sirolimus and Hypersensitivity

Recent publications on drug-eluting stents (DES) report a significant reduction in restenosis rates as compared to bare metal stents in patients mostly with single vessel disease. We have recently observed however, late stent thrombosis following CYPHER DES implantation. The patient developed a hypersensitivity reaction around stent struts limited to the polymer with aneurysmal dilatation and extensive inflammation of the arterial wall in the absence of vascular healing. This incidence promotes a cautionary view and perhaps supports the use of DES only in high-risk patients.

Topics: Animals; Coronary Restenosis; Device Approval; Humans; Hypersensitivity; Immunosuppressive Agents; Paclitaxel; Polymers; Sirolimus; Stents; Thrombosis; United States; Wound Healing

Metallic allergy is associated with restenosis following bare metal stent implantation, but the impact of metallic allergy on the outcome after implantation of drug-eluting stents (DES) has not been investigated.. The present study group consisted of 88 consecutive patients (109 lesions) who underwent percutaneous coronary intervention with sirolimus-eluting stents (SES). Follow-up angiography was obtained at 8 months in all patients. At that time, the patients underwent epicutaneous patch tests for nickel, chromate, molybdenum, manganese, and titanium, which were evaluated after 48 h of contact. The patch test was positive in 14 patients (16%) (5 for manganese, 3 for nickel, 1 for chromate, 1 for Nickel and manganese, and 4 for manganese and chromate). The binary restenosis rate in the patients with a positive patch test was similar to those with negative patch test (6.3% vs 6.5%, p=0.98). Serial quantitative coronary angiography analyses identified no significant differences in late lumen loss of in-stent segments between patients with positive patch test and those with negative patch test (0.19+/-0.49 mm vs 0.12+/-0.48 mm, p=0.55).. SES prevent restenosis irrespective of metallic allergy. The classic relationship between metallic allergy and in-stent restenosis, seen with bare metal stents, does not appear to arise with DES, possibly because of the immunosuppressive effect of sirolimus.

Topics: Aged; Angioplasty, Balloon, Coronary; Chromates; Coronary Angiography; Coronary Artery Disease; Coronary Restenosis; Drug-Eluting Stents; Female; Follow-Up Studies; Humans; Hypersensitivity; Immunosuppressive Agents; Male; Manganese; Metals; Middle Aged; Molybdenum; Nickel; Patch Tests; Sirolimus; Titanium; Treatment Outcome; Tunica Intima

Bladder disorders associated with interstitial cystitis are frequently characterized by increased contractility and pain. The purposes of this study were to examine (1) the effects of blocking mammalian target of rapamycin (mTOR) on the exaggerated bladder activity and pain evoked by cystitis and (2) the underlying mechanisms responsible for the role of mTOR in regulating cystic sensory activity.. The expression of p-mTOR, mTOR-mediated phosphorylation of p70 ribosomal S6 protein kinase 1 (p-S6K1), 4 E-binding protein 4 (p-4 E-BP1), as well as phosphatidylinositide 3-kinase (p-PI3K) pathway were amplified in cyclophosphamide rats as compared with control rats. Blocking mTOR by intrathecal infusion of rapamycin attenuated bladder hyperactivity and pain. In addition, blocking PI3K signal pathway attenuated activities of mTOR, which was accompanied with decreasing bladder hyperactivity and pain. Inhibition of either mTOR or PI3K blunted the enhanced spinal substance P and calcitonin gene-related peptide in cyclophosphamide rats.. The data for the first time revealed specific signaling pathways leading to cyclophosphamide-induced bladder hyperactivity and pain, including the activation of mTOR and PI3K. Inhibition of these pathways alleviates cystic pain. Targeting one or more of these signaling molecules may present new opportunities for treatment and management of overactive bladder and pain often observed in cystitis.

Topics: Animals; Calcitonin Gene-Related Peptide; Chromones; Cyclophosphamide; Cystitis; Disease Models, Animal; Enzyme Inhibitors; Female; Hypersensitivity; Immunosuppressive Agents; Morpholines; Pain; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Sirolimus; Urinary Bladder

