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)

In summary, synthetic peptides corresponding to linear sequences of HLA class I molecules can inhibit T-cell responses in vitro and in vivo. These peptides induce immunologic tolerance by binding to hsp-70 family members, causing an increase in intracellular calcium, and down-regulating the nuclear factor of activated T cells, NF-AT. We suggest that heat shock proteins may function as novel immunophilins (Fig 2). Like cyclophilins and FK 506 binding proteins, heat shock proteins are ubiquitous, are involved in protein folding and trafficking, and bind exogenous drugs. Cyclosporine and FK 506 exert immunosuppressive effects by binding immunophilins, which as a result interrupt the phosphatase activity of calcineurin. Although the precise pathways involved in the synthetic HLA peptide effects are not as well worked out, it seems likely that peptide binding to heat shock protein is disrupting normal events in T-cell activation, giving rise to an apparently permanent state of anergy.
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PMID:Immunologic tolerance: tailored antigen. 876 60

1. The increased utilization of Neoral, Tacrolimus and mycophenolate mofetil correlated with the dramatic decrease in rejection rates in the 1990s. 2. The 4% difference in the incidence of rejection noted for recipients treated with Tacrolimus (20%) compared with Neoral (16%) corresponded to a 34% increased odds ratio in the multivariate analysis. The risk of graft loss and patient death were similar for the 2 calcineurin inhibitors. 3. Almost every renal transplant recipient received mycophenolate mofetil in 1999. This agent reduced the risk of 3-year graft loss by 60% and halved the risk of death compared with azathioprine. 4. Use of solumedrol as a corticosteriod increased from 26-67% in the 1990s, but this change in practice did not significantly impact outcome. 5. Although recipients given induction ATG or OKT3 had increased risk of graft failure, these recipients more likely were sensitized or required early dialysis. 6. The risk of rejection was 90% higher for recipients with 5-6 HLA mismatches than those with 0 A,B,DR mismatches. Recipients with a poorly HLA-matched kidney had 50% increased risk of graft loss within 3 years compared with HLA-matched transplants.
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PMID:Maintenance immunosuppression. 1151 60

TWO TYPES OF RECOGNITION: Direct recognition occurs when the recipient's T cells recognize allogenic antigens presented by the donor antigen presenting cells. Indirect recognition occurs when donor antigens on recipient antigen presenting cells are recognized. DIRECT RECOGNITION: Direct recognition occurs during the first days or weeks after transplantation when naive recipient cells recognize donor dendritic cells that have migrated to secondary lymphoid organs. This explains why acute rejection occurs mainly during the first weeks after transplantation. INDIRECT RECOGNITION: This is certainly a less intense mechanism than direct recognition. It probably is involved in acute rejection but is known to play a major role in chronic rejection. CD4 cells that have been activated by indirect recognition play an essential role in activating B cells, leading to the formation of anti-HLA antibodies as well as in activating macrophages and monocytes, endothelial cells and smooth muscle cells. INDUCTION OF TOLERANCE: Three mechanisms of action for regulating the allo-immune response leading to graft tolerance have been put forward: consumption of interleukin-2, production of suppressive cytokins, direct or indirect suppressive contact. T CELL ACTIVATION: Knowledge of the intracellular signals induced by T cell receptor activation makes it possible to target key proteins that could be blocked leading to better immunosuppression than with calcineurin inhibition.
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PMID:[Allorecognition]. 1157 85

