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: UMLS:C0021051 (immunodeficiency)
71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A few protein targets were found to display a specific high-affinity interaction with the immunosuppressant cyclosporin A (CsA): cytosolic cyclophilins (CyP)A, B, C, D, E containing from 122 to 174 amino acid residues in a polypeptide chain, and secreted forms of CyP; CyP-40, 40-kDa CsA-binding polypeptide complexed with steroid receptor (SR); CyP-related 150-kDa receptor of natural killer (NK) cells; interleukin 8 (IL-8); actin; a family of molecular chaperones hsp70 and P-glycoprotein (P-GP). All CyPs possess peptidyl-prolyl cis-trans isomerase activity (PPIase) and may serve as ATP-independent molecular chaperone proteins. The CsA-CyP complexes are specific inhibitors of Ca(2+)-and calmodulin-dependent protein phosphatase calcineurin (CaN). The inhibition of CaN blocks the activation of genes of IL-2, IL-2R, IL-4, etc. in T cells. In addition, immunosuppressive and/or antiinflammatory activity of CsA can be executed via CyP-40 and hsp 70 complexed with SR, and following the interaction with CyP-related receptor of NK and with IL-8. CsA binding to CyPC, P-GP and actin may throw light on the biochemical events leading to nephrotoxicity and graft vessel disease, two major side effects produced by CsA. The discovery of the interaction of human immunodeficiency virus type 1 (HIV-1) Gag protein with CyP and effective disruption of this interaction by CsA may be important for our understanding of the pathology caused by this immunosuppressive virus and will inspire therapeutic strategies to nip HIV in the bud. Bacterial immunophilins (ImPs) contribute to the virulence of pathogenic microorganisms. Elucidation of molecular mechanisms of microbial ImPs' action in the pathogenesis of bacterial infections may lead to new strategies for designing antibacterial drugs.
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PMID:Some new aspects of molecular mechanisms of cyclosporin A effect on immune response. 754 42

Cyclosporins, in particular the nonimmunosuppressive derivative SDZ NIM 811, exhibit potent anti-human immunodeficiency virus type 1 (HIV-1) activity in vitro. SDZ NIM 811 interferes at two stages of the viral replication cycle: (i) translocation of the preintegration complex to the nucleus and (ii) production of infectious virus particles. Immunosuppressive activity is not correlated with anti-HIV-1 activity of cyclosporins. However, binding to cyclophilin A, the major cellular receptor protein of cyclosporins, is a prerequisite for HIV inhibition: all structural changes of the cyclosporin A molecule leading to loss of affinity to cyclophilin abolished the antiviral effect. Cyclosporin derivatives did not interact directly with HIV-1 proteins; cyclophilin was the only detectable receptor protein for antivirally active cyclosporins. There is no evidence that inhibition of HIV occurs via a gain of function of cyclophilin in the presence of cyclosporins: the complex of cyclophilin A with SDZ NIM 811 does not bind to calcineurin or to any other viral or cellular proteins under conditions in which calcineurin binding to the cyclophilin A-cyclosporin A complex is easily detectable. Thus, the loss of function caused by binding of cyclosporins to cyclophilin seems to be sufficient for the anti-HIV effect. Cyclophilin A was demonstrated to bind to HIV-1 p24gag, and the formation of complexes was blocked by cyclosporins with 50% inhibitory concentrations of about 0.7 microM. HIV-2 and simian immunodeficiency virus are only weakly or not at all inhibited by cyclosporins. For gag-encoded proteins derived from HIV-1, HIV-2, or simian immunodeficiency virus particles, cyclophilin-binding capacity correlated with sensitivity of the viruses to inhibition by cyclosporins. Cyclophilin A also binds to HIV-1 proteins other than gag-encoded proteins, namely, p17gag, Nef, Vif, and gp120env; the biological significance of these interactions is questionable. We conclude that HIV-1 Gag-cyclophilin A interaction may be essential in HIV-1 replication, and interference with this interaction may be the molecular basis for the antiviral activity of cyclosporins.
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PMID:Mode of action of SDZ NIM 811, a nonimmunosuppressive cyclosporin A analog with activity against human immunodeficiency virus (HIV) type 1: interference with HIV protein-cyclophilin A interactions. 788 93

