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)

Rapamycin (RAPA) is a potent immunosuppressant. In this study we investigated the effect of RAPA on T cell proliferation triggered by various stimuli in an in vitro human model. The proliferation of T cells stimulated via an alternative pathway using phorbol myristate acetate (PMA) and anti-CD28 antibody (alpha CD28) in the absence of antigen-presenting cells (APC) was strongly inhibited by RAPA. T cell proliferation provoked via a combination of CD3/TCR and CD28 pathways using anti-CD3 antibody (alpha CD3) plus alpha CD28 was also inhibited by RAPA in the presence of APC. The mitogen (phytohaemagglutinin (PHA) or alpha CD3)-induced up-regulation of expression of the IL-2 receptor alpha chain (IL-2R alpha) and the IL-4 receptor (IL-4R) was sensitive to RAPA. This suggests that RAPA's interference with the IL-2 and IL-4 autocrine loops during T cell activation might contribute to RAPA's overall immunosuppressive effect. We have further demonstrated in a two-stage culture system that RAPA strongly inhibited IL-4-stimulated proliferation of T cells, the latter being either pretreated with alpha CD3 in the presence of APC, or with PMA plus alpha CD28 in the absence of APC. The result suggests that the Ca++ influx during the pretreatment is not obligatory for T cells to achieve IL-4 responsiveness. The results also indicate that RAPA's antiproliferative effect on IL-4-stimulated T cells is not contingent on the various mechanisms of cell priming. Therefore, RAPA's major target is probably at the second stage after the priming. Our study has extended current knowledge about the effect of RAPA on human T cells.
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PMID:Anti-CD28 antibody- and IL-4-induced human T cell proliferation is sensitive to rapamycin. 822 29

Autocrine stimulation of the IL-2 receptor (IL-2R) is required for commitment of a T cell to enter the cell cycle and may involve transmission of the IL-2R signal to cell cycle control proteins. Candidates for such proteins are the D-type cyclins which are expressed in G1. Short-term cultures of primary human T cells were used to show that expression of cyclins D2 and D3 is regulated by IL-2 in a concentration- and time-dependent manner. Cyclin D2 RNA was induced rapidly to peak levels well before initiation of DNA synthesis and gradually declined during the remainder of G1. Cyclin D3 RNA and protein showed a slower induction during G1 to maximal levels as cells initiated DNA synthesis that remained high throughout S phase. Induction of cyclins D2 and D3 was independent of the cyclosporin A-sensitive calcineurin pathway and of rapamycin-sensitive pathways, despite the ability of rapamycin to severely inhibit entry into S phase. These observations suggest that cyclins D2 and D3 may monitor the IL-2R signal but that their induction does not guarantee entry into S phase. Rapamycin was found to target a pathway late in G1 that is distal to induction of D-type cyclin gene expression but proximal to DNA replication, perhaps involving the function of the D-type cyclin proteins or their associated kinases.
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PMID:IL-2-dependent induction of G1 cyclins in primary T cells is not blocked by rapamycin or cyclosporin A. 826 27

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

T cell cytokine expression may be induced by the cytokine IL-2 or via the TCR complex. The comparative effects of cytokine- and TCR-mediated signalling on the induction of human IL-5 mRNA were examined. Cytokine mRNA expression was analysed by RT-PCR in fresh peripheral blood mononuclear cells (PBMC) from normal individuals and in populations of activated T lymphocytes, derived from phytohaemagglutinin (PHA)-stimulated PBMC. rIL-2 induced IL-5 expression in PBMC, the kinetics of which were similar to the effects of PHA. rIL-4 induced IL-5 mRNA expression in activated T lymphocytes. IL-5 expression induced by either IL-2 or PHA was completely abolished by the protein synthesis inhibitor cycloheximide. rIL-2-induced IL-5 expression was resistant to cyclosporin A (CsA), whereas IL-5 expression elicited by PHA was inhibited by CsA, at doses as low as 10 ng/ml. Rapamycin (RAP) had no effect on rIL-2-stimulated IL-5 expression, but suppressed IL-5 expression induced by PHA. The inhibitory effect of RAP on PHA-induced IL-5 expression was more apparent at 12 and 24 h after stimulation than at earlier times. The resistance of IL-2 receptor (IL-2R) signalling to CsA and RAP indicates that the IL-2R and the TCR are associated with different pathways regulating IL-5 expression.
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PMID:Induction of IL-5 expression by IL-2 is resistant to the immunosuppressive agents cyclosporin A and rapamycin. 923 6

