Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0032285 (pneumonia)
 54,520 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We previously demonstrated that hematopoietic cell protein-tyrosine phosphatase is one of the molecules that can transduce Fas-mediated apoptosis signals in lymphoid cells. The present study analyzed the effect of defective Fas signaling on the T cell phenotype and apoptosis function in hematopoietic cell protein-tyrosine phosphatase-deficient motheaten mice. Viable motheaten (me(v)/me(v)) mice exhibited increased T cell proliferation and defective activation-induced apoptosis of Fas+ T cells in the lymph node, which was not ascribed to defective Fas ligand function. Furthermore, the Fas-mediated apoptosis defect in activated T cells from me(v)/me(v) mice was confirmed by their resistance to anti-Fas-induced apoptosis. No protein tyrosine dephosphorylation signal was delivered after anti-Fas cross-linking in the lymph node cells of me(v)/me(v) mice as revealed by 32Pi labeling of protein phosphatase substrates. The defective activation-induced apoptosis of Fas+ T cells in me(v)/me(v) mice led to lymphadenopathy with an accumulation of CD4- CD8- B220+ CD3+ T cells. Pneumonitis in me(v)/me(v) mice was associated with infiltration of cycling T cells detected by bromodeoxyuridine uptake in vivo. Thus, T cells from me(v)/me(v) mice are resistant to Fas-mediated apoptosis which results in lymphoproliferative disease and tissue infiltration.
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PMID:Hematopoietic cell protein-tyrosine phosphatase-deficient motheaten mice exhibit T cell apoptosis defect. 866 88

Rapamycin is an immunosuppressive drug with a distinct and unique mode of action and a specific side effect profile. We report here briefly on our personal clinical experience using this immunosuppressive drug in different combinations and settings. Rapamycin is without any doubt an efficient drug capable of preventing acute allograft rejection in a variety of immunosuppressive combinations. It is also a very potent drug that is not devoid of serious side effects. Infectious complications as a result of strong inhibition of the immune system are a frequent cause of hospitalization with severe morbidity and even mortality. Fungal infections and pneumonia are among the most devastating complications. As clinical experience with rapamycin grows and the therapeutic window of the drug can be further narrowed, these infectious complications will improve. Wound healing problems and lymphocoeles form another frequent surgical dilemma and are related to the antiproliferative properties of rapamycin. Last, hyperlipidemia warrants the use of statins in the majority of rapamycin-treated patients and whether this unfavorable side effect will offset the theoretically beneficial cardiovascular effects of the drug remains to be determined in controlled trials with long-term follow-up. Finally, the specific antiproliferative properties of rapamycin and the fact that it exerts no nephrotoxicity make this drug an alternative for calcineurin inhibitors and could make it an ideal candidate for treating chronic allograft dysfunction.
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PMID:Clinical use of rapamycin in renal allograft recipients identifies its relevant toxicity profile and raises unsolved questions: a single-center experience. 1274 86

During the past decade, numerous Mn2+-dependent protein serine, threonine and/or tyrosine phosphatases (O-phosphatases) from prokaryotes have been characterized. Based on their amino acid sequences, they belong to PPP, PPM or PHP superfamilies. Both the PPP and PPM families of protein phosphatases are metalloenzymes which active centers contain two metal ions that function as cofactors. Results from sequence analysis also suggest that PHP family protein phosphatase is a metalloenzyme. The identified functions for PPP family protein phosphatases from different prokaryotic organisms include regulation of stress-response, nitrogen fixation and vegetative growth. At least one phosphatase, PrpB from Escherichia coli, is also implicated in bacterial pathogenesis. Prokaryotic PPM family protein phosphatases are involved in controlling spore formation, stress-response, cell density during stationary phase, carbon and nitrogen assimilation, vegetative growth, development of fruiting bodies and cell segregation. The function of CpsB, a PHP family protein tyrosine phosphatase from Streptococcus pneumonia, is to regulate biosynthesis of capsular polysaccharide, an important virulence determinant. Thus, this group of functionally diverse protein phosphatases plays an important role in prokaryotes. Discovery of Mn2+-dependent prokaryotic protein O-phosphatases and their functions also contributes to new insight into Mn2+ homeostasis and many roles played by Mn2+ and protein O-phosphorylation in prokaryotic cells.
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PMID:Manganese-dependent protein O-phosphatases in prokaryotes and their biological functions. 1497 54