Tissue injury is probably the central feature leading to CRAD, whether that injury is produced by immunological or nonimmunological factors. Tissue injury may expose cryptic antigens that, in an allogeneic situation, stimulate immune responses that further increase tissue damage. With acute rejection the immunological factor most strongly predictive of CRAD, HLA mismatches may facilitate rejection or otherwise lead to CRAD. However, clinical studies have not always demonstrated an increasing risk of CRAD with increased numbers of HLA mismatches. Antibodies produced against HLA or other donor-specific antigens may play a role in initiating the CRAD process or may occur secondary to tissue damage. Several human transplant studies have demonstrated an association between anti-HLA or anti-B cell antibodies and CRAD. In animal models of CRAD, antibodies are produced against antigens associated with glomerular and tubular basement membranes and mesangial cells, as well as antigens associated with vascular endothelial cells. The pathogenetic significance of these antibody responses is unclear at this time, but these responses may interfere with repair processes that follow tissue injury or otherwise facilitate mechanisms leading to CRAD. Whether similar antibody responses against components of basement membrane and mesangial cells occur in human renal transplant patients with CRAD is not yet known. The most effective way to prevent CRAD is to prevent tissue damage, especially immunity-related injury that involves maintaining appropriate immunosuppression. When using calcineurin inhibitors for immunosuppression, there is a risk of chronic calcineurin inhibitor-associated nephrotoxicity. Nonnephrotoxic immunosuppressive agents, such as sirolimus and mycophenolate mofetil, may be considered in therapeutic strategies designed to prevent acute rejection and to minimize renal tissue damage due to nephrotoxic drugs.
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PMID:Immunologic risk factors for chronic renal allograft dysfunction. 1158 84

Left ventricular assist device (LVAD) implantation is frequently complicated by B-cell activation and allosensitization, posing a significant risk to successful transplant outcome. This study investigated whether B-cell hyperreactivity and alloantibody production in LVAD recipients involves T-cell dependent pathways. T-cell calcium flux and nuclear translocation of NFATc were used to determine states of T-cell activation. Flow cytometry was used to assess human T- and B-cell activation after culture with LVAD-derived biomaterial particles. Sera from LVAD recipients and controls were tested for the presence of anti-HLA antibodies, and for soluble CD40 ligand. LVAD-derived biomaterial induced rapid and sustained calcium flux into normal T cells, resulting in calcineurin-dependent nuclear translocation of NFATc. This resulted in increased T-cell expression of CD40 ligand and subsequent B-cell activation, which was reduced by inhibitors of T-cell activation (CsA or anti-CD25 mAb) or by anti-CD40 ligand mAb. LVAD recipients demonstrated higher frequencies of anti-HLA antibodies and serum levels of soluble CD40 ligand compared with heart failure controls. The results indicate that exposure of human mononuclear cells to LVAD-derived biomaterial leads to T-cell dependent B-cell activation via CD40--CD40 ligand interaction, and suggest that treatment with calcineurin inhibitors or monoclonal antibodies against either CD25 or CD40 ligand could be effective at preventing B-cell hyperreactivity and allosensitization after LVAD implantation.
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PMID:B-cell activation and allosensitization after left ventricular assist device implantation is due to T-cell activation and CD40 ligand expression. 1187 39

Between February 1963 and December 2000, 1,627 kidney transplants were performed at the Massachusetts General Hospital. The majority (62%) were from cadaveric donors, although in recent years (1996-2000) 52% have been allografts from living donors, with an increase in living unrelated donors. The introduction of CsA and OKT3 in 1984 was associated with a significant improvement in actuarial renal allograft survival, although a persistent late attrition of allografts continues beyond the first year after transplantation. As reported in other centers, current actuarial survival for living unrelated allografts is superior to that of cadaveric allografts, and is quite similar to that observed in recipients of non-HLA identical living-related transplants. Our preliminary laparoscopic donor nephrectomy experience is encouraging as excellent allograft survival and function has been observed, with minimal morbidity associated with the procedure and a low rate of conversion to open nephrectomy. Recent changes in immunosuppressive protocols have resulted in lower early acute rejection rates, however the incidence of delayed graft function remains unchanged in cadaveric renal transplantation. The role of humoral immunity in allograft rejection has been progressively clarified and new approaches to control donor specific alloantibody production have been shown to be effective. Current clinical studies are ongoing to determine the optimal type and dose of calcineurin inhibitors beyond the first year after transplantation and to study whether avoidance of steroids is safe and feasible. Finally, an innovative tolerance induction protocol using the mixed chimerism approach has been successfully accomplished in selected patients with end-stage renal disease secondary to multiple myeloma. These encouraging observations emphasize that major changes from current immunosuppressive regimens are likely to occur over the next few years as more approaches to tolerance induction are explored clinically.
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PMID:The kidney transplant program at the Massachusetts general hospital. 1221 74

