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

Cyclosporine has dramatically improved the success rates for all forms of organ transplantation. However, its use is complicated by the frequent occurrence of hypertension and reversible nephrotoxicity. The iatrogenic hypertension induced by cyclosporine resembles a low-renin, salt-sensitive form of essential hypertension, which is often controlled with salt restriction and therapies counteracting renal salt acquisition, e.g., diuretics and calcium channel blockers (CCBs). CCBs may also counteract the direct vasoconstrictive effects of cyclosporine, as well as the effects of other vasoconstrictors, such as endothelin or thromboxane, that may be stimulated by cyclosporine. Additionally, CCBs may potentiate the immunosuppression of cyclosporine, yet minimize nephrotoxicity. We demonstrated that the in vitro combination of verapamil and cyclosporine had an additive inhibitory effect on the activation and function of human peripheral blood mononuclear cells in several assays of the afferent and efferent limbs of immunologic responses. This additive immunosuppression was not likely to have been related to these drugs' effects on interleukin-2 (IL-2) circuitry, since no additive inhibition of IL-2 production or IL-2 responsiveness was found. There was some additive inhibition of IL-2 receptor expression at the higher concentrations of verapamil and cyclosporine that were tested. Although the combination of verapamil and cyclosporine additively inhibited mitogen-induced 45Ca uptake, the inhibitory effect of cyclosporine appears to be due to an inhibition of lymphocyte activation rather than direct inhibition of calcium flux through the slow calcium channel, suggesting that the two drugs do not have additive effects in depressing the transmembrane flux of calcium. More recently, we have demonstrated that the inactive enantiomer of verapamil, which does not block the slow calcium channel, has identical immunosuppressive capabilities as the active enantiomer. Thus, the antiproliferative effect of verapamil is probably slow-calcium-channel independent and may represent the ability of the drug to interfere with muscarinic, alpha 1-adrenergic, or even opiate receptors on lymphocytes or to block lymphocyte potassium channels. An even better possibility is that verapamil may diminish necessary precursor molecule uptake into lymphocytes, since both the inactive and active isomeric forms of verapamil are capable of diminishing thymidine, uridine, and leucine incorporation into stimulated lymphocytes--necessary for DNA, RNA, and protein synthesis, respectively. These in vitro observations may have clinical applicability, as early studies demonstrate reduced rejection rates of cyclosporine-treated transplant patients receiving CCBs. Consequently, CCBs are important medications to be considered for use in cyclosporine-treated organ transplant recipients.
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PMID:Therapeutic benefits of calcium channel blockers in cyclosporine-treated organ transplant recipients: blood pressure control and immunosuppression. 203 18

A murine IgG1 antibody specific for the IL-2-binding site on the human lymphocyte IL-2 receptor beta chain (CD25) was evaluated in 11 patients who developed acute graft-versus-host disease following allogeneic marrow transplantation. All patients had received cyclosporine and methotrexate for prophylaxis of GVHD, either alone (4 cases), or in combination with antithymocyte globulin (4 cases) or with prednisone (3 cases). Patients had developed GVHD at 7-53 days (median 12) after transplantation and had failed treatment with corticosteroids for 3-44 days (median 19). Residual GVHD was of grade II severity in 4 patients, grade III in 5 patients, and grade IV in 2 patients. Sequential patients received monoclonal antibody in escalating doses from 0.1 mg/kg/day to 1.0 mg/kg/day for 7 days. Side effects were fever, respiratory distress, hypertension, hypotension, and chills occurring in 11 of 72 (14%) antibody infusions. Trough antibody levels greater than 6 micrograms/ml were achieved in patients treated with 0.5 or 1.0 mg/kg/day. Four of eight evaluable patients had an IgM antibody response, and one had an IgG response to the murine immunoglobulin. Clinical response of GVHD was evaluated in 10 patients who received the entire course of the antibody treatment. Among 7 patients treated within 40 days from transplantation, one patient had a complete response in the skin as the only involved organ, and 3 patients had a partial response, 2 in the skin and one in the gastrointestinal tract. No responses were achieved with liver disease at anytime or in any organ in patients treated beyond 40 days after transplantation. Since administration of this antibody was well tolerated and some efficacy was observed in patients with acute GVHD treated early after transplantation, there is a rationale for testing this antibody as an agent for prophylaxis of GVHD.
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PMID:A phase I-II study evaluating the murine anti-IL-2 receptor antibody 2A3 for treatment of acute graft-versus-host disease. 236 50

