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)

The effects of the immunosuppressive drugs cyclosporin A and FK 506 were studied on cells chronically infected with human immunodeficiency virus type 1 (HIV-1) as well as on uninfected and newly infected cells. When cells chronically infected with HIV-1 or with HIV-2 were cocultivated with uninfected cells in the presence of cyclosporin A or FK 506 there was a delay in the formation of syncytia and of cytopathic effects. This inhibitory effect was not due to decreased membrane expression of CD4. In addition, there was an approximately 100-fold reduction in the yield of infectious HIV-1 when the infected cells were grown in the presence of these drugs, a finding consistent with other evidence of decreased HIV expression. Both drugs were found to inhibit the growth of chronically infected cells at concentrations that did not inhibit the growth of the uninfected cells. These results, demonstrating that cyclosporin A and FK 506 interfere with HIV production and selectively inhibit the growth of infected cells, suggest that they may be useful in the treatment of this infection and indicate further cellular targets for antiviral agents.
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PMID:Inhibition of human immunodeficiency virus and growth of infected T cells by the immunosuppressive drugs cyclosporin A and FK 506. 138 9

Theoretically, drugs that inhibit programmed cell death could be used to inhibit the increased apoptotic decay of lymphocyte populations in human immunodeficiency virus (HIV) infection. The concept that immunopathologic processes cause immune suppression provides a further rationale for the use of agents such as cyclosporin A (CsA) or tacrolimus (formerly known as FK506) early in HIV infection to reduce cytotoxic CD8+ T cell-mediated destruction of HIV-infected target cells.
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PMID:Inhibition of T lymphocyte activation and apoptotic cell death by cyclosporin A and tacrolimus (FK506). Its relevance to therapy of HIV infection. 757 94

PTLD may be considered as an "opportunistic cancer" in which the immunodeficiency state of the host plays a key role in fostering the environment necessary for abnormal lymphoproliferation. The following discussion reflects our own current thoughts regarding events which may result in PTLD and its sequelae. Many of the individual steps have not been rigorously proved or disproved at this point in time. Following transplantation and iatrogenic immunosuppression, the host:EBV equilibrium is shifted in favor of the virus. Most seronegative patients will become infected either via the graft or through natural means; seropositive patients will begin to shed higher levels of virus and may become secondarily superinfected via the graft. There is a "grace" period of approximately one month posttransplant before increased viral shedding begins. PTLD is almost never seen during this interval. In many cases infection continues to be silent whereas in rare individuals there is an overwhelming polyclonal proliferation of infected B lymphocytes. This is the parallel of infectious mononucleosis occurring in patients with a congenital defect in virus handling (X-linked lymphoproliferative disorder). It is possible that transplant patients with this presentation also suffer a defect in virus handling. In other cases excessive iatrogenic immunosuppression may paralyze their ability to respond to the infection. With CsA and FK506 regimens, individual tumors may occur within a matter of months following transplant. The short time of incubation suggests that these are less than fully developed malignancies. It may be that local events conspire to allow outgrowth of limited numbers of B-lymphocyte clones. A cytokine environment favoring B-lymphocyte growth may be one factor and differential inhibition by the immuno-suppressive drugs of calcium-dependent and -independent B-cell stimulation may be another. In addition, there is some evidence that CsA itself may inhibit apoptosis within B cells. Since most patients do not develop PTLDs, an additional signal(s) for B-cell stimulation may be required. Indeed, it is possible that the virus may simply serve to lower the threshold for B-cell activation and/or provide a survival advantage to these cells. The ability of individual cell clones to evade a weakened immune system may set into play a Darwinian type of competition in which the most rapidly proliferating cells with the least number of antigenic targets predominate. In this regard, differences in host HLA types may determine the repertoire of viral antigens which are subject to attack.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Epstein-Barr virus, infectious mononucleosis, and posttransplant lymphoproliferative disorders. 780