Sirolimus (rapamycin) is a macrocyclic lactone isolated from a strain of Streptomyces hygroscopicus that inhibits the mammalian target of rapamycin (mTOR)-mediated signal-transduction pathways, resulting in the arrest of cell cycle of various cell types, including T- and B-lymphocytes. Sirolimus has been demonstrated to prolong graft survival in various animal models of transplantation, ranging from rodents to primates for both heterotopic, as well as orthotopic organ grafting, bone marrow transplantation and islet cell grafting. In human clinical renal transplantation, sirolimus in combination with ciclosporin (cyclosporine) efficiently reduces the incidence of acute allograft rejection. Because of the synergistic effect of sirolimus on ciclosporin-induced nephrotoxicity, a prolonged combination of the two drugs inevitably leads to progressive irreversible renal allograft damage. Early elimination of calcineurin inhibitor therapy or complete avoidance of the latter by using sirolimus therapy is the optimal strategy for this drug. Prospective randomised phase II and III clinical studies have confirmed this approach, at least for recipients with a low to moderate immunological risk. For patients with a high immunological risk or recipients exposed to delayed graft function, sirolimus might not constitute the best therapeutic choice--despite its ability to enable calcineurin inhibitor sparing in the latter situation--because of its anti-proliferative effects on recovering renal tubular cells. Whether lower doses of sirolimus or a combination with a reduced dose of tacrolimus would be advantageous in these high risk situations remains to be determined. Clinically relevant adverse effects of sirolimus that require a specific therapeutic response or can potentially influence short- and long-term patient morbidity and mortality as well as graft survival include hypercholesterolaemia, hypertriglyceridaemia, infectious and non-infectious pneumonia, anaemia, lymphocele formation and impaired wound healing. These drug-related adverse effects are important determinants in the choice of a tailor-made immunosuppressive drug regimen that complies with the individual patient risk profile. Equally important in the latter decision is the lack of severe intrinsic nephrotoxicity associated with sirolimus and its advantageous effects on arterial hypertension, post-transplantation diabetes mellitus and esthetic changes induced by calcineurin inhibitors. Mild and transient thrombocytopenia, leukopenia, gastrointestinal adverse effects and mucosal ulcerations are all minor complications of sirolimus therapy that have less impact on the decision for choosing this drug as the basis for tailor-made immunosuppressive therapy. It is clear that sirolimus has gained a proper place in the present-day immunosuppressive armament used in renal transplantation and will contribute to the development of a tailor-made immunosuppressive therapy aimed at fulfilling the requirements outlined by the individual patient profile.
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PMID:Benefit-risk assessment of sirolimus in renal transplantation. 1569 Dec 25

Recently, we have used an anti-T-cell agent, alemtuzumab, as induction or conversion therapy to achieve a calcineurin (CNI) and steroid-free immunosuppressive regimen. We identified recipients who developed systemic fungal infections after the initiation of alemtuzumab and looked at their outcomes. The study population consisted of all pancreas transplant recipients who received alemtuzumab. Only invasive fungal infections were included in the analysis (eg, fungemia, meningitis, or pneumonia; fungal urinary tract infections were excluded). The organism was confirmed by culture, histopathology, or latex antigen test. Between February 2003 and February 2004, a total of 121 pancreas transplant recipients received alemtuzumab-56 as part of induction, and 65 as part of conversion. Of these, 8 (6.6%) developed an invasive fungal infection; 2 (3.6%) recipients as part of induction therapy and 6 (9.2%) as part of conversion therapy. Mean recipient age was 42.1 years. The mean length of time from alemtuzumab administration (first dose) to the diagnosis of the fungal infection was 115.9 days (range 5 to 318). The organisms identified initially were: Cryptococcus, Histoplasma, Aspergillus, and Candida. Overall, 3 (38%) of the eight patients died during ongoing treatment of their fungal infection: two from sepsis, one due to myocardial infarction. The other five recipients were treated successfully and have functioning grafts. The initial therapeutic agents used included: amphotericin B/liposomal AMB (n = 6), voriconazole (n = 3), capsofungin (n = 2), and fluconazole (n = 1). The use of alemtuzumab as induction or conversion therapy in pancreas transplant recipients may predispose patients to the development of systemic fungal infections. It would be important to determine what the most appropriate prophylaxis regimen would be for these patients.
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PMID:Fungal infections in transplant recipients receiving alemtuzumab. 1584 79

