Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The chemokine superfamily consists of small (8-10 kDa) molecules that function to attract, selectively, different subsets of leukocytes. Binding of chemokines to their appropriate G-protein-coupled receptors is necessary for primary immune responses and for homing of leukocytes to lymphoid tissues. Here, we have characterized the signaling pathways in primary T lymphocytes that regulate chemokine gene induction using an RNase protection assay. Dependence on stimulation through the coreceptor CD28 and sensitivity to the calcineurin inhibitors cyclosporine and tacrolimus were studied using purified human peripheral blood lymphocytes. Lymphotactin (Ltn), macrophage inflammatory protein (MIP)-1alpha, and MIP-1beta were all rapidly induced and sensitive to cyclosporine treatment. At later time points, the expression of MIP-1alpha and MIP-1beta, but not of Ltn, was restored despite the inhibition of calcineurin activity. By contrast, the induction of interleukin-8 was delayed and was found to be cyclosporine insensitive. Calcineurin activity of IP-10 mRNA induction was contingent on the specific T-cell stimulation conditions, suggesting that IP-10 expression is modulated by calcineurin-dependent and -independent signaling pathways. Differential chemokine expression profiles result from the engagement of T-cell coreceptors and the requirement for, and the dependence on, calcineurin phosphatase activity.
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PMID:Differential chemokine expression profiles in human peripheral blood T lymphocytes: dependence on T-cell coreceptor and calcineurin signaling. 1239 16

Cyclosporin A (CsA) is a potent immuno-suppressant and is approved for the treatment of various disease conditions. The molecular biological mechanism of CsA has been investigated intensively in T cells and has been shown to involve the intracellular calcineurin pathway. Recently, it was reported that CsA has capacities to affect not only T cells but also antigen-presenting cells such as B cells and dendritic cells (DCs). DCs are a master regulator of immune responses that have an integral capacity to prime naive T cells. In the present study, we investigated the biological effects of CsA on human peripheral blood DC subsets: CD11c+ myeloid and CD11c- lymphoid subsets. CsA inhibited the up-regulation of co-stimulatory molecules induced with or without microbial stimuli and CD40L on both CD11c+ and CD11c- subsets. In addition, CsA negatively regulated the endocytic activity of CD11c+ DC during the immature state. CsA inhibited the interleukin-12 (IL-12) production, but augmented the IL-10 production from the LPS-stimulated CD11c+ subset, whereas CsA reduced the interferon-alpha (IFN-alpha) production from the CD11c- subset infected with Sendai virus (SV). Both the LPS-stimulated CD11c+ subset and SV-infected CD11c- subset preferentially induced the development of IFN-gamma-producing T helper-type 1 (Th1) cells. Pretreatment of these DC subsets with CsA inhibited the Th1 skewing. These findings suggested a DC-mediated mechanism of immunosuppression by CsA.
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PMID:Immunomodulatory effects of cyclosporin A on human peripheral blood dendritic cell subsets. 1260 98

Interferon-gamma (IFN-gamma) is a major effector cytokine of the immune system with an expression pattern strictly restricted to cells of the lymphoid lineage. Several years ago, we reported that, during early pregnancy, the trophectoderm of the pig blastocyst, which represents a monolayer of polarized epithelial cells secretes high amount of IFN-gamma in a transient and developmentally regulated manner. In an effort to study the molecular basis of this atypical IFN-gamma gene expression, a pig trophectoderm cell line, TBA B4-3, was established in our laboratory. These cells developed a polarized phenotype with high transepithelial electrical resistance (TER) when grown on a microporous membrane. We found that treatment of polarized TBA B4-3 cells with the strong PKC agonist PMA induced, 3-4 days later, a transient IFN-gamma mRNA expression and vectorial IFN-gamma protein secretion. In order to better understand IFN-gamma gene regulation in TBA B4-3 cells, we examined in this system the effect of several drugs and factors known to affect the inducibility of this cytokine in T lymphocytes, the main source of IFN-gamma in the immunocompetent animal. We found that cyclosporine A (CsA) treatment of TBA B4-3 cells induces a partial inhibition of IFN-gamma secretion, thus indicating a minor role for the calcineurin signaling pathway in IFN-gamma expression. In addition, we found that although PMA alone can induce IFN-gamma secretion, the calcium ionophore A23187 synergizes with PMA for induction. We also analyzed by Southern blot the methylation status of a CpG dinucleotide in the 5' flanking region of IFN-gamma promoter and found that it was unmethylated in TBA B4-3 cells and in several pig epithelial cell lines that do not express IFN-gamma thus indicating the absence of correlation between demethylation and the ability to express IFN-gamma. Taken together, these results indicate that the mechanisms involved in IFN-gamma induction in TBA B4-3 cells are atypical compared to those presently known to operate in the T cell lineage.
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PMID:Atypical mechanisms regulate the PMA-induced expression of IFN-gamma in a porcine trophectoderm cell line. 1273 16