The mammalian target of rapamycin (mTOR) signalling pathway regulates immune responses, and promotes cell growth and differentiation. Inhibition of mTOR with rapamycin modulates allergic asthma, while the underlying molecular mechanisms remain elusive. Here, we demonstrate that rapamycin, effectively inhibits eosinophil differentiation, contributing to its overall protective role in allergic airway inflammation.. Rapamycin was administered in a mouse model of ovalbumin-induced allergic airway inflammation, and the eosinophil differentiation was analysed in vivo and in vitro.. Rapamycin significantly attenuated allergic airway inflammation and markedly decreased the amount of eosinophils in local airways, peripheral blood and bone marrow, independently of levels of interleukin-5 (IL-5). In vitro colony forming unit assay and liquid culture demonstrated that rapamycin directly inhibited IL-5-induced eosinophil differentiation. In addition, rapamycin reduced the production of IL-6 and IL-13 by eosinophils. Rapamycin was also capable of reducing the eosinophil levels in IL-5 transgenic NJ.1638 mice, again regardless of the constitutive high levels of IL-5. Interestingly, rapamycin inhibition of eosinophil differentiation in turn resulted in an accumulation of eosinophil lineage-committed progenitors in bone marrow.. Altogether these results clearly demonstrate a direct inhibitory role of rapamycin in eosinophil differentiation and function, and reemphasize the importance of rapamycin and possibly, mTOR, in allergic airway disease.

Topics: Animals; Asthma; Cell Differentiation; Disease Models, Animal; Eosinophils; Hypersensitivity; Immunosuppressive Agents; Inflammation; Interleukins; Leukocyte Count; Mice; Mice, Inbred BALB C; Mice, Transgenic; Ovalbumin; Serine Proteinase Inhibitors; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Rapamycin has been reported to inhibit mesenchymal cell proliferation in a murine model of pulmonary fibrosis. In the present study, we examined the effects of rapamycin on vascular remodeling including intraluminal myofibroblast proliferation in a murine model of allergic vasculitis with eosinophil infiltration.. C57BL/6 mice were sensitized with ovalbumin (OVA) and alum. The positive controls were exposed to aerosolized OVA daily for 7 days. The other group of mice was administered with rapamycin (1mg/kg) intraperitoneally, in parallel with daily exposure to aerosolized OVA for 7 days. On the 3rd and 7th day, bronchoalveolar lavage (BAL) was performed and the lungs were excised for pathological analysis. Cell differentials were determined and concentrations of IL-4, IL-5, IL-13 and TGF-β in the BAL fluid (BALF) were measured. Semi-quantitative analysis of pathological changes in the pulmonary arteries was evaluated according to the severity of vasculitis.. The number of eosinophils in BALF was reduced significantly in the mice treated with rapamycin compared to the positive control. There was a significant decrease in the TGF-β concentration of the BALF in the rapamycin-treated group compared to that of the positive control. The pathological scores were reduced significantly in the rapamycin-treated group compared to the positive control group. Intraluminal myofibroblasts in pulmonary arteries were reduced dramatically in the rapamycin-treated group compared to the positive control group.. Rapamycin suppressed pulmonary vascular remodeling in a murine model of allergic vasculitis with eosinophil infiltration through reducing eosinophil infiltration and TGF-β production in the lung and inhibition against biological action of TGF-β.

Topics: Animals; Cell Proliferation; Disease Models, Animal; Disease Progression; Eosinophils; Female; Humans; Hypersensitivity; Immunosuppressive Agents; Lung Diseases; Mice; Mice, Inbred C57BL; Myofibroblasts; Pulmonary Artery; Sirolimus; Transforming Growth Factor beta; Vascular Remodeling; Vasculitis

Rapamycin-induced translocation systems can be used to manipulate biological processes with precise temporal control. These systems are based on rapamycin-induced dimerization of FK506 Binding Protein 12 (FKBP12) with the FKBP Rapamycin Binding (FRB) domain of mammalian target of rapamycin (mTOR). Here, we sought to adapt a rapamycin-inducible phosphatidylinositol 4,5-bisphosphate (PIP2)-specific phosphatase (Inp54p) system to deplete PIP2 in nociceptive dorsal root ganglia (DRG) neurons.. We genetically targeted membrane-tethered CFP-FRBPLF (a destabilized FRB mutant) to the ubiquitously expressed Rosa26 locus, generating a Rosa26-FRBPLF knockin mouse. In a second knockin mouse line, we targeted Venus-FKBP12-Inp54p to the Calcitonin gene-related peptide-alpha (CGRPα) locus. We hypothesized that after intercrossing these mice, rapamycin treatment would induce translocation of Venus-FKBP12-Inp54p to the plasma membrane in CGRP+ DRG neurons. In control experiments with cell lines, rapamycin induced translocation of Venus-FKBP12-Inp54p to the plasma membrane, and subsequent depletion of PIP2, as measured with a PIP2 biosensor. However, rapamycin did not induce translocation of Venus-FKBP12-Inp54p to the plasma membrane in FRBPLF-expressing DRG neurons (in vitro or in vivo). Moreover, rapamycin treatment did not alter PIP2-dependent thermosensation in vivo. Instead, rapamycin treatment stabilized FRBPLF in cultured DRG neurons, suggesting that rapamycin promoted dimerization of FRBPLF with endogenous FKBP12.. Taken together, our data indicate that these knockin mice cannot be used to inducibly deplete PIP2 in DRG neurons. Moreover, our data suggest that high levels of endogenous FKBP12 could compete for binding to FRBPLF, hence limiting the use of rapamycin-inducible systems to cells with low levels of endogenous FKBP12.

