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

---

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

In vitro studies have demonstrated that cyclosporine A (CsA) acts by inhibiting the phosphatase activity of calcineurin, an important mediator of T-cell activation. The relationship of CsA administration in vivo, calcineurin activity, and graft-versus-host disease (GVHD) has yet to be studied. The calcineurin activities of mononuclear cells isolated from 62 bone marrow transplant recipients and 12 normal volunteers were determined and analyzed with respect to administration of CsA, presence or absence of CsA in plasma, and presence or absence of GVHD. Of 62 patients, 33 were taking CsA and 29 were not. Early posttransplant (< 100 days), the calcineurin activity of patients on CsA was significantly lower than that of patients not on CsA (P = .0004) and than that of normal volunteers (P < .0001). Similarly, late posttransplant (> 100 days), the calcineurin activity of patients taking CsA was inhibited compared with normal volunteers (P < .05). The calcineurin activity of patients with acute GVHD who were taking CsA was lower than that of patients on CsA without acute GVHD matched for time posttransplant (P = .02). Calcineurin activity in patients on CsA with chronic GVHD was similar to those without chronic GVHD on drug. In conclusion, calcineurin activity is significantly suppressed by in vivo administration of CsA. The lower calcineurin activity of patients on CsA with acute GVHD suggests that CsA-resistant GVHD is not the result of inadequate suppression of calcineurin activity. These data suggest that if inhibition of calcineurin is the only physiologic target of CsA administration, simply increasing doses of CsA or treatment with other inhibitors of calcineurin, such as FK506, would not be expected to ameliorate GVHD.
...
PMID:Inhibition of calcineurin phosphatase activity in adult bone marrow transplant patients treated with cyclosporine A. 794 53

Tacrolimus (FK506) is a macrolide lactone with potent immunosuppressive activity 100 times that of cyclosporine by weight. The molecular mechanism of action is mediated via an inhibition of the phosphorylase activity of calcineurin by drug-immunophilin complex, resulting in the inhibition of IL-2 gene expression. There are emerging studies now showing significant efficacy of tacrolimus in GVHD prevention in both related and unrelated donor transplantation. Three multicenter randomized studies comparing tacrolimus to cyclosporine have been completed, one each in related and unrelated donor transplantation; the remaining study involved both related and unrelated donor transplantation. All three studies showed a significantly lower incidence of grade II-IV acute GVHD in patients who received tacrolimus. One study in sibling donor transplantation showed that patients with advanced disease who received tacrolimus had a poorer survival than patients who received cyclosporine, but the survival was similar in patients with non-advanced disease. The remaining two studies, one in unrelated donors and the other combining both related and unrelated donors did not show any survival difference between the tacrolimus and cyclosporine groups. In addition, this review also highlights some of the critical questions regarding the role of this agent in allogeneic stem cell transplantation: (1) the contribution of methotrexate in combination with tacrolimus; (2) the starting i.v. dose of tacrolimus; (3) the suggested whole blood level of tacrolimus and its effect on nephrotoxicity; and (4) whether tacrolimus should be used in patients with advanced malignancy. Future studies using tacrolimus in combination with other immunosuppressants, and its use in patients with advanced malignancy will be warranted.
...
PMID:Tacrolimus: a new agent for the prevention of graft-versus-host disease in hematopoietic stem cell transplantation. 972 Jul 34

Over the last few years, improved knowledge of the immunological mechanisms underlying transplant rejection have resulted in the development of new immunosuppressive agents capable of selectively blocking various steps of the immune response. It is anticipated that these agents will prove useful in the treatment of autoimmune disease and graft-versus-host disease. Neoral is a cyclosporin microemulsion characterized by better and more consistent absorption as compared to the conventional galenic form. Tacrolimus shares with cyclosporin an ability to inhibit calcineurin and may have similar indications. Rapamycin and RAD are two related molecules that inhibit signal transduction by cytokines to T-cells, although they have not yet been proved clinically effective in large studies of solid organ transplant recipients. Mycophenolate mofetil selectively inhibits purine synthesis and lymphocyte proliferation; it is easy to use and has been found effective in a number of autoimmune disorders. Further clinical work is needed to determine the therapeutic indications for each of these new drugs. Elucidation of their mechanisms of action may help to identify drug combinations providing both enhanced efficacy and improved safety.
...
PMID:[New immunosuppressive agents]. 1057 3