Pregnancy is associated with modifications in the maternal immune system that may be involved in the absence of rejection of the fetoplacental graft characterized by the presence of paternal antigens. This active and specific tolerance towards the fetoplacental unit seems to be compromised in pregnancy-induced hypertension (PIH). To evaluate whether the immunological state in patients with PIH is altered with respect to normal pregnant women we studied 15 patients with PIH, 15 uncomplicated pregnant and 10 healthy nonpregnant women using monoclonal antibodies directed to specific lymphocyte antigen determinants, cytokines (TNF) and soluble molecules (sIL-2R, sCD8). The percentage of CD4 lymphocytes and of natural killer (NK) cells was significantly higher in PIH patients compared to controls (CD4: 42.9 +/- 10.5 vs. 32.7 +/- 12.5%; p < 0.05; NK: 14.7 +/- 6.3 vs. 8.3 +/- 3.4%; p < 0.01). However, these values did not differ when compared to normotensive nonpregnant controls (CD4: 53.1 +/- 5.9%; NK: 17.2 +/- 7.1%). In addition, the soluble IL-2 receptor (sIL-2R) was higher in PIH patients when compared to control patients (725.5 +/- 194.2 vs. 482.5 +/- 187.2 U/ml; p < 0.01). The immune response observed in normal pregnancies responsible for the tolerance towards the fetoplacental unit seems to be altered in PIH patients as suggested by higher levels of CD4 and NK cells, and sIL-2R. This may lead to a chronic rejection syndrome and be involved in the pathophysiology of PIH.
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PMID:Cell-mediated immunity imbalance in pregnancy-induced hypertension. 785 7

Several studies have shown a significant reduction of acute cellular graft rejection in adult liver and kidney graft recipients treated with monoclonal anti-interleukin-2 (IL-2)-receptor antibodies. The mechanism was inhibition of activated T-helper cells by blocking the alpha-chain (CD25) of the IL-2 receptor. The pilot study described here evaluated the use of basiliximab in pediatric liver transplantation (LTx), which is the first report on its use in children. Fifty-two liver-transplanted children were analyzed in this study. A matched-pair historical control group (n = 26) received cyclosporin A (CsA) and prednisolone, and patients in the basiliximab group (n = 26) were treated with low-dose CsA and basiliximab (after reperfusion and on day 4 post-transplant). The incidences were compared of acute graft rejections, infectious complications, and the adverse effects of immunosuppressive medication within the first 6 months post-transplant. The incidence of acute rejection was significantly higher in the control group (61.5% vs. 11.5%, p = 0.0004). The frequency of infectious complications was similar (46.1% vs. 53.8%). Patients in the basiliximab group showed less arterial hypertension; however, the differences were not statistically significant (30.7% vs. 7.7%, p = 0.07). Nephrotoxicity, hepatotoxicity or neurotoxicity were only seen in the control group (7.7%; 3.8%; 3.8%, respectively). Hence, the use of basiliximab in combination with CsA and steroids in pediatric liver transplant recipients is safe and reduces the incidence of acute graft rejection. Further studies are needed to confirm our preliminary results and to analyze long-term effects on post-transplant lymphoproliferative disease, chronic rejection, and patient survival.
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PMID:First experience with basiliximab in pediatric liver graft recipients. 1173 61

SDZ RAD (everolimus, Certican is a novel macrolide immunosuppressant that blocks growth factor-driven transduction signals in the T-cell response to alloantigen. After stimulation of the IL-2 receptor on the activated T-cell, SDZ RAD inhibits p70S6 kinase, acting at a later stage in the T-cell mediated response than do cyclosporine and other calcineurin inhibitors (CNIs). Unlike the CNIs, SDZ RAD is a proliferation signal inhibitor, blocking growth factor-driven proliferation of both hematopoietic and nonhematopoietic cells. These activities are complementary to those of cyclosporine and provide a rationale for the addition of SDZ RAD to cyclosporine-based immunosuppression, with the potential for minimizing CNI nephrotoxicity, reducing the incidence of acute rejection, and favoring long-term graft survival. Potential also exists for beneficial effects on other factors that may influence the development of chronic rejection. These factors include comorbid diseases such as hypertension, which may affect transplant vasculopathy, and opportunistic infection with cytomegalovirus (CMV) and other viruses, which may increase the risk of chronic rejection. The synergistic effect of SDZ RAD and cyclosporine has been confirmed in preclinical models, with graft survival being significantly prolonged in rat models of kidney and heart allotransplantation. Clinical experience with SDZ RAD in cyclosporine-based immunosuppression, including low-dose cyclosporine regimens, has also resulted in predictable and favorable clinical outcomes. Low rates of acute rejection, excellent rates of patient and graft survival, lower incidence of CMV infections, better cholesterol, triglyceride and creatinine profiles, and better renal function have been demonstrated with SDZ RAD and lower doses of cyclosporine (Neoral; Novartis) in recipients of renal transplants. These findings, combined with good tolerability rates and an acceptable side-effect profile, indicate that the synergistic profile of SDZ RAD in combination with nontoxic dosages of CNI's and IL2 inhibitors will further improve longterm results in renal transplantation.
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PMID:Early clinical experience with a novel rapamycin derivative. 1180 23