Cyclosporin A (CsA) blocks T cell activation by interfering with the Ca2+-dependent phosphatase, calcineurin. Proinflammatory responses to bacteria that are activated by Ca2+-fluxes in airway cells are a potential target for CsA. Although local immunosuppression may be advantageous to control airway inflammation, it could also increase susceptibility to bacterial pneumonia and invasive infection. As aerosolized CsA is currently under study in lung transplantation, we examined its direct effects on airway cells as well as in a murine model of pneumonia. Epithelial interleukin-6 production was very effectively inhibited by CsA, whereas CXCL8 production, the major PMN chemokine, was only modestly diminished. Responses to a TLR2 agonist Pam3Cys were more sensitive to CsA inhibition than those activated by Pseudomonas aeruginosa. CsA substantially blocked activation of nuclear factor of activated T cells and cAMP-responsive element-binding protein (P<0.001), inhibited CCAAT/enhancer-binding protein by 50% (P<0.05), and minimally blocked activator protein-1 and nuclear factor-kappaB responses to bacteria in epithelial cells. The in vitro effects were confirmed in a mouse model of P. aeruginosa infection with similar rates of PMN recruitment, pneumonia and mortality in CsA treated and control mice. These studies indicate that airway epithelial signaling is a potential target for CsA, and such local immunosuppression may not increase susceptibility to invasive infection.
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PMID:The effect of cyclosporin A on airway cell proinflammatory signaling and pneumonia. 1587 61

While bronchiolitis obliterans organizing pneumonia (BOOP) has been associated with the use of sirolimus (SIR), the incidence in a consecutive group of patients given SIR to replace a calcineurin-inhibitor (CI) is unknown. Twenty-nine consecutive cardiac transplant recipients were switched from a CI to SIR to ameliorate CI-associated nephropathy or coronary graft atherosclerosis. Seven patients (24%) developed BOOP. The clinical characteristics and biopsy results of these patients are presented. The clinical course and response to withdrawal of SIR in all and steroids in four of seven patients suggested the diagnosis of BOOP. Chest X-rays and CT scans showed typical findings of BOOP in all seven patients. Infection was excluded in all patients. Biopsy results were characteristic of BOOP in six of seven patients. Six patients recovered and one died. BOOP is a common and potentially serious adverse event in cardiac transplant patients switched from a CI to SIR, especially when SIR is started late post-transplantation.
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PMID:BOOP is common in cardiac transplant recipients switched from a calcineurin inhibitor to sirolimus. 1588 46