Maintenance immunosuppressive drugs act by partially blocking rate-limiting steps in the immune response. The new maintenance immunosuppressive drugs are either inhibitors of de novo synthesis of nucleotides (purines or pyrimidines), or are immunophilin-binding drugs that inhibit signal transduction in lymphocytes. The new inhibitors of de novo nucleotide synthesis include mycophenolate mofetil (MMF), mizoribine (MZ), brequinar (BQR), and leflunomide (LEF). MMF and MZ act to inhibit de novo purine synthesis, by inhibition of inosine monophosphate dehydrogenase (IMPDH). They create a selective immunodeficiency in T and B lymphocytes. MMF is hydrolyzed to mycophenolic acid (MPA), an uncompetitive inhibitor of IMPDH. MPA reduces the pools of guanine nucleotides, and increases some adenine nucleotides, inhibiting the cell cycle. Thus the number of specific effector T and B lymphocytes is reduced by limiting clonal expansion. MZ is a competitive inhibitor of IMPDH, which creates a similar defect. The relative clinical effectiveness of MMF versus MZ is not known. MMF has been approved in a number of countries; MZ has been approved in Japan. The inhibitors of de novo pyrimidine synthesis (BQR, LEF) act on the enzyme dehydroorotate dehydrogenase. Neither is currently in clinical trials in transplantation. The new immunophilin-binding drugs inhibit either the calcium-dependent phosphatase calcineurin (CN) [tacrolimus (or FK-506) and the microemulsion form of cyclosporine (CsA)] or signaling from growth factor receptors [rapamycin (sirolimus)]. Tacrolimus binds to FK binding protein-12 (FKBP-12) to create a complex that inhibits CN. CsA binds to cyclophilin to create a complex that inhibits CN. Inhibition of CN prevents activation of cytokine genes in T cells. The relative clinic effectiveness of tacrolimus versus microemulsion CsA is unknown. Rapamycin inhibits signaling from growth factor receptors, such as IL-2R. Rapamycin binds to FKBP to create a complex that engages proteins called TOR (target of rapamycin), or RAFT (rapamycin and FKBP target), which may be kinases. The result is a block in the ability of cytokine receptors to activate cell cycling, interfering with clonal expression. Deoxyspergualin, a parenteral drug in development for induction or antirejection therapy, may inhibit intracellular chaperoning by Hsc70, a member of the heat shock protein family. It may have its principal effect by inhibiting the activation of transcription factor NF-kappa B in antigen-presenting cells and monocytes.
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PMID:Molecular mechanisms of new immunosuppressants. 868 47

Previous reports have indicated that benzothiophenes exhibit broad anti-inflammatory properties and inhibit human immunodeficiency virus-type 1 (HIV-1) replication. We show that the immunosuppressant cyclosporin A (CsA) and benzothiophene-2-carboxamide, 5-methoxy-3-(1-methyl ethoxy)-1-oxide (PD 144795) block the induction of p53 and NF-kappaB binding to the HIV-1 long terminal repeat (LTR) by the T cell receptor activator phytohemagglutinin. CsA and PD 144795 also inhibit the induction by phytohemagglutinin of the transcription mediated by an HIV-1 LTR fragment containing the p53 and NF-kappaB sites. These effects of PD 144795 on HIV-1 transcription correlate with its ability to inhibit the phosphatase activity of calcineurin and are similar to those previously described for CsA. Moreover, a constitutive active form of calcineurin is able to induce expression from the HIV-1 LTR in a p53- and NF-kappaB-dependent manner and PD 144795 is able to block this induction. These results demonstrate that the DNA binding of p53 to the HIV-1 LTR can be modulated by calcineurin and provide a framework to understand the anti-HIV properties of benzothiophene derivatives.
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PMID:p53 transactivation of the HIV-1 long terminal repeat is blocked by PD 144795, a calcineurin-inhibitor with anti-HIV properties. 950 19