The immune response to an allogeneic transplanted organ is T-cell dependent. It is governed partially by the context in which the T-cell encounters the antigen and can range from apoptosis, anergy, and neglect to full activation. The current armamentarium of immunosuppressive agents acts to inhibit the various steps of this T-cell activation pathway; at the level of the T-cell receptor (monoclonal antibodies such as OKT3), intracellular signally (calcineurine-inhibitors), DNA synthesis (azathioprine), or to cause lymphocyte depletion (ATG, ALG). Most protocols use a combination of agents for induction and maintenance immunosuppression. Although successful in preventing and treating allograft rejection, they are not without side effects. With improved patient and graft survival rates, adverse events such as hypertension, nephrotoxicity, hyperglycaemia, and lymphoproliferative disease become increasingly important issues. Newer drugs (IL-2 receptor antagonists, mycophenolate mofetil, rapamycin) have been introduced in an attempt to spare or avoid these adverse effects. Inducing graft tolerance and long-term drug-free survival is the goal of transplant immunologists. Postulated mechanisms include clonal deletion, anergy, and immunoredirection. Although a number of methods have been tested experimentally, none has been proven to induce tolerance for routine clinical use. Immunosuppression remains the cornerstone of the success of organ transplantation. Until investigators are able to induce tolerance in their transplant recipients or develop a tolerance assay, they would need to continue to tailor their immunosuppressive therapy according to the risk profile of the individual recipient.
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PMID:Transplant immunology. 1452 5

The introduction of cyclosporine in the early 1980s meant a decisive improvement in post-transplant outcomes for all solid-organ transplants and, in particular, it allowed heart transplantation to emerge as a viable therapeutic option for patients with end-stage cardiac failure. Many factors, including recipient and donor selection, organ preservation and the technical aspects of the transplant itself, influence post-operative outcomes following heart transplantation but the continued need to treat the recipient's immune response plays a key role in determining long-term outcomes. Thereby interactions between immunosuppressive drugs used in different combinations play an important role in patients' outcome. After more than two decades, significant controversy still exists as to the best immunosuppressive regimen for long-term maintenance. During the 1990s and 2000s, newer immunosuppressive medications, specifically, tacrolimus, mycophenolate mofetil, sirolimus, everolimus and the IL-2 receptor blockers (daclizumab and basiliximab), were introduced that allow the clinician several options to try to minimize side effects and maximize the desired therapeutic effects. The side effects involve direct organ toxicity (e.g. renal and hepatic dysfunction), metabolic disturbances, (e.g. diabetes, hyperlipidemia and hypertension), neurotoxicity, and several other significant adverse events, such as cholestasis and myelosuppression. Newer immunosuppressive drugs can impair wound healing, induce lung toxicity and produce various cytopenic states. Steroids continue to plague patients with their well-known side effects. This article reviews the current data on the benefits and risks of the various therapeutic regimens available, which are analyzed under three main themes: calcineurin inhibitor based therapies, calcineurin minimization protocols and calcineurin free regimens.
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PMID:Impact of different long-term maintenance immunosuppressive therapy strategies on patients' outcome after heart transplantation. 2043 59

Circulating antiangiogenic factors and proinflammatory cytokines are implicated in the pathogenesis of preeclampsia. This study was performed to test the hypothesis that steroids modify the balance of inflammatory and proangiogenic and antiangiogenic factors that potentially contribute to the patient's evolving clinical state. Seventy singleton women, admitted for antenatal corticosteroid treatment, were enrolled prospectively. The study group consisted of 45 hypertensive women: chronic hypertension (n=6), severe preeclampsia (n=32), and superimposed preeclampsia (n=7). Normotensive women with shortened cervix (<2.5 cm) served as controls (n=25). Maternal blood samples of preeclampsia cases were obtained before steroids and then serially up until delivery. A clinical severity score was designed to clinically monitor disease progression. Serum levels of angiogenic factors (soluble fms-like tyrosine kinase-1 [sFlt-1], placental growth factor [PlGF], soluble endoglin [sEng]), endothelin-1 (ET-1), and proinflammatory markers (IL-6, C-reactive protein [CRP]) were assessed before and after steroids. Soluble IL-2 receptor (sIL-2R) and total immunoglobulins (IgG) were measured as markers of T- and B-cell activation, respectively. Steroid treatment coincided with a transient improvement in clinical manifestations of preeclampsia. A significant decrease in IL-6 and CRP was observed although levels of sIL-2R and IgG remained unchanged. Antenatal corticosteroids did not influence the levels of angiogenic factors but ET-1 levels registered a short-lived increase poststeroids. Although a reduction in specific inflammatory mediators in response to antenatal steroids may account for the transient improvement in clinical signs of preeclampsia, inflammation is unlikely to be the major contributor to severe preeclampsia or useful for therapeutic targeting.
Hypertension 2014 Jun
PMID:Antenatal corticosteroids impact the inflammatory rather than the antiangiogenic profile of women with preeclampsia. 2466 92