Mature dendritic cells (DCs), in addition to providing costimulation, can define the Th1, in contrast to the Th2, nature of a T-cell response through the production of cytokines and chemokines. Because calcium signaling alone causes rapid DC maturation of both normal and transformed myeloid cells, it was evaluated whether calcium-mobilized DCs polarize T cells toward a Th1 or a Th2 phenotype. After human monocytes were cultured for 24 hours in serum-free medium and granulocyte-macrophage colony-stimulating factor to produce immature DCs, additional overnight culture with either calcium ionophore (CI) or interferon gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), and soluble CD40L resulted in phenotypically mature DCs that produced interleukin-8 (IL-8) and displayed marked expression of CD80, CD86, CD40, CD54, CD83, DC-LAMP, and RelB. DCs matured by IFN-gamma, TNF-alpha, and soluble CD40L were additionally distinguished by undetectable CD4 expression, marked secretion of IL-12, IL-6, and MIP-1beta, and preferential ability to promote Th1/Tc1 characteristics during T-cell sensitization. In contrast, DCs matured by CI treatment were distinguished by CD4 expression, modest or absent levels of IL-12, IL-6, and MIP-1beta, and preferential ability to promote Th2/Tc2 characteristics. Calcium signaling selectively antagonized IL-12 production by mature DCs activated with IFN-gamma, TNF-alpha, and soluble CD40L. Although the activation of DCs by calcium signals is largely mediated through calcineurin phosphatase, the inhibition of IL-12 production by calcium signaling was independent of this enzyme. Naturally occurring calcium fluxes in immature DCs, therefore, negatively regulate Dc1 differentiation while promoting Dc2 characteristics and Th2/Tc2 polarization. Calcium-mobilized DCs may have clinical usefulness in treating disease states with excessive Th1/Tc1 activity, such as graft-versus-host disease or autoimmunity.
...
PMID:Calcium signaling inhibits interleukin-12 production and activates CD83(+) dendritic cells that induce Th2 cell development. 1158 47

Cord blood (CB) cells are now an important source of stem cells for bone marrow reconstitution as a result of the decreased risk of graft-versus-host disease that was attributed to previously reported absent or diminished nuclear factor of activated T (NFAT) cell 1 expression by CB T cells. This study reexamines NFAT1 expression in CB T cells. CB T cells were examined for NFAT1 mRNA and protein expression. These cells were then stimulated, and NFAT1 translocation and interleukin-2 production were assessed. Our results show that resting CB CD4+ T cells express NFAT1 mRNA and protein at levels similar to their adult counterparts. On stimulation, NFAT1 is translocated into the nucleus where DNA binding can occur, whereas calcineurin inhibition prevents interleukin-2 production. We conclude that differential responsiveness of CB T cells cannot be attributed to differences at the level of NFAT1 expression or its ability to function in these cells but may represent an altered sensitivity to stimulation.
...
PMID:Equivalent functional nuclear factor of activated T cell 1 mRNA and protein expression in cord blood and adult T cells. 1465 99

Acute graft-versus-host disease (GVHD) and chronic GVHD remain the major barriers to successful hematopoietic cell transplantation. The induction of GVHD may be divided into three phases--(I) recipient conditioning, (II) donor T cell activation, and (III) effector cells mediating GVHD. Cytokines have been shown to be extremely important in the initiation and propagation of GVHD. Of note, IL-2 and TNF-alpha lead to cellular activation as well as local tissue damage. There has been a major development in the last few years of monoclonal antibodies that target cytokines. Drugs that target the IL-2 receptor (daclizumab and basiliximab) are now commonly used to prevent renal transplant rejection. Furthermore, drugs that target TNF-alpha (infliximab and etanercept) are used in rheumatoid arthritis and Crohn's disease but are also being tested for a number of other autoimmune diseases. These agents are very selective immunosuppressants that have different mechanisms of action than the calcineurin inhibitors and therefore are potentially promising for treatment or prevention of GVHD. The authors present up-to-date data regarding the use and development of anti-cytokine therapy for GVHD. 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.
...
PMID:Anti-cytokine therapy for the treatment of graft-versus-host disease. 1507 35

During hematopoietic stem cell transplantation (HSCT), endothelial damage is the pathological hallmark of veno-occlusive disease of the liver, thrombotic microangiopathy, capillary leak syndrome and graft-versus-host disease. Events prior to conditioning, the conditioning regimen itself as well as calcineurin inhibitors may all induce endothelial damage. Unfortunately, the relative importance of these factors and their interactions, the time frame of endothelial damage and individual susceptibility remain unknown. Moreover, it is conceivable that conditioning regimens differ markedly in their propensity to initiate endothelial damage. Monitoring endothelial damage and response to treatment is hampered by the current lack of suitable markers. In this regard, an ideal marker should be sensitive and specific and indicate the development of an endothelial disorder prior to the onset of symptoms and organ dysfunction. Soluble markers, such as thrombomodulin, are easily amenable with immunoassays; yet, the interpretation of their levels is hampered by the influence of comorbidity. Evaluation of circulating endothelial cells in HSCT demonstrated a marked and dose-dependent increase in cell numbers after conditioning. The challenge ahead is to establish and evaluate novel markers of endothelial damage to permit early detection of disease, monitor response to treatment and evaluate different conditioning regimens.
...
PMID:Counting the cost: markers of endothelial damage in hematopoietic stem cell transplantation. 1551 35