FTY720, a synthetic analogue of myriocin (ISP-1), is derived from culture filtrates of the fungus Isaria sinclairii. As a sphingosine analogue, FTY720 appears to undergo phosphorylation and thereby interact with specific G-protein-linked receptors. In vivo, FTY720 causes emigration of lymphocytes from peripheral blood to secondary lymphoid structures. Thus, the drug is the archetype of a new class of agents that alter cellular homing patterns: the adhesion-migration paradigm. Since FTY720 seems to spare nonspecific elements of host resistance, it may address the not infrequent complications of infections associated with existing therapies. In experimental rodent, canine and non-human primate models, FTY720 produces lymphopenia and immunosuppression, prolonging the survival of allografts. Because of synergistic interactions, it promotes the immunosuppressive effects not only of calcineurin antagonists, but also of proliferation signal inhibitors. These interactions proffer the possibility of large reductions in exposure to and mitigated toxicity of existing drugs. In humans, FTY720 causes dose-dependent peripheral blood lymphopenia, a reduced incidence of acute rejection episodes and only one apparent adverse reaction - a negative chronotropic effect - particularly after the loading dose. While the clinical utility of FTY720 is difficult to predict before completion of Phase III studies that elucidate its benefits versus unanticipated side effects, the initial data suggest several potential advantages: it does not produce hyperlipidaemia, diabetes mellitus, nephrotoxicity, neurotoxicity or myelosuppression, which are characteristic of other immunosuppressants. Furthermore, it displays high oral bioavailability and a low interindividual coefficient of variation. Clearly, structural analogues, as well as other agents that alter the balance of chemokines or affect cellular adhesion to activated endothelium, will represent important components of future regimens.
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PMID:FTY720: A new kid on the block for transplant immunosuppression. 1283 71

Graft rejections as well as tolerance are true representation of the specificity, sophistication and redundancy of an elegantly and meticulously designed immune system. Tolerance is in a way similar to the process of self-recognition where lymphoid clones, during development, baring self-reactive receptor are eliminated or rendered in active by "clonal deletion" leading to a state of accommodation and acceptance (anergic). On the other hand, both acute and chronic rejections are manifestation of the purpose of existence of the immune system, which is to defend the host against foreign invaders. Thus, in order to treat (control) graft rejection it is necessary to determine and understand the steps leading to recognition, stimulation, activation, and amplification of the immune system. The first step leading to the initiation of the immune system cascade is recognition. Which can either be direct where donor antigens of the major histocompatibility complex (MHC) expressed on the donor cells (passenger leukocytes) or tissues are recognised by the host immune system. The direct recognition pathway initiates acute graft rejection. Alternatively processed donor MHC peptides presented by the recipient antigen presenting cells (APC) initiate the indirect pathway of immune response, which is as important as the direct recognition especially in chronic rejection. Recognition is followed by the ligation of a series of adhesion molecules starting with an antigen to its specific T-cell receptor (TCR)/cluster of differentiation (CD) complex, expressed on the surface of the T cell. In order for the activation to precede additional costimulatory signals, such as ligation of the CD28/B7, CD4/HLA class II and CD/HLA class I antigens are required. The activation process is accompanied by an increase of cytokines production such as interleukin (IL)-2, IL-12, interferon (INF) and tumour necrosis factor (TNF) by the primed T cell. The complexity and the polymorphic nature of the immune system have necessitated designing agents that inhibit the immune system at different levels. Cyclosporine and Tacrolimus, collectively known as calcineurin inhibitors, seems to act on the IL-2 by inhibiting its production thus leading to a decrease in the proliferation of the activated lymphocyte. Rapamycin, which is similar to Tacrolimus, inhibits graft rejection by blocking IL-2 activation and phosphorylation of 70 S6 kinase thus inhibiting the progression of T-cell from G to S phase. While Cellcept (MMF) reduce the proliferation of T cell by inhibiting purine synthesis and by its action on ionosine monophosphate dehydrogenase. Anti-lymphocyte antibodies (ATG) deplete circulating lymphocytes while selective monoclonal antibodies are directed against IL-2 receptor thus reducing the rate of proliferation of activated T cells. Recently, antibodies to the CD40/CD40 ligand have been shown to induce long-term graft survival with the inhibition of the Th1 cytokines (INF), IL-2 and IL-12 and upregulating the Th2 cytokines IL-4 and IL-10. Lastly graft rejection can be reduced by blockade of the B7/CD28 costimulation pathway with the fusion protein CTLA-4Ig. With the availability of such potent and diverse agents it is now possible to develop multi drug regiments that can depress the immune system at the different steps of the activation cascade, with minimal side effects, thus improving graft and patient survival rates.
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PMID:The mosaic of immunosuppressive drugs. 1283 79