Topics: Animals; Biosensing Techniques; Calcitonin Gene-Related Peptide; Cell Membrane; Cells, Cultured; Ganglia, Spinal; HEK293 Cells; Heterozygote; Humans; Hypersensitivity; Inflammation; Inositol Phosphates; Mice; Models, Biological; Neurons; Peptides; Phosphoprotein Phosphatases; Protein Transport; Rats; Recombinant Fusion Proteins; Sensory Receptor Cells; Sirolimus; Tacrolimus Binding Protein 1A

The mammalian target of rapamycin (mTOR) plays an important role in cell growth/differentiation, integrating environmental cues, and regulating immune responses. Our lab previously demonstrated that inhibition of mTOR with rapamycin prevented house dust mite (HDM)-induced allergic asthma in mice. Here, we utilized two treatment protocols to investigate whether rapamycin, compared to the steroid, dexamethasone, could inhibit allergic responses during the later stages of the disease process, namely allergen re-exposure and/or during progression of chronic allergic disease. In protocol 1, BALB/c mice were sensitized to HDM (three i.p. injections) and administered two intranasal HDM exposures. After 6 weeks of rest/recovery, mice were re-exposed to HDM while being treated with rapamycin or dexamethasone. In protocol 2, mice were exposed to HDM for 3 or 6 weeks and treated with rapamycin or dexamethasone during weeks 4-6. Characteristic features of allergic asthma, including IgE, goblet cells, airway hyperreactivity (AHR), inflammatory cells, cytokines/chemokines, and T cell responses were assessed. In protocol 1, both rapamycin and dexamethasone suppressed goblet cells and total CD4(+) T cells including activated, effector, and regulatory T cells in the lung tissue, with no effect on AHR or total inflammatory cell numbers in the bronchoalveolar lavage fluid. Rapamycin also suppressed IgE, although IL-4 and eotaxin 1 levels were augmented. In protocol 2, both drugs suppressed total CD4(+) T cells, including activated, effector, and regulatory T cells and IgE levels. IL-4, eotaxin, and inflammatory cell numbers were increased after rapamycin and no effect on AHR was observed. Dexamethasone suppressed inflammatory cell numbers, especially eosinophils, but had limited effects on AHR. We conclude that while mTOR signaling is critical during the early phases of allergic asthma, its role is much more limited once disease is established.

Topics: Animals; Asthma; Bronchoalveolar Lavage Fluid; CD4-Positive T-Lymphocytes; Dexamethasone; Disease Models, Animal; Goblet Cells; Hypersensitivity; Immunoglobulin G; Inflammation; Interleukin-4; Mice; Pyroglyphidae; Sirolimus; TOR Serine-Threonine Kinases

Presence of allergy to iodinated contrast may prevent percutaneous coronary intervention (PCI) to be performed. We present a 76-year-old male with a history of allergic reaction to iodinated contrast who successfully underwent intravascular ultrasound (IVUS) and a Doppler guidewire-guided PCI. Stent size was determined based on IVUS. After PCI, stent expansion and a lack of edge dissection or incomplete apposition were confirmed by IVUS and a good antegrade coronary flow was confirmed by a Doppler guidewire. Thus, PCI without contrast injection under IVUS and a Doppler guidewire-guidance may be feasible in selected patients with allergy to iodinated contrast.

Topics: Aged; Angina, Unstable; Angioplasty, Balloon, Coronary; Contraindications; Contrast Media; Coronary Restenosis; Drug-Eluting Stents; Everolimus; Humans; Hypersensitivity; Iodine; Male; Sirolimus; Treatment Outcome; Ultrasonography, Doppler; Ultrasonography, Interventional

The mammalian target of rapamycin (mTOR) signaling pathway integrates environmental cues, promotes cell growth/differentiation, and regulates immune responses. Although inhibition of mTOR with rapamycin has potent immunosuppressive activity, mixed effects have been reported in OVA-induced models of allergic asthma. We investigated the impact of two rapamycin treatment protocols on the major characteristics of allergic asthma induced by the clinically relevant allergen, house dust mite (HDM). In protocol 1, BALB/c mice were exposed to 10 intranasal HDM doses over a period of 24 d and treated with rapamycin simultaneously during the sensitization/exposure period. In protocol 2, rapamycin was administered after the mice had been sensitized to HDM (i.p. injection) and prior to initiation of two intranasal HDM challenges over 4 d. Airway hyperreactivity (AHR), IgE, inflammatory cells, cytokines, leukotrienes, goblet cells, and activated T cells were assessed. In protocol 1, rapamycin blocked HDM-induced increases in AHR, inflammatory cell counts, and IgE, as well as attenuated goblet cell metaplasia. In protocol 2, rapamycin blocked increases in AHR, IgE, and T cell activation and reduced goblet cell metaplasia, but it had no effect on inflammatory cell counts. Increases in IL-13 and leukotrienes were also blocked by rapamycin, although increases in IL-4 were unaffected. These data demonstrated that rapamycin can inhibit cardinal features of allergic asthma, including increases in AHR, IgE, and goblet cells, most likely as a result of its ability to reduce the production of two key mediators of asthma: IL-13 and leukotrienes. These findings highlight the importance of the mTOR pathway in allergic airway disease.