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

Autoimmune enteropathy is characterized by chronic secretory diarrhea, villous atrophy, associated autoantibodies, and a partial response to immunosuppression. Currently available therapy (including steroids and cyclosporine) has resulted in remission only in a subset of patients. We evaluated the effects of tacrolimus (FK506) in patients with autoimmune enteropathy refractory to steroids and cyclosporine. Three patients with diagnosed autoimmune enteropathy who continued to have intractable diarrhea despite treatment with steroids and/or cyclosporine were treated with oral tacrolimus. Despite documented histological villous atrophy and poor absorption of oral cyclosporine, therapeutic tacrolimus levels were easily achieved in all 3 patients. All patients showed clinical improvement as documented by decreased stool output and ability to be weaned off parenteral nutrition; response time ranged from 1 to 4 months after tacrolimus was begun. Histological improvement was noted in all patients, and the small bowel biopsy specimens of 2 of the 3 patients showed a return to normal. All patients have been followed up for at least 6 months and are in clinical remission; 1 has received a bone marrow transplant for underlying immunodeficiency. Tacrolimus is a useful drug in the treatment of autoimmune enteropathy, even in patients who have not responded to steroids or cyclosporine. No long-term follow-up of patients with autoimmune enteropathy treated with tacrolimus is currently available.
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PMID:Treatment of pediatric autoimmune enteropathy with tacrolimus (FK506). 869 5

It has been shown that the combined use of two pharmacologic agents can inhibit human immunodeficiency virus (HIV) production by peripheral blood mononuclear cells in vitro. One, an anti-CD25 immunotoxin (IT), kills activated T cells that produce virus; the other, the immunosuppressive drug cyclosporine, prevents the quiescent cells, which harbor HIV, from becoming activated. The present study compares the antiviral activities of two agents, SDZ NIM811 and FK506, to that of cyclosporine. In combination with the anti-CD25 IT, these drugs significantly suppressed virus production. In the absence of prior addition of the IT, the ability of the drugs to inhibit virus production was much lower, suggesting that they work effectively in latently infected cells. In the case of SDZ NIM811, the inhibition of virus production was accompanied by a modest inhibition of cell proliferation. In contrast, FK506 exerted strong antiproliferative activity. Cyclosporine was both moderately antiproliferative and a potent antiviral agent.
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PMID:The use of cyclosporine, FK506, and SDZ NIM811 to prevent CD25- quiescent peripheral blood mononuclear cells from producing human immunodeficiency virus. 884 28

We report two cases of Kaposi's sarcoma (KS) after orthotopic liver transplantation for cirrhosis of the liver related to hepatitis C virus. Both cases were Saudi-born Arabs who were negative for human immunodeficiency virus; one patient was receiving FK506 plus prednisolone, and the other patient was receiving FK506. One patient died of fulminant multicentric KS. The other patient, with lesions confined to the lower limbs, is still alive. These are the first case reports of KS in liver transplant recipients in the Kingdom of Saudi Arabia and, to our knowledge, these are the first case reports of KS in liver transplant recipients on FK506. All previous reports were related to either cyclosporine or conventional immunosuppressive therapy, i.e., azathioprine plus prednisolone.
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PMID:Kaposi's sarcoma in liver transplant recipients on FK506: two case reports. 917 20