FTY720, a synthetic myriocin analogue derived from culture filtrates of Isaria sinclairii, is a novel immunosuppressant that in experimental animals and nonhuman primates produces lymphocytopenia and prolongs allograft survival in dose-dependent fashion. FTY720 exerts synergistic interactions not only with calcineurin antagonists, but also with proliferation signal inhibitors. These interactions offer the possibility of reducing exposure to and mitigating toxicity of existing drugs. The mechanism of drug action is not entirely clear. FTY720 appears to undergo phosphorylation by sphingosine phosphokinase 2, rendering it capable of interacting with the specific G protein-linked receptors for its structural homologue-sphingosine-1-phosphate. However, it is not clear how this interaction leads to emigration of lymphocytes from the peripheral blood and sequestration in secondary lymphoid structures. Present theories suggest that the drug prevents emigration rather than directing the onset of sequestration. Thus, the drug is the archetype of a new class of agents that alter lymphocyte homing patterns: the adhesion-migration paradigm. These modalities reduce interstitial infiltration of grafts and attenuate their release from lymph nodes. Since FTY720 seems to spare nonspecific elements of host resistance, it may not only represent a useful addition to the immunosuppressive armamentarium but also address the not infrequent complications of infections associated with existing therapies.
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PMID:FTY720: from bench to bedside. 1504 2

Existing immunosuppressants inhibit lymphocyte activation and T cell cytokine signal transduction pathways, reducing the rate of acute rejection episodes to < 10%. However, the widespread tissue distribution of their molecular targets engenders pleiotropic toxicities. One strategy to address this problem seeks to identify compounds that selectively inhibit a target restricted in distribution to the lymphoid system. Janus kinase (Jak) 3 is such a molecule; it mediates signal transduction via the gamma common chain of lymphokine surface receptors. Disruption of this lymphoid-restricted enzyme would not be predicted to produce collateral damage in other organ systems. Development of selective Jak3 inhibitors has been difficult due to crossreactivity with its homologue, Jak2. In contrast to all other putative antagonists, which are discussed in detail herein, one Jak3 inhibitor, NC1153, shows at least 40-fold greater selective inhibition for Jak3 than for Jak2, is robustly synergistic with calcineurin antagonists, and, either alone or in combination with cyclosporin, produces no adverse effects in rodents preconditioned to be at heightened risk for nephrotoxicity, bone marrow suppression, or altered lipid metabolism.
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PMID:Janus kinase 3: a novel target for selective transplant immunosupression. 1558 66