The PBj14 isolate of the simian immunodeficiency virus SIVsmmPBj14 is unique among primate lentiviruses in its ability to induce lymphocyte proliferation and acutely lethal disease. The studies reported here show that viral induction of T-cell proliferation requires accessory cells, such as primary monocytes or Raji B-lymphoma cells, as well as the presence of a putative immunoreceptor tyrosine-based activation motif within the viral Nef protein. Addition of CTLA4-immunoglobulin fusion protein or anti-B7 antibodies to virally infected T cells led to substantial, but not complete, inhibition of monocyte-costimulated T-cell proliferation-suggesting that both CD28/B7-dependent and non-CD28-dependent pathways may contribute to the costimulation of virally induced lymphoproliferation. Finally, cyclosporin A, a specific inhibitor of the calcium-calmodulin-regulated phosphatase activity of calcineurin, which influences activation of the transcription factor nuclear factor of activated T cells, was shown to block virally mediated T-cell proliferation. Taken together, these findings suggest that the effect of SIVsmmPBj14 on T-cell activation may be functionally analogous, at least in part, to the effect of engagement of the T-cell receptor.
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PMID:Costimulatory pathways in lymphocyte proliferation induced by the simian immunodeficiency virus SIVsmmPBj14. 962 Oct 81

This study investigates the second messengers involved in NF-kappaB activation by the bisperoxovanadium (bpV) phosphotyrosyl phosphatase inhibitors. We first initiated a time course analysis of bpV-mediated activation of the human immunodeficiency virus type-1 long terminal repeat- and NF-kappaB-driven reporter gene. Our results showed a slower and more transient activation of both kappaB-regulated luciferase-encoding vectors by bpV compounds when compared with the action of tumor necrosis factor-alpha (TNF). Time course analyses of NF-kappaB translocation by shift assay experiments further confirmed these results, hence implying distinct pathways of NF-kappaB activation for bpV compounds and TNF. Attempts to characterize the bpV-dependent signaling cascade revealed that the src family protein tyrosine kinase p56(lck) was critical for NF-kappaB induction by bpV. Furthermore, p56(lck) interaction with the intracytoplasmic tail of CD4 markedly enhanced such induction. Optimal activation of NF-kappaB following bpV treatment necessitated downstream effectors of p56(lck) such as the syk family protein tyrosine kinase ZAP-70 and the molecular adaptor SLP-76. Importantly, reduced NF-kappaB activation was observed when capacitative calcium entry was deficient but also upon pharmacological inhibition of calmodulin and calcineurin. Altogether, these results suggest that induction of NF-kappaB by phosphotyrosyl phosphatase bpV inhibitors necessitates both proximal and distal effectors of T cell activation.
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PMID:p56(lck), ZAP-70, SLP-76, and calcium-regulated effectors are involved in NF-kappaB activation by bisperoxovanadium phosphotyrosyl phosphatase inhibitors in human T cells. 1057 81

Nef is a lentiviral protein involved in pathogenesis of AIDS, but its molecular mechanisms of action remain incompletely understood. Here we report a novel effect of Nef on lymphocyte signaling, which is mediated via a T cell receptor (TCR)-independent contribution of Nef to induction of nuclear factor of activated T cells (NFAT), a transcription factor that plays a central role in coordinating T cell activation. Expression of Nef did not significantly alter the basal level of NFAT activity in Jurkat cells nor the increased activity following T cell receptor stimulation by anti-CD3 or anti-CD3 + anti-CD28. We also mimicked NFAT induction by TCR triggering by simultaneous activation of the Ras and calcium signaling pathways with phorbol 12-myristate 13-acetate and ionomycin, respectively. Strikingly, whereas activation of either of these pathways individually did not induce NFAT activity in control cells, in Nef-expressing cells phorbol 12-myristate 13-acetate treatment alone resulted in a 100-fold increase in NFAT-directed gene expression. Experiments with different dominant negative mutant signaling proteins, inhibitory chemicals, and Lck-deficient Jurkat cells revealed that this effect was mediated via activation of calcineurin by Nef-induced changes in calcium metabolism, but was independent of TCR-associated signaling events. This ability of Nef to substitute for triggering of the calcium pathway in induction of NFAT could promote activation of human immunodeficiency virus (HIV)-infected T cells in response to stimuli mediated via TCR or other cell surface receptors under conditions when activation of Ras rather than calcium signaling would otherwise predominate.
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PMID:Synergistic activation of NFAT by HIV-1 nef and the Ras/MAPK pathway. 1074 82

