Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P14784 (IL-2 receptor)
 3,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The immunosuppressive macrolide rapamycin inhibits cytokine-driven proliferation of lymphocytes, acting at a later stage of T lymphocyte activation than the related compound FK506 or cyclosporin, which block IL-2 transcription. However, the effect of rapamycin on the expression of the IL-2 receptor alpha-chain (CD25) is less well documented. This study has investigated the effect of rapamycin on mRNA levels of CD25 and membrane expression of IL-2 receptor in human primary T lymphocytes activated by various stimuli. Rapamycin surprisingly inhibits CD25 upregulation subsequent to anti-CD3 or ionomycin stimulation. These effects are not secondary to an IL-2-mediated CD25 up-regulation, as rapamycin inhibits neither IL-2 synthesis nor IL-2-induced CD25 mRNA. Interestingly, sensitivity to rapamycin correlates with the requirement of de novo protein synthesis, as demonstrated by anisomycin inhibition of both ionomycin- and CD3-induced CD25 transcription. Thus, rapamycin inhibition of T cell activation may involve not only IL-2-driven proliferation, but also suppression of CD25 up-regulation.
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PMID:Effect of rapamycin on the expression of the IL-2 receptor (CD25). 856 19

Experimental data show that relatively low concentrations of 15-deoxyspergualin (DSG) inhibit the induction of cytotoxic T lymphocytes (CTL) and the generation of antibody-producing cells. Considerably higher concentrations of DSG are required to inhibit proliferative responses. In this in vitro study, the effects of DSG on CTL induction, on proliferative responses induced by different stimuli, and on the production of interleukins IL-1, IL-2 and IL-6 and IFN-gamma (gamma-interferon) were assessed and compared with the effects of CsA (cyclosporine A) and/or FK506. We confirmed the suppressive action of DSG on the generation of CTL. Quite unexpectedly, however, we found that, although DSG did not affect the proliferative response to allogeneic lymphocytes or a superantigen, it did inhibit proliferation of peripheral blood leucocytes (PBL) stimulated with Staphyloccus aureus. DSG was active even when added on day 2 of in vitro culture, suggesting that DSG does not inhibit early events. The fraction of CD3+ lymphoblasts and the CD4/CD8 ratio was lower in cells stimulated by S. aureus in the presence of DSG, showing a selective effect on CD3+CD4+ responder T lymphocytes. The proportion of IL-2 receptor (CD25) positive cells was also reduced by DSG treatment. Moreover, we found that DSG inhibited the proliferation induced by PHA (phytohaemagglutinin) but not by Con A (concanavalin A). This effect of DSG was time-dependent, since PHA induced proliferation was not affected until day 4 after stimulation, and indicated that DSG may inhibit proliferation induced via a CD2- but not via a CD3-mediated pathway. DSG did not influence the production of IL-2 or IFN-gamma or the lipopolysaccharide induced production of IL-2 or IL-6. In contrast, the production of IL-6 was inhibited when cells were stimulated by allogeneic lymphocytes, S. aureus, PHA or Con A. This suggested to us that the DSG-suppressed IL-6 production could be the basis for the other observed effects. We tried to mimic the DSG effects with antibodies and indeed found that the IL-6 specific antibodies had similar effects. Furthermore, recombinant IL-6 completely overcame the suppressive effects of DSG on S. aureus and PHA induced proliferation, whereas addition of IL-6 to DSG treated PBL only partly restored the cytotoxic activity of lymphoblasts induced by allogeneic cells. Thus, the inhibitory effect of DSG on de novo synthesis of IL-6 could explain some of its immunosuppressive effects, but additional DSG-sensitive steps are obviously involved in CTL induction and differentiation.
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PMID:15-Deoxyspergualin inhibits interleukin 6 production in in vitro stimulated human lymphocytes. 884 90

Regulation of T cell IL-5 synthesis was investigated using human Th cell clones. Immunosuppressant FK506 suppressed IL-5 synthesis of T cells activated through TCR in a dose-dependent manner. IL-5 gene transcription and protein synthesis were also induced in the same T cell clones upon stimulation with IL-2 and were suppressed by FK506 in a dose response similar to that induced by TCR stimulation. In contrast to TCR stimulation, neither activating protein-1, nuclear factor-AT (NF-AT), nor NF-kappaB binding activity was significantly up-regulated by IL-2 stimulation. Human IL-5 promoter/enhancer-luciferase gene construct transfected to T cell clones was transcribed upon either TCR or IL-2 stimulation and was clearly down-regulated by FK506, indicating that the approximately 500-bp human IL-5 gene segment located 5' upstream of the coding region contained FK506-sensitive enhancer elements. Our present findings clearly indicate that FK506-sensitive signaling molecules are involved in T cell IL-5 production induced by both TCR and IL-2 stimulation and suggest that IL-2 receptor signal leading to IL-5 gene transcription is transduced by a unique FK506-sensitive pathway other than the Ca2+-dependent signal transduction pathway, such as the calcineurin-NF-AT system.
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PMID:IL-2-induced IL-5 synthesis, but not proliferation, of human CD4+ T cells is suppressed by FK506. 910 28