Enormous advancements in visceral transplantation have led to significant improvements in the quality of life of patients. However, despite these developments, the average graft half-life after transplantation has remained almost unchanged and chronic rejection is still considered a major problem. In this regard, more concerns have shifted to factors influencing long-term graft survival, patient survival, and quality of life. To achieve this goal, detrimental effects of immunosuppressive (IS) agents, which have deleterious influence on the quality of life and/or patient survival, should be reduced. In the course of recent years, the transplant community has worked on reducing these side effects by developing new ISs, employing new combination regimens, or finding and adjusting optimal dosages and blood level concentrations. Among the IS agents, the antifungal, antitumoral and IS activity of mammalian target of rapamycin (mTOR) inhibitors without nephrotoxicity, have received special attention regarding this new class of IS. Sirolimus (SRL), as the first member of mTOR inhibitors, has been utilized in many clinical trials with respect to its benefit-risk assessment. In our review, the clinical evolution of SRL, as well as the evidence-based clinical benefits of SRL in kidney and liver transplantation (KTx, LTx), are summarized. Various studies of SRL in KTx and LTx have shown that combination therapy with SRL will enrich the variety of IS modalities. It also can be regarded as a safe base therapy to which other necessary drugs can be added. In addition to the enhanced acute rejection prophylaxis, and in contrast to the calcineurin inhibitors (CNI) and steroids, this drug solely does not have common side effects such as nephrotoxicity, neurotoxicity, diabetes mellitus and hypertension. Moreover, this agent might diminish vasculopathic processes that mediate chronic allograft nephropathy (CAN). Therefore, by reducing the likelihood of CAN it can decrease the rate of long-term organ failure. One possibly desirable characteristic of SRL is its antiproliferative effect, which could provoke antitumoral or antiatherogenic activity following transplantation. Despite all promising impacts of SRL in organ transplantation, there are some concerns regarding the adverse effects of this drug, for instance dyslipidemia, pneumonitis and wound healing problems. However, the majority of these side effects can be reduced or ceased by careful dose adjustments and correct timing of use. In conclusion, after a decade of both in vivo and in vitro studies on SRL, it can be advocated that SRL is a promising, potent and effective IS agent as it reduces the rate of acute rejection episodes in de novo transplants. It could improve the quality of life, graft and patient survival rate, and achieve excellent outcomes with few adverse effects when wisely used in combination with other immunosuppressants.
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PMID:The role and value of sirolimus administration in kidney and liver transplantation. 1710 Jun 99

Sirolimus is a potent immunosuppressive drug that began to be used in the last few years. This drug was initially used in renal transplantation but its use in other solid organ transplantations such as liver, heart, lung and pancreas, has been increasing. Sirolimus is indicated in rescue therapies and to reduce the secondary toxic effects of calcineurin inhibitors. However, this drug has been associated with infrequent but severe pulmonary toxicity and cases of interstitial pneumonitis, bronchiolitis obliterans with organizing pneumonia, and alveolar proteinosis have been described. We present the case of a male liver transplant recipient who developed interstitial pneumonitis associated with sirolimus use.
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PMID:[Pulmonary toxicity associated with sirolimus therapy in liver transplantation]. 1719 38

Sirolimus is a mammalian target of rapamycin (mTOR) inhibitor that inhibits cell cycle progression and has proven to be a potent immunosuppressive agent for use in solid organ transplant recipients. The drug was initially studied as an adjunct to ciclosporin (cyclosporine) to prevent acute rejection in kidney transplant recipients. Subsequent studies have shown efficacy when combined with a variety of other immunosuppressive agents. The most common adverse effects of sirolimus are hyperlipidaemia and myelosuppression. The drug has unique antiatherogenic and antineoplastic properties, and may promote immunological tolerance and reduce the incidence of chronic allograft nephropathy. Although sirolimus is relatively non-nephrotoxic when administered as monotherapy, it pharmacodynamically enhances the toxicity of calcineurin inhibitors. Ironically, the drug has been used to facilitate calcineurin inhibitor-free protocols designed to preserve renal function after solid organ transplantation. Whether sirolimus can be used safely over the long term with low doses of calcineurin inhibitors requires further study. The use of sirolimus as a corticosteroid-sparing agent also remains to be proven in controlled trials. Postmarketing studies have revealed a number of unforeseen adverse effects including impaired wound healing and possibly proteinuria, oedema, pneumonitis and thrombotic microangiopathy. Overall, sirolimus is a powerful agent when used judiciously with other available immunosuppressants. As is true for all immunosuppressive drugs available for treatment of solid organ transplant recipients, the efficacy of the drug must be balanced against its considerable adverse effects.
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PMID:Use of sirolimus in solid organ transplantation. 1733 96


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