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. The study found that OCL does not affect the proliferation of CD4+ T cells or the number of IFN-γ- and IL-17-producing CD4+ and CD8+ T cells. Moreover, OCL was found to counteract the induction of type 1 regulatory T (Tr1) cells and to act as a strong inhibitor of IL-10 production in both CD4+ and CD8+ T cells. Thus, these results indicate that beneficial effects of OCL in the treatment of skin allergic diseases are not mediated through: (a) the abolishment of IFN-γ and IL-17-production in CD4+ and CD8+ T cells; (b) generation of Tr1 cells; (c) inhibition of CD4+ T cell proliferation; (d) induction of IL-10 production in CD4+ T cells. The results of this study strongly suggest that, with respect to the evaluated parameters, OCL exerts a suppressive effect on Th2- but not Th1-mediated immunity.

Electrodegradation of Acid Mixture Dye through the Employment of Cu/Fe Macro-Corrosion Galvanic Cell in Na2SO4 Synthetic Wastewater.

Traditional wastewater purification processes are based on a combination of physical, chemical, and biological methods; however, typical electrochemical techniques for removing pollutants require large amounts of electrical energy. In this study, we report on a process of wastewater purification, through continuous anodic dissolution of iron anode for aerated Cu/Fe galvanic cell in synthetic Na2SO4 wastewater solution. Electrochemical experiments were conducted by means of a laboratory size electrolyzer, where electrocoagulation along with electrooxidation phenomena were examined for wastewater containing Acid Mixture dye. The above was visualized through the employment of electrochemical (cyclic voltammetry and ac impedance spectroscopy techniques) along with instrumental spectroscopy analyses.

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.e., IL-10 and TGF-ß), respectively, the development of allergic asthma. Studies using ovalbumin(OVA)-immunized mice have demonstrated that all the tested therapeutic strategies prevented the OVA-induced increase in the absolute number of IL-4- and IL-17-producing CD4+ T cells (i.e., Th2 and Th17 cells, respectively) indirectly, i.e., through the inhibition of the clonal expansion of these cells in the mediastinal lymph nodes. Additionally, the blockade of NF-κB translocation and RANKL/RANK interaction, but not IKK, prevented the OVA-induced increase in the percentage of IL-4-, IL-10- and IL-17-producing CD4+ T cells. These latter results strongly suggest that both therapeutic strategies can directly decrease IL-4 and IL-17 production by Th2 and Th17 cells, respectively. This action may constitute an important mechanism underlying the anti-asthmatic effect induced by the blockade of NF-κB translocation and of RANKL/RANK interaction. Thus, in this context, both these therapeutic strategies seem to have an advantage over the blockade of IKK. None of the tested therapeutic strategies increased both the absolute number and frequency of IL-10- and TGF-ß-producing Treg cells, and hence they lacked the potential to inhibit the development of the disease via this mechanism.

Comparative pharmacokinetics of chlortetracycline, tetracycline, minocycline, and tigecycline in broiler chickens.

Tetracyclines continue to be important antimicrobials in veterinary medicine. However, the pharmacokinetics (PK) of tigecycline (TIG) and minocycline (MIN) in broiler chickens has not been investigated to date, and the PK of chlortetracycline (CTC) and tetracycline (TET) remains insufficiently researched, especially in terms of absorption. These antimicrobials have never been compared in a single setting in a single species; therefore, the aim of the present study was to compare the PK of TIG, MIN, CTC, and TET in broiler chickens. Each drug (10 mg/kg) was administered intravenously (IV) and orally (PO). The plasma concentrations of each drug were determined by liquid chromatography-tandem mass spectrometry, and the results were analyzed using compartmental and non-compartmental PK models. Despite the fact that all of the studied antimicrobials were administered at an identical IV dose, the area under the concentration-time curve between zero and the last sampling point (AUC0→t) for MIN (35,014 ± 3,274 µg × hour/mL) and CTC (41,851 ± 10,965 µg × hour/mL) differed significantly from that determined for TIG (18,866 ± 4,326 µg × hour/mL) and TET (17,817 ± 4,469 µg × hour/mL). After IV administration, the values of AUC0→t were also directly related to total body clearance values which were significantly higher for TIG (0.56 ± 0.14 L/hour × kg) and TET (0.60 ± 0.14 L/hour × kg) than for CTC (0.25 ± 0.05 L/hour × kg) and MIN (0.29 ± 0.03 L/hour × kg). In turn, after PO administration, TIG was absorbed in only 1.55% ± 0.82, and CTC in 30.54% ± 6.99, whereas the bioavailability of MIN and TET was relatively high at 52.33% ± 3.92 and 56.45% ± 9.71, respectively. The differences in PK parameters between these drugs, despite their structural similarities, suggest that active transport mechanisms may play a role in their absorption and distribution.

Teriflunomide inhibits activation-induced CD25 expression on T cells and may affect Foxp3-expressing regulatory T cells.

Teriflunomide (TER) is an immunomodulatory agent. Although the first reports on the use of TER in dogs have already appeared, immune mechanisms underlying the immunomodulatory effect of TER do not seem to have been fully elucidated yet. There were two aspects of this study. First, further insight into the mode of action of TER was gained by investigating its effect on the expression of IL-2 receptor α-chain (CD25) and Forkhead box P3 (Foxp3) by CD4+ and CD8+ T cells and apoptosis of these cells. Second, in view in the earlier lack of data on the effect of TER on T cells in dogs, the results of this study filled in this gap. TER at a concentration which can be achieved in vivo prevented or reduced the activation-induced CD25 expression on CD4+ and CD8+ T cells, respectively. Taking into consideration the role of CD25 in T cell proliferation, this effect may constitute an additional mechanism responsible for the antiproliferative effect of the drug. Under stimulation conditions, TER induced Foxp3 expression in Foxp3-negative CD4+ and CD8+ T cells, while down-regulating it under unstimulated conditions. These results suggest that TER may generate iTreg cells, but this process requires cell activation. TER was not found to affect on the absolute count and apoptosis of CD4+ and CD8+ T cells. The results suggest that the impairment of CD25 expression during T cell activation and generation of iTreg cells may constitute additional mechanisms, besides the principal one, underlying the immunomodulatory effect of TER.

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 CD25+CD4+ and CD25+CD8+ T cells. Moreover, OCL did not influence constitutive CD25 expression on these cells although it reduced the activation-induced CD25 expression on CD4+ T cells. Unexpectedly, the research demonstrated the cytoreductive and proapoptotic effects of OCL on the cells examined. Exposure to OCL caused a dramatic loss of both CD4+ and CD8+ T cells and this effect was observed in both Treg and Teff cell subsets. On the one hand, cytoreductive and proapoptotic effects of OCL toward CD4+ and CD8+ Teff cells, as well as the drug-induced inhibition of CD4+ T cell activation, may be considered as additional mechanisms involved in producing anti-inflammatory and anti-allergic properties of the drug. On the other hand, these effects also represent the immunosuppressive action in the sense of an unwanted effect because CD4+ and CD8+ Teff cells play a crucial role in the production of cellular immunity. Further studies are needed to determine whether the use of OCL actually creates the risk of such action.