GVHD continues to be a major complication after allogeneic hematopoietic stem cell transplantation even when the recipient is given immunosuppression for the prophylaxis of this severe disease. There have been many advances in the prevention and treatment of GVHD, using compounds such as cyclosporine, FK506, mycophenolate mofetil or monoclonal IL-2 receptor antagonist. New strategies seem to include sequential therapy involving the blocking of both endogenous cytokines and alloreactive donor cells. However, further clinical and laboratory studies are needed in order to improve the therapy of established GVHD.
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PMID:New strategies in the treatment of graft-versus-host disease. 1093 79

Acute and chronic GvHD are still a major concern in allogeneic hematopoietic stem cell transplantation, still contributing substantially to morbidity and mortality in this therapeutic procedure. Over the past decade, many advances have been made with regard to the prevention and treatment of GvHD using various drugs such as cyclosporine A, FK506, mycophenolate mofetil and/or monoclonal IL-2 receptor antagonists. Despite these measurements with regard to the prevention of acute GvHD, it is very difficult to treat these clinical conditions successfully. However, if patients do not experience any GvHD often the desired effect of graft versus leukemia (GvL) remains absent increasing the probability of a relapse, in particular, in patients transplanted, which are considered at higher risk for relapse. At the present time, new strategies in the prevention of acute GvHD are in progress in particular the use of genetic manipulated donor T cells expressing suicide genes. Further clinical and laboratory studies are required in order to improve the prevention and, in particular, the therapy of established GvHD.
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PMID:New therapeutic modalities in the treatment of graft-versus-host disease. 1131 59

Sanglifehrin A (SFA) is a novel immunosuppressive natural product that binds to cyclophilin but is structurally distinct from cyclosporin A (CsA). We have investigated the cellular and molecular mechanisms of the action of SFA in T lymphocytes. We show that SFA inhibits T cell proliferation induced by IL-2 with an IC(50) of 200 nM. Distinct from CsA, which also binds to cyclophilin, SFA does not affect calcium-dependent IL-2 production, although SFA enhanced IL-2 gene transcription in the same cells. SFA blocks T cell proliferation induced by IL-2 in G(1) with no appreciable effect on IL-2 receptor expression in a manner similar to that of the immunosuppressant rapamycin. Unlike rapamycin, however, SFA has no effect on the phosphorylation or enzymatic activity of p70(s6k) kinase, distinguishing SFA from rapamycin in their mode of action. SFA inhibits hyperphosphorylation of Rb and the activity of cyclin E-cyclin-dependent kinase 2 on IL-2 signaling. These results suggest that SFA has a novel mode of action in comparison with CsA, FK506, and rapamycin, and that its use as a molecular probe may lead to the discovery of a novel target involved in T cell activation.
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PMID:Sanglifehrin A, a novel cyclophilin-binding immunosuppressant, inhibits IL-2-dependent T cell proliferation at the G1 phase of the cell cycle. 1131 1

In this review, the authors discuss immunologic targets and events in T cells that are dysregulated by commonly used immunosuppressive agents. These include a description of glucocortcoid receptors as well as targets of glucocorticoids, targets of cyclosporine and FK506, and the mammalian target of rapamycin. In addition, novel antibody-based targets on T cells and antigen-presenting cells including the IL-2 receptor and costimulatory molecules are described. Finally, the authors provide a rationale for an optimal approach to immunosuppression in pediatrics. Because many of the newer immunosuppressive agents are currently in clinical trials, the "optimal" immunosuppressive strategy for the next decade is forthcoming.
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PMID:Immunologic targets for currently available immunosuppressive agents: what is the optimal approach for children? 1155 92