Chronic rejection remains a major complication in solid organ transplantation. Host alloreactive T cells (TC) can be activated by donor dendritic cells (DCs; direct allorecognition) or by recipient DCs (indirect allorecognition). A fundamental aspect of DC function is vascular invasion to present donor antigens to recipient naive TC in secondary lymphoid organs. We investigated the impact of calcineurin inhibitors on DC binding and transmigration to allogeneic human microvascular endothelial cells (ECs) with and without blocking of specific adhesion molecules. Recipient immature DCs were generated by culturing CD14 human peripheral blood monocytes with GM-CSF and IL-4. DC adhesion and transmigration were investigated on allogeneic ECs preincubated with increasing concentrations of cyclosporine and tacrolimus. Experiments were repeated in the presence of blocking antibodies against LFA-1, PECAM-1, VCAM-1, and ICAM-1. Endothelial stimulation with cyclosporine A (100 and 300 ng/mL) and tacrolimus (15 ng/mL) significantly enhanced DC-EC adhesion and transmigration (P<0.01). LFA-1 blockade on DCs significantly reduced cyclosporine- and tacrolimus-induced DC adhesion (P<0.001). VCAM-1 blockade on ECs partially reversed cyclosporine-induced DC adhesion (P<0.001), whereas DC adhesion under tacrolimus exposure was significantly decreased by ICAM-1 (P<0.01) and PECAM-1 (P<0.001) blockade. DC binding and transmigration on allogeneic ECs exposed to calcineurin inhibitors is concentration-dependently increased. Different adhesion molecule patterns on ECs are responsible for enhanced DC invasion under cyclosporine and tacrolimus exposure. We speculate that long-term immunosuppression mediates enhanced invasion of recipient DCs to the donor organ and therefore may aggravate chronic rejection.
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PMID:Dendritic cell adhesion is enhanced on endothelial cells preexposed to calcineurin inhibitors. 1611 27

B cell receptor (BCR) cross-linking induces B cell proliferation and sustains survival through the phosphorylation-dependent signals. We report that a loss of the protein phosphatase component G5PR increased the activation-induced cell death (AICD) and thus impaired B cell survival. G5PR associates with GANP, whose expression is up-regulated in mature B cells of the peripheral lymphoid organs. To study G5PR function, the G5pr gene was conditionally targeted with the CD19-Cre combination (G5pr(-/-) mice). The G5pr(-/-) mice had a decreased number of splenic B cells (60% of the controls). G5pr(-/-) B cells showed a normal proliferative response to lipopolysaccharide or anti-CD40 antibody stimulation but not to BCR cross-linking with or without IL-4 in vitro. G5pr(-/-) B cells did not show abnormalities in the BCR-mediated activation of Erks and NF-kappaB, cyclin D2 induction, or Akt activation. However, G5pr(-/-) B cells were sensitive to AICD caused by BCR cross-linking. This was associated with an increased depolarization of the mitochondrial membrane and the enhanced activation of c-Jun NH(2)-terminal protein kinase and Bim. These results suggest that G5PR is required for the BCR-mediated proliferation associated with the prevention of AICD in mature B cells.
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PMID:Protein phosphatase subunit G5PR is needed for inhibition of B cell receptor-induced apoptosis. 1612 5

Transplant-associated microangiopathy (TAM) is a life-threatening complication after allogeneic HSCT, particularly with the use of calcineurin inhibitors as post-transplantation immunosuppressive therapy. We report our experience with TAM after HSCT with tacrolimus-based GVHD prophylaxis in a single-center study. Sixty-six of 1219 transplant recipients developed TAM with a cumulative incidence of 5.9%. Risk factors for TAM were female gender, lymphoid malignancy, receipt of a matched unrelated donor, and grade II-IV aGVHD. Most patients had infection and/or active GVHD at the diagnosis of TAM (82%). In the absence of renal dysfunction or encephalopathy, tacrolimus was generally continued, maintaining blood levels within the lower therapeutic range. Sixty-three patients were treated with plasma exchange. The cumulative incidence of response of TAM was 60%. Only 1 patient had a response of TAM without resolution of concomitant infections or GVHD. Six-month survivals were 0% and 50% for TAM nonresponders and responders, respectively. In conclusion, TAM is a common, life-threatening complication of allogeneic hematopoietic transplantation using tacrolimus prophylaxis. Control of TAM generally requires response of associated infections and GVHD. TMA response may occur despite continuation of tacrolimus treatment.
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PMID:Transplant-associated microangiopathy in patients receiving tacrolimus following allogeneic stem cell transplantation: risk factors and response to treatment. 1738 53


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