Diabetes mellitus (DM) is the most common metabolic disease, an independent risk factor of coronary disease, and shortens lifetime in all populations of patients, including kidney transplant recipients. Patients after kidney transplantation are exceptionally predisposed to develop or to exacerbate the preexisting DM. Age, DM in family, CMV infections, genetic factor (HLA A26 and B27), immunosuppressive treatment with steroids or calcineurin inhibitors belong to the major risk factors of diabetes. We analyzed 1300 renal transplant recipients in our center. Out of them 153 suffered from DM. DM de novo revealed 80 pts. Mean age in type I pts was 44.88 years and in type II pts was 57.27 years. De novo diabetics were 56.41 years old in average. CMV infection, potentially pathogenic in development of DM de novo, coexisted in 7.5% of these cases as frequently as in whole TPN population. Most frequently detected HLA antigens were: A2, B8 and DR5. Use of cyclosporine and tacrolimus promoted incidence of DM. We conclude, that low percentage of de novo DM in patients after renal transplantation may result from flexibility in administration of immunosuppressive regimens. Cyclosporine and tacrolimus treatment was switched to sirolimus or mycophenolate mofetil when the glucose intolerance was detected to prevent development of DM.
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PMID:[Treatment of diabetes mellitus in patients after renal transplantation]. 1262 76

The human major histocompatibility complex (HLA) encodes two sets of HLA class I molecules, which have been termed class Ia (or classical) and class Ib (or nonclassical) molecules. The class Ia molecules include the gene products of HLA-A, HLA-B, and HLA-C loci and are characterized by broad tissue expression and by a high degree of polymorphism. The class Ib molecules include the gene products of HLA-E, HLA-F, and HLA-G loci and are characterized by a restricted tissue distribution and by limited polymorphism. Besides being expressed on nucleated cells, classical and nonclassical HLA class I molecules are present in serum in soluble form (sHLA-I). The serum level of sHLA-I molecules is significantly increased in a variety of physiological and pathological conditions such as pregnancy, acute rejection episodes following organ allografts, acute graft-versus-host-disease (GVHD) following bone marrow transplantation, autoimmune diseases, viral infections, and malignant melanoma. Because of the statistically significant association with clinical parameters, the level of sHLA-I antigens has been suggested to represent a useful marker to predict the evolution of viral infections and to monitor the clinical course of allografts. Moreover, elevated levels of functional sHLA-I and soluble Fas-ligand molecules have been detected by our group in blood components and might play a role in the immunomodulatory effect of autologous and allogeneic transfusions. Several lines of evidence suggest that sHLA-I molecules are immunologically functional and may play an immunoregulatory role. In fact, they have been shown to elicit antibodies in both allogeneic and xenogeneic combinations, to inhibit the activity of alloreactive cytotoxic T lymphocytes (CTL), and to induce apoptosis in alloreactive and virus-specific CTL, in activated autologous and allogeneic CD8+ T cells, and in CD8+ NK cells. There is general agreement about the mechanism underlying the inhibition of CTL activity by sHLA antigens. This inhibition appears to be mediated by interactions of sHLA-I antigens a1 and a2 domains with T cell receptor (TCR). By contrast, there is conflicting information about the mechanism underlying induction of apoptosis of activated T cells by sHLA-I antigens. Several authors reported that sHLA-I molecules induced apoptosis of alloreactive CD8+ cytotoxic T lymphocytes through interaction with their TCR. However, our own data and those other groups indicate that classical and nonclassical sHLA-I molecules trigger Fas/Fas-ligand mediated apoptosis of phytohemoagglutinin (PHA)-activated and virus-specific CD8+ T lymphocytes as well as of CD8+ NK cells by interacting with CD8 coreceptor. Recently, we performed a series of experiments in our laboratory to clarify the intracellular mechanism(s) leading to Fas-ligand upregulation and secretion. These unpublished data indicate that sHLA-I/CD8 ligation elicits the phosphorylation of p56lck protein thyrosin kinase (PTK) associated with CD8 cytoplasmic domain in the absence of any other TCR-derived signal, the activation of syk-like ZAP-70 PTK and protein kinase C, and extracellular calcium influx. Then, activation and nuclear translocation of NF-kB and NF-AT occurs, leading to Fas-ligand mRNA transcription and soluble Fas-ligand secretion, which delivers the death signal. Interestingly, soluble Fas-ligand secretion and CD8+ cell apoptosis, but not CD8+ cell cytolitic activity, are completely inhibited by Cyclosporin A, which specifically blocks the activation of the calcineurin/calmodulin pathway. Taken together, these data suggest that sHLA-I molecules are involved in a signal-transduction pathway leading to Fas-ligand expression, soluble Fas-ligand secretion, and CD8+ cells apoptosis.
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PMID:Soluble HLA class I molecules/CD8 ligation trigger apoptosis of CD8+ cells by Fas/Fas-ligand interaction. 1280 26