We conducted a phase II trial in 19 chronic graft-versus-host disease (cGVHD) patients with rapamycin, calcineurin inhibitors, and prednisone with the goals of controlling cGVHD, reducing prednisone use, and defining the safety of this regimen. Rapamycin was begun as second-line (n = 9) or more than second-line (n = 10) therapy. With a median follow-up of 42 months, 16 patients were evaluable for response. Nine patients discontinued rapamycin because of poor compliance/patient request (n = 2) or an adverse event (n = 7), 3 of whom were not evaluable because of withdrawal at < or =1 month or noncompliance. The adverse events included serum creatinine > or =2.4 mg/dL (n = 4), hemolytic uremic syndrome (n = 2), and relapse of malignancy (n = 1). Fifteen of 16 evaluable patients had a clinical response. Five of the 16 discontinued the drug, and 1 died of relapsed leukemia. Of the 10 patients who continued rapamycin, 2 discontinued and 1 successfully tapered all systemic immunosuppression. Three of the 10 developed progressive cGVHD with tapering immunosuppression; all responded to resumption of prior medications. Four of the 10 patients required alternate therapy for persistent or progressive cGVHD while receiving rapamycin; prednisone was discontinued (n = 2) or tapered at the time of progressive disease (n = 2). Seventeen of 19 original patients were alive. One death was due to relapsed malignancy, and 1 was due to congestive heart failure. In this report of rapamycin as cGVHD therapy, there is evidence of rapamycin's efficacy. Given the significant toxicities described, investigation of altered administration of rapamycin and calcineurin inhibitors should be pursued in future cGVHD trials.
...
PMID:Rapamycin (sirolimus) for treatment of chronic graft-versus-host disease. 1604 15

Thrombotic microangiopathy (TMA) may occur after allogeneic hematopoietic stem cell transplantation (HSCT) and is related in part to calcineurin inhibitor toxicity. We observed a higher-than-expected rate of TMA when calcineurin inhibitors were combined with sirolimus. To determine the incidence of and risk factors for TMA after HSCT, we performed a retrospective cohort analysis of myeloablative allogeneic HSCT recipients between 1997 and 2003. TMA diagnosis required the simultaneous occurrence of (1) creatinine increase >2 mg/dL or >50% above baseline, (2) schistocytosis, (3) increased lactate dehydrogenase, and (4) no evidence of disseminated intravascular coagulopathy. A total of 111 sirolimus-exposed subjects were compared with 216 nonexposed subjects after HSCT. TMA occurred in 10.8% of the sirolimus group and 4.2% in the nonsirolimus group (odds ratio, 2.79; P=.03). Sirolimus exposure was associated with TMA earlier than in nonsirolimus patients (25 versus 58 days; P=.04). Only the use of sirolimus (exact odds ratio, 3.49; P=.02) and grade II to IV acute graft-versus-host disease (exact odds ratio, 6.60; P=.0002) were associated with TMA in regression analyses. Treatment of TMA varied among affected individuals. Renal recovery was complete in 92% of sirolimus-treated patients. Overall survival after TMA diagnosis was better for sirolimus subjects than for nonsirolimus subjects (58.3% versus 11.1%; P=.02). Sirolimus seems to potentiate the effects of calcineurin inhibitors on TMA after HSCT. TMA associated with sirolimus seems reversible and has a favorable prognosis when compared with TMA associated with calcineurin inhibitors alone. A careful monitoring strategy for TMA should be used with a sirolimus-containing graft-versus-host disease prophylaxis regimen.
...
PMID:Sirolimus and thrombotic microangiopathy after allogeneic hematopoietic stem cell transplantation. 1598 55

To evaluate the efficacy of reduced-intensity stem-cell transplantation (RIST), we retrospectively compared outcomes of 207 consecutive Japanese patients aged between 50 and 59 years with hematologic malignancies who received RIST (n=70) and conventional stem-cell transplantation (CST) (n=137). CST recipients received total body irradiation (TBI)-based or busulfan/cyclophosphamide-based regimens. RIST regimens were purine analog-based (n=67), 2 Gy TBI-based (n=2), and others (n=1). Most CST recipients (129/137) received calcineurin inhibitors and methotrexate as graft-versus-host (GVHD) prophylaxis, while 32 RIST recipients received cyclosporin. In all, 23 CST and five RIST recipients died without disease progression within 100 days of transplant. Grade II to IV acute GVHD occurred in 56 CST and 38 RIST recipients. There was no significant difference in overall survival (OS) and progression-free survival between CST and RIST. On multivariate analysis on OS, five variables were significant: preparative regimens (CST vs RIST) (hazard ratio=1.92, 95% confidence interval, 1.25-2.97; P=0.003), performance status (2-4 vs 0-1) (2.50, 1.51-4.16; P<0.001), risk of underlying diseases (1.85, 1.21-2.83; P=0.004), acute GVHD (2.57, 1.72-3.84; P<0.001), and CML (0.38, 0.21-0.69; P=0.002). We should be careful in interpreting results of this small-sized retrospective study; however, reduced regimen-related toxicity might contribute to better survival in RIST. The low relapse rates following RIST suggest a strong antitumor activity through allogeneic immunity.
...
PMID:Comparison between reduced intensity and conventional myeloablative allogeneic stem-cell transplantation in patients with hematologic malignancies aged between 50 and 59 years. 1611 74


1 2 3 4 5 6 7 8 9 10 Next >>

---