Polyclonal horse antilymphocyte and rabbit antithymocyte globulins (ATGs) are currently used in severe aplastic anemia and for the treatment of organ allograft acute rejection and graft-versus-host disease. ATG treatment induces a major depletion of peripheral blood lymphocytes, which contributes to its overall immunosuppressive effects. Several mechanisms that may account for lymphocyte lysis were investigated in vitro. At high concentrations (.1 to 1 mg/mL) ATGs activate the human classic complement pathway and induce lysis of both resting and phytohemagglutinin (PHA)-activated peripheral blood mononuclear cells. At low, submitogenic, concentration ATGs induce antibody-dependent cell cytotoxicity of PHA-activated cells, but not resting cells. They also trigger surface Fas (Apo-1, CD95) expression in naive T cells and Fas-ligand gene and protein expression in both naive and primed T cells, resulting in Fas/Fas-L interaction-mediated cell death. ATG-induced apoptosis and Fas-L expression were not observed with an ATG preparation lacking CD2 and CD3 antibodies. Susceptibility to ATG-induced apoptosis was restricted to activated cells, dependent on IL-2, and prevented by Cyclosporin A, FK506, and rapamycin. The data suggest that low doses of ATGs could be clinically evaluated in treatments aiming at the selective deletion of in vivo activated T cells in order to avoid massive lymphocyte depletion and subsequent immunodeficiency.
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PMID:Induction of Fas (Apo-1, CD95)-mediated apoptosis of activated lymphocytes by polyclonal antithymocyte globulins. 951 35

An in vitro model of acute and chronic infections with feline immunodeficiency virus (FIV) was used to examine the effect of two immunosuppressive agents, cyclosporin A (CsA) and tacrolimus (also known as FK506), on the inhibition of the replication of the virus and of apoptosis. Both drugs significantly suppressed virus production in a dose-dependent manner in acutely and chronically infected cells. The ability of FK506 to inhibit virus replication was much lower than that of CsA, and was accompanied by marked antiproliferative activity. Treatment of infected cells with either CsA or FK506 did not affect the rise of free intracellular Ca2+ but did protect the cells against apoptosis. Thus, the antiviral activity of CsA and FK506 makes these compounds promising candidates for the development of drugs suitable for the treatment of AIDS.
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PMID:The use of two immunosuppressive drugs, cyclosporin A and tacrolimus, to inhibit virus replication and apoptosis in cells infected with feline immunodeficiency virus. 1006 29

Cyclosporine A therapy for prophylaxis against graft rejection revolutionized human organ transplantation. The immunosuppressant drugs cyclosporin A (CsA), FK506 and rapamycin block T-cell activation by interfering with the signal transduction pathway. The target proteins for CsA and FK506 were found to be cyclophilins and FK506-binding proteins, (FKBPs), respectively. They are unrelated in primary sequence, although both are peptidyl-prolyl cis-trans isomerases catalyzing the interconversion of peptidylprolyl imide bonds in peptide and protein substrates. However, the prolyl isomerase activity of these proteins is not essential for their immunosuppressive effects. Instead, the specific surfaces of the cyclophilin-CsA and FKBP-FK506 complexes mediate the immunosuppressive action. Moreover, the natural cellular functions of all but a few remain elusive. In some cases it could be demonstrated that prolyl isomerization is the rate-limiting step in protein folding in vitro, but many knockout mutants of single and multiple prolyl isomerases were viable with no detectable phenotype. Even though a direct requirement for in vivo protein folding could not be demonstrated, some important natural substrates of the prolyl isomerases are now known, and they demonstrate the great variety of prolyl isomerization functions in the living cell: (i) A human cyclophilin binds to the Gag polyprotein of the human immunodeficiency virus-1 (HIV-1) virion and was found to be essential for infection with HIV to occur, probably by removal of the virion coat. (ii) Together with heat shock protein (HSP) 90, a member of the chaperone family, high molecular weight cyclophilins and FKBPs bind and activate steroid receptors. This example also demonstrates that prolyl isomerases act together with other folding enzymes, for example the chaperones, and protein disulfide isomerases. (iii) An FKBP was found to act as a modulator of an intracellular calcium release channel. (iv) Along with the cyclophilins and FKBPs, a third class of prolyl isomerases exist, the parvulins. The human parvulin homologue Pin1 is a mitotic regulator essential for the G2/M transition of the eukaryotic cell cycle. These findings place proline isomerases at the intersection of protein folding, signal transduction, trafficking, assembly and cell cycle regulation.
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PMID:Peptidyl-prolyl cis-trans isomerases, a superfamily of ubiquitous folding catalysts. 1022 56


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