma. Ciclesonide and methylprednisolone were used as a model for inhaled and systemic GCs, respectively.

Effect of inhaled and systemic glucocorticoid treatment on CD4 regulatory and effector T cells in a mouse model of allergic asthma.

To achieve a better understanding of mechanisms underlying the anti-asthmatic action of inhaled and systemic glucocorticoids (GCs) and to provide more data regarding the risk of a negative effect of inhaled GCs on CD4 T cells, a study was conducted on the effect of ciclesonide and methylprednisolone on CD4 effector (Teff), regulatory (Treg) and resting (Trest) T cells within respiratory and extra-respiratory tissues in a mouse model of allergic asthma. The study indicated that one, and possibly a key mechanism, underlying the anti-asthmatic action of inhaled and systemic GCs is the prevention of the activation and clonal expansion of CD4 Teff cells in the mediastinal lymph nodes (MLNs), which consequently prevents infiltration of the lungs with CD4 Teff cells. The beneficial effects of GCs in asthma treatment were not mediated through increased recruitment of Treg cells into the MLNs and lungs and/or local generation of Treg cells.

CD25+CD127+Foxp3- Cells Represent a Major Subpopulation of CD8+ T Cells in the Eye Chambers of Normal Mice.

The aim of this study has been to determine whether eye chambers constitute part of the normal migratory pathway of naive CD4+ and CD8+ T cells in mouse and if natural CD4+CD25+Foxp3+ and CD8+CD25+Foxp3+ regulatory T cells are present within these eye compartments. To this aim, the cells obtained from aqueous humor (AH) of normal mice were phenotyped in terms of the expression CD4, CD8, CD25, CD127 and transcription factor Foxp3. The mean percentage of CD8+ T cells in the total AH lymphocyte population was as high as 28.

Prostaglandin E2 exerts the proapoptotic and antiproliferative effects on bovine NK cells.

The aim of this research was to determine whether prostaglandin E2 (PGE2) affects bovine NK cells in respect of their counts, apoptosis and proliferation, and if it does, then which of the PGE2 receptor (EP) subtype(s) mediate(s) these effects. We here report that long-term, but not short-term, exposure of bovine peripheral blood mononuclear cells to PGE2 at 10(-5)M, 10(-6)M and 10(-7)M, but not at 10(-8)M, caused a significant increase in the percentage of early apoptotic cells among NK cell subset. Moreover, PGE2 at 10(-5)M and 10(-6)M, but not at 10(-7)M and 10(-8)M, induced a considerable decrease in the absolute count of NK cells.

Involvement of regulatory T cells and selected cytokines in the pathogenesis of bronchial asthma.

Asthma pathogenesis is complex and involves the interplay of many factors and actions. Airway inflammation in allergic asthma is characterized by an exaggerated activation of T helper type 2 cells, IgE production and infiltration and activation of eosinophils. The results of studies conducted in recent years indicate that the deficit of naturally occurring Foxp3+CD25+CD4+ and Foxp3+CD25+CD8+ regulatory T cells and type 1 regulatory T cells plays a pivotal role in the development of this disease.

Distribution of CD4+CD8+ double positive T cells in a mouse model of allergic asthma.

The present study describes the distribution of CD4+CD8+ double-positive (DP) T cells in various immune compartments of mice with ovalbumin (OVA)-induced allergic asthma. It was found that the absolute number of DP T cells was considerably increased in the mediastinal lymph nodes and lungs of asthmatic mice as compared with that determined in the healthy subjects. On the contrary, the absolute counts of DP T cells was significantly decreased in the head and neck lymph nodes, and in peripheral blood of OVA-immunized mice.

The influence of prostaglandin E2 on the production of IFN-γ by bovine CD4(+), CD8(+) and WC1(+) T cells.

The aim of these studies was to assess the influence of prostaglandin E2 (PGE2) on the production of interferon-gamma (IFN-γ) by bovine CD4(+), CD8(+), and WC1(+) T cells and furthermore, should this effect exist, to identify the E-prostanoid (EP) receptor subtype(s) responsible for this influence. We here report that exposure of bovine peripheral blood mononuclear cells (PBMCs) to PGE2 significantly and dose-dependently decreased the percentage of IFN-γ-producing CD4(+) and CD8(+) T cells. It was also shown that PGE2 reduced IFN-γ production by WC1(+) T cells, but this effect was not dose dependent.