Acute graft-versus-host disease (GVHD) and chronic GVHD remain the major barriers to successful haematopoietic cell transplantation. The induction of GVHD may be divided into three phases: recipient conditioning, donor T cell activation and effector cells mediating GVHD. This review examines GVHD prevention and treatment using this conceptual model as framework. The various pharmacological agents discussed impact on different phases of the GVHD cascade. For example, keratinocyte growth factor and IL-11 are cytokines that may be useful in disrupting Phase I of the GVHD cascade by blocking gastrointestinal tract damage and lowering serum levels of lipopolysaccharide and TNF-alpha. Cyclosporin, FK506 and sirolimus are some of the main agents that disrupt Phase II (donor T cell activation). Mycophenolate mofetil likely acts on this phase as well. Other novel drugs that affect Phase II are tolerance-induction agents such as cytotoxic T lymphocyte antigen (CTLA)-4 Ig and anti-CD40 ligand, and preliminary results using CTLA-4 Ig in GVHD prevention are encouraging. Two exciting agents that appear to affect only activated lymphocytes are ABX-CBL and visilizumab. Examples of agents that disrupt Phase III are the IL-2 receptor antagonist daclizumab and the anti-TNF-alpha monoclonal antibody infliximab. These anticytokine antibodies have shown promising results in early studies. The most effective approach to GVHD prevention will likely be a combination regimen where the three phases of the GVHD cascade are disrupted. Once GVHD has occurred, all three phases of the cascade are activated. Developments of combination therapy for treatment of both acute and chronic GVHD will likely yield better results than monotherapy. The numerous new treatment modalities presented should improve the outlook for acute and chronic GVHD.
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PMID:Novel therapeutics for the treatment of graft-versus-host disease. 1222 48

HIV infection of primary human T cells requires T cell activation signals. However, how strength, duration, and quality of TCR signals affect susceptibility of resting human T cells to HIV infection remains poorly understood. We found that the same threshold and duration of antigen signals that lead to optimal T cell activation are required for HIV to progress beyond the level of reverse transcription within resting T cells. Remarkably, sustained cytokine signaling from the IL-2 receptor following TCR triggering was critical in establishing productive infection. While blockade of TCR signaling pathways with inhibitors of the phosphatidylinositol 3-kinase pathway caused a partial pre-integration block, another inhibitor, rapamycin, completely suppressed the infection. In contrast, cyclosporin A or FK506, inhibitors of NFAT, failed to block infection if the T cells were pre-activated. Collectively, these results bring to light significant parallels between successful HIV infection and optimal thresholds of T cell activation. Furthermore, our results underscore the critical role of IL-2 signaling in establishing productive HIV infection. These findings have important implications for our understanding of the complex interplay of HIV with host factors induced upon T cell activation.
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PMID:HIV infection of primary human T cells is determined by tunable thresholds of T cell activation. 1516 41

Uveitis, or intraocular inflammation, remains an ongoing challenge to ophthalmologists and patients alike. In most patients, uveitis is limited to the anterior ocular structures and is readily managed with topical steroids. The inflammatory process can extend behind the lens to involve the pars plana, the vitreous cavity, the choroid and the retina. These intermediate and posterior uveitides are relatively rare but contribute disproportionately to visual morbidity and present serious diagnostic and therapeutic difficulties. Systemic steroids constitute the first line of treatment for most sight-threatening uveitides. Their long term use is limited by universal and debilitating adverse effects. Second-line, steroid-sparing agents allow a reduction in steroid dosage. Cyclosporin and azathioprine are the main steroid-sparing agents currently in use. However, these compounds are limited by a narrow therapeutic window and significant adverse effects. This paper offers a brief discussion of some of the immune mechanisms involved in the pathogenesis of uveitis and reviews categories of investigational compounds. Inhibitors of T cell function: tacrolimus (previously FK506), licensed for use in liver transplantation, and sirolimus (rapamycin) are macrolide antibiotics. Sirolimus is a functional cytokine antagonist and in vitro studies suggest it could be up to 100 times more potent than cyclosporin. Drug synergy between sirolimus and cyclosporin has been demonstrated, resulting in immunosuppression at lower drug doses and with fewer adverse effects. Nucleotide synthesis inhibitors: mycophenolate mofetil (MMF) and leflunomide. Human lymphocytes are only able to synthesise nucleic acids de novo. Having no alternative or 'salvage' pathway, they are exquisitely sensitive to interference with the de novo nucleotide synthesis enzymatic pathway. MMF is a purine synthesis inhibitor. Compared to other purine inhibitors, early data suggest that MMF is more efficacious and less toxic than azathioprine. Leflunomide is an inhibitor of pyrimidine synthesis. Monoclonal surface receptor antibodies and immunoadhesins: the IL-2 receptor is essential for clonal expansion of activated T cells; this has led to the development of anti-IL-2 receptor antibodies. Daclizumab is a genetically engineered humanised IgG1 monoclonal antibody. In conjunction with cyclosporin, it significantly reduces renal allograft rejection rates and is also showing promise in the treatment of T cell mediated autoimmune disorders. The mechanism of action of monoclonal antibodies to other pro-inflammatory cytokines such as TNFalpha and IL-12 and data from animal and human uveitis trials are also discussed. Finally, new avenues of research in immunopharmaco-modulation are mentioned.
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PMID:The potential of newer immunomodulating drugs in the treatment of uveitis: a review. 1803 46


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