Discovery of novel biological and pharmaceutical agents directed against discrete molecular targets in the lympnocyte activation sequence has enabled the effective control of graft rejection by the use of combinatorial immunosuppressive therapy. Chimeric and humanized monoclonal antibodies against T-cell receptor CD3 complex chains or the IL-2 receptor block T-cell function without inducing activation, and do not cause the cytokine release syndrome of first generation products. Biological blockade of co-stimulatory molecules including CD40L and CD28 produces immunological allograft unresponsiveness in primates, though this effect is not yet proven in humans. Heterogeneity in clinical response to pharmaceutical agents is often explained by pharmacokinetic factors of absorption, metabolism and elimination. The use of microemulsion technology has increased the absorption and efficacy of cyclosporine in all organ transplants, so that there is little difference in efficacy between this agent and tacrolimus. Mycophenolate mofetil is not maximally effective alone, but significantly reduces the relative risk of acute rejection in combination with an immunophilin binding agent. It is also effective when introduced at the time of rejection. Whether it can replace other agents for maintenance immunosuppression is now under investigation. Sirolimus, the latest pharmaceutical agent to complete phase III trials, acts to inhibit IL-2 driven lymphocyte proliferation and reduces the risk of acute rejection to below 20%. Multiple pharmacokinetic interactions occur within and between these agents, so that pharmacokinetic monitoring is increasingly important. At present there are few tools to detect pharmacodynamic interactions, although reporter gene constructs and intracellular cytokine labeling offer exciting possibilities for biological monitoring. Despite these advances, none of these interventions confers demonstrable long-term benefit in graft survival or function. Acute rejection can not therefore be assumed to be a simple surrogate for chronic injury, and research must be re-focused to determine the relevant targets for long-term immunosuppression.
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PMID:New immunosuppressive strategies. 986 62

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

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

Simultaneous pancreas-kidney transplantation (SPKT) is the treatment of choice for patients with end-stage renal failure due to type 1 diabetes mellitus. With advances in surgical techniques and immunosuppression management, outcomes have improved, with current 1- and 10-year pancreas graft survival rates of 86% and 53%, respectively. Induction therapy with either alemtuzumab or rabbit antithymocyte globulin (rATG) in combination with a calcineurin inhibitor (CNI) and mycophenolate mofetil (MMF) or sirolimus appears to be safe and effective in the setting of rapid steroid withdrawal (RSW), with excellent graft survival and low rejection rates. There are no large randomized trials between alemtuzumab and rATG to determine whether one is better than the other. Anti-interleukin (IL)-2 receptor antibody induction and no induction in combination with a CNI, MMF or sirolimus, and prednisone have demonstrated excellent graft survival rates but are associated with a higher incidence of acute rejection. The efficacy of anti-IL-2 receptor antibodies or no induction in the setting of RSW is unproven. Both of the CNIs, ciclosporin and tacrolimus, are effective in preventing acute rejection in SPKT recipients; however, pancreas allograft survival may be better with tacrolimus. MMF is more effective than azathioprine in preventing acute rejection. Sirolimus appears to be effective in preventing acute rejection, but the combination of sirolimus with a CNI may accentuate the nephrotoxicity of the CNI. RSW with induction therapy is safe and effective in SPKT recipients, but longer follow-up data on outcomes are needed. Recent analysis of registry data shows that most transplant centres are using an induction agent followed by a combination of tacrolimus, MMF and corticosteroids in SPKT recipients.
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PMID:Immunosuppression in simultaneous pancreas-kidney transplantation: progress to date. 2042 94