Severe Combined Immunodeficiency (SCID) is a primary immunodeficiency affecting T cells, B cells, or both. Whereas the clinical symptoms are uniformly dominated by recurrent infections, the molecular causes for SCID are very heterogeneous. Mutations in cell surface receptors, signal transduction molecules and transcription factors have been described, including the common gamma chain of the IL-2 (and IL-4, IL-7, IL-9 and IL-15) receptors, the kinase JAK-3, the epsilon and gamma chains of CD3, the protein tyrosine kinase ZAP-70, as well as CIITA and RFX5 involved in MHC class II gene expression. In this work we describe two infants with SCID whose T cells display a severe defect in T cell activation and cytokine transcription due to impaired activation of the transcription factor NFAT. We show that this defect in activation is not due to mutations in the NFAT proteins expressed in T cells or the phosphatase calcineurin which regulates the activation of NFAT. However, nuclear import of NFAT in response to T cell activation was severely compromised in the patients' T cells. A modest degree of nuclear translocation of NFAT was achieved in the patients' T cells when nuclear export was inhibited using lithium chloride. This low level of nuclear NFAT in the nucleus was not sufficient to compensate for the defect in cytokine production in the patients' T cells. However, elevated levels of extracellular calcium led to an increase in cytokine gene transcription by the SCID T cells, suggesting that the underlying genetic defect in the patients involved calcium influx or the initiation of calcium signalling.
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PMID:Impaired NFAT regulation and its role in a severe combined immunodeficiency. 1099 88

The authors discuss the importance that molecular medicine has assumed in recent years. Molecular methodologies have clearly demonstrated that immunological diversity is based fundamentally on the rearrangement of the genes encoding antigen B and T cell receptors. The importance of oncogenes, and their translocation in tumoral pathologies is emphasized, a case in point being the alterations observed in chronic myeloid leukemia and acute promyelocytic leukemia and their implication for innovative therapy. The importance of prothrombin and factor V genetic-molecular alterations in thromboembolic pathology and of the activation of calcineurin phosphatase or other intracellular signal regulator molecules during cardiac insufficiency genesis is also discussed. Particular attention is paid to progress regarding the socially important Alzheimer's syndrome, and the diagnosis of endocrine tumors. Moreover, the authors believe that the identification of new endocrine nuclear receptors, "orphans" of hormonal ligands, will open up interesting prospects--even therapeutic--in endocrinology. The authors conclude by reviewing the therapeutic prospects for immunodeficiency syndromes and malignant tumors, offered by new gene therapy methodologies. They also discuss recent results of studies on the aging process which, until not many years ago, appeared adventuristic. Today they are opening prospects of great interest.
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PMID:[Molecular medicine: new tools for better understanding and treatment of diseases in humans]. 1105 61

Modulation of many signaling pathways in antigen-stimulated T and B cells results in global changes in gene expression. Here we investigate the contribution of calcium signaling to gene expression in T cells using cell lines from two severe-combined immunodeficiency patients with several cytokine deficiencies and diminished activation of the transcription factor NFAT nuclear factor of activated T cells. These T cells show a strong defect in transmembrane calcium influx that is also apparent in their B cells and fibroblasts. DNA microarray analysis of calcium entry-deficient and control T cells shows that Ca2+ signals both activate and repress gene expression and are largely transduced through the phosphatase calcineurin. We demonstrate an elaborate network of signaling pathways downstream of the T cell receptor, explaining the complexity of changes in gene expression during T cell activation.
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PMID:Gene regulation mediated by calcium signals in T lymphocytes. 1127 2


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