Cardiovascular disease post-transplant, particularly ischemic heart disease, is a significant problem for all transplant recipients. The major risk factors-smoking, obesity, diabetes, dyslipidemia and hypertension-are often more prevalent in heart transplant populations than in the general population. One of the main risk factors influencing graft loss and patient survival is cardiac allograft vasculopathy (CAV). Because CAV affects between 30% and 60% of cardiac transplant recipients within 5 years of surgery, prevention is a key focus for cardiac transplant teams today. CAV is caused by both immunologic mechanisms (e.g., acute rejection and anti-HLA antibodies) and non-immunologic mechanisms relating to the transplant itself or the recipient (e.g., donor age, hypertension, hyperlipidemia and pre-existing diabetes) or to the side effects often associated with immunosuppression with calcineurin inhibitors or corticosteroids (e.g., cytomegalovirus infection, nephrotoxicity and new-onset diabetes after transplantation). The calcineurin inhibitors, cyclosporine and tacrolimus, effectively prevent acute rejection, but do not prevent the development of CAV. CAV prevention will require a combined approach of new adjunct immunosuppressant agents (e.g., the proliferation signal inhibitors) and reduction in cardiovascular risk. Hypertension, hyperlipidemia and diabetes are also associated with the immunosuppression required to prevent organ rejection. Some studies have shown that hypertension is present more frequently in cyclosporine-treated patients than in tacrolimus-treated patients and that tacrolimus may be associated with a more favorable lipid profile. On the other hand, tacrolimus may be more diabetogenic than cyclosporine with current data suggesting a trend but no statistically significant supporting evidence. New-onset diabetes after transplantation is at times difficult to manage and may be an important determinant along with hypertension and hyperlipidemia of ischemic heart disease, cerebrovascular disease and peripheral vascular disease. The choice of calcineurin inhibitor for an immunosuppressive regimen in heart transplantation should consider the associated relative cardiovascular risks.
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PMID:Cardiac allograft vasculopathy after heart transplantation: risk factors and management. 1509 4

In spite of considerable progress in immunosuppressive and supportive treatment, numerous problems persist which interfere with the success of renal transplantation. Before transplantation has been performed, factors impacting on outcome include the donor (living vs cadaver, age and HLA system) as well as the recipient (age, immunological reactivity, potential sensitization and duration of dialysis). These are the main factors that affect the outcome of the transplant, particularly in the long-term. After transplantation a number of events may put graft function at risk: potential recurrence of the primary renal disease in the allograft; 'de novo' renal disease triggered by infections, drugs or autoimmunity; and non-specific progression promoters, such as diabetes, hypertension, proteinuria, nephrotoxic agents and/or viral infections. The two most frequent causes of chronic allograft dysfunction are (i) chronic rejection (often triggered by preceding acute rejection, delayed graft function or poor compliance) and (ii) calcineurin-inhibitor nephrotoxicity (more likely to develop in kidneys of older donors or in marginal kidneys). The differential diagnosis between these two entities is generally difficult, but some histological clues (reduplication of glomerular basement membrane, obliterating vasculopathy and C4d deposits) as well as the demonstration of humoral antibodies are pointers suggesting rejection. Treatment of chronic graft dysfunction is difficult, whatever the cause, particularly in cases with advanced renal lesions. Therefore, early diagnosis is of paramount importance. In this regard, graft biopsy can be of great help. In spite of many problems and complications, not only short-term but also long-term results of renal transplantation are improving progressively, as documented by CTS data showing that in Europe for transplants performed between 1982 and 1984 the mean graft half-life was 7 years, while for transplants performed between 1997 and 1999 it was 20 years.
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PMID:Renal transplantation 2004: where do we stand today? 1557 92


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