A total of 1,859 intestinal transplants was reported to UNOS during the past 20 years (1,822 deceased, and 37 living donors). Forty-three US transplant centers reported at least one intestinal transplant, among them, Jackson Memorial Hospital, Nebraska Medical Center and University of Pittsburgh Medical Center were the 3 largest centers, each performing more than 300 cases. The University of Illinois Medical Center performed the most (N = 24) living donor intestinal transplants. The one-, five-, and ten-year graft survival rates of all recipients are 71%, 45%, and 32%. The longest surviving adult intestine transplant is 19 years posttransplant and the longest surviving pediatric transplant is 18 yrs. Both were simultaneous intestine and liver transplants from deceased donors. The first living-donor intestine transplant was reported to UNOS in 1995. The patient received an intestine-alone transplant which functioned for 501 days. The longest surviving living donor intestine transplant is still functioning after 11 years. Among transplants that included the intestine, 37% were intestine-alone transplants, 30% included intestine+liver+pancreas, and 24% were intestine+liver. One-, 5-, and 10-year graft survival rates of intestine-alone recipients were 80%, 44% and 26%; while those for Intestine+liver and intestine+liver+pancreas, were, 62%, 45%, 36%, and 69%, 48%, 33%, respectively. HLA mismatches seemed to have no effect on graft survival for primary intestinal graft recipients, but the most poorly matched (5-6-HLA antigen mismatches) regraft recipients had notably lower graft survival rates. Patients who received ABO blood type compatible intestinal grafts from an "O" donor had a significantly lower graft survival than AB recipients of an A or B donor or those who received ABO identical transplants. Only 4 ABO incompatible intestinal transplants have been reported and all of them have failed. The first ABO incompatible transplant in the US was performed in 1990 and the graft survived for 7 days. The longest survival of an ABO incompatible transplant was 3.5 years. Ischemic time of intestine, patient's and recipient's CMV status had no effect on graft survival. Patients with a history of rejection episodes posttransplant or who had been previously transplanted had significantly lower graft survival rates. Acute rejection, chronic rejection and infection were among the major causes of graft failure. Infection, multiple organ system failure and graft rejection were the major causes of patient death. Induction therapy was used for 67% of all intestine recipients, which is lower than for kidney (83%) but higher than for liver recipients (59%). Thymoglobulin remained the most commonly used antibody since its introduction into intestine transplantation in 1999. In recent years, more patients received Zenapax/Simulect (anti-IL-2 receptor), Campath (anti-CD52) and Rituximab (anti-CD20). These antibodies were usually used in combination with other immunosuppressants. Patients receiving steroids and Campath induction therapy had higher graft and patient survival than other protocols. Prograft, steroids, Cellcept and Rapamycin were the 4 major immunosuppressants used in maintenance therapy. Prograft and steroids have been used more than 20 years since the initiation of the UNOS intestine database in 1990. Among all maintenance immunosuppression protocols, Prograft+steroids (43%), Prograft-alone (14%), Prograft+steroids+ Cellcept (11%), and Prograft+steroids+Rapamycin (6%) are the top 4 major protocols. Patients on Prograft+steroids+Rapamycin had the highest graft and patient survival rates, while those on steroids alone had the lowest.
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PMID:Intestine and multivisceral transplantation in the United States: a report of 20-year national registry data (1990-2009). 2052 78

The last decade has witnessed an expansion of the arsenal of new immunosuppressive agents to include several novel drugs and antibodies. The main indication of all these immunosuppressive agents is organ transplantation. In terms of its action, tacrolimus resembles cyclosporin A and is employed as the mainstay immunosuppressant or for what is referred to as rescue therapy in refractory rejection. Mycophenolate mofetil is an anti-metabolite replacing azathioprine in immunosuppressive protocols. Sirolimus is an agent for prophylactic use, either as part of a cyclosporin-based regimen to enhance the effect of cyclosporin or as an alternative of non-nephrotoxic immunosuppression to cyclosporin-based regimens; its indications are still being specified. Gusperimus could be used for anti-rejection therapy; however, it is not being used in this country as yet. Recently, two monoclonal antibodies against the IL-2 receptor, chimeric basiliximab and humanized daclizumab, have been employed. Both agents are of non-depletion type and are indicated for induction therapy in the early post-transplant period.
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PMID:[Newer immunosuppressive agents and their place in current practice]. 2266 25


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