Topics: Animals; Asthma; Blotting, Western; Bronchial Hyperreactivity; Cell Separation; Cytokines; Disease Models, Animal; Female; Flow Cytometry; Goblet Cells; Hypersensitivity; Immunoglobulin E; Immunohistochemistry; Immunosuppressive Agents; Mice; Mice, Inbred BALB C; Pyroglyphidae; Real-Time Polymerase Chain Reaction; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Topics: Drug-Eluting Stents; Equipment Design; Everolimus; Humans; Hypersensitivity; Immunosuppressive Agents; Nickel; Paclitaxel; Sirolimus; Thrombosis

Topics: Angioplasty, Balloon, Coronary; Cardiovascular Agents; Drug-Eluting Stents; Everolimus; Humans; Hypersensitivity; Myocardial Infarction; Paclitaxel; Prosthesis Design; Sirolimus; Syndrome; Thrombosis; Treatment Outcome

(1) Angioplasty is one method of unblocking a stenosed coronary artery. A metal stent is sometimes placed in the vessel lumen. Drug-eluting stents coated with an immunosuppressant or cytotoxic drug have been developed with the objective of reducing the risk of recurrent stenosis; (2) We examined the available literature on the efficacy and adverse effects of drug-eluting stents, based on the standard Prescrire methodology; (3) We found a plethora of clinical trials of drug-eluting stents, and numerous meta-analyses, reflecting the broad economic implications of the market for these devices. Yet drug-eluting stents appear to be no more effective than bare metal stents in reducing overall morality, cardiac mortality, the risk of myocardial infarction, or stent thrombosis. Few follow-up data are available beyond 4 years; (4) Revascularisation of the treated coronary artery was about half as frequent with drug-eluting stents as with bare metal stents. However, the apparent advantage is difficult to quantify because in some trials the decision to re-operate was based solely on angiographic criteria, leading to more frequent revascularization. Sirolimus-eluting stents appear to be slightly more effective than paclitaxel-eluting stents in terms of the revascularisation rate; (5) In contrast, late thrombosis (more than a year after stent placement) seems to be more frequent with drug-eluting stents than with bare metal stents. This risk can be reduced by long-term antiplatelet treatment (with clopidogrel plus aspirin), but the benefit is offset by the accompanying increased risk of severe haemorrhagic events. Serious allergic reactions have also been reported; (6) In most cases, especially when the risk of restenosis is low or moderate, it is better to use a bare metal stent. Coronary artery bypass grafting should be considered when there is a high risk of restenosis. Drug-eluting stents are just one alternative to surgery.

Topics: Angina, Unstable; Angioplasty, Balloon; Angioplasty, Balloon, Coronary; Clinical Trials as Topic; Coated Materials, Biocompatible; Coronary Angiography; Coronary Artery Bypass; Coronary Restenosis; Coronary Stenosis; Drug-Eluting Stents; Humans; Hypersensitivity; Meta-Analysis as Topic; Myocardial Infarction; Myocardial Revascularization; Paclitaxel; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Sirolimus; Thrombosis; Ticlopidine; Treatment Outcome

Topics: Alloys; Cardiovascular Agents; Clinical Trials as Topic; Coronary Restenosis; Drug-Eluting Stents; Humans; Hypersensitivity; Incidence; Paclitaxel; Platelet Aggregation Inhibitors; Risk Factors; Sirolimus; Thrombosis; Time Factors

A 74-year-old woman presented with effort-induced chest pain. Diagnostic coronary angiography revealed three-vessel disease. A successful angioplasty was performed with two sirolimus-eluting stents placed in the left anterior descending artery (LAD) and left circumflex artery (LCX). The right coronary artery (RCA) was treated with a bare-metal stent. Follow-up angiography and intravascular ultrasound (IVUS) assessment were performed 8 months later, which showed late stent malapposition (LSM) with marked positive vascular remodeling around the drug-eluting stents (DES) in both LAD and LCX lesions, but there was no evidence of ectatic area around the BMS in the RCA lesion. Compared with the baseline IVUS, a significant increase in external elastic membrane (EEM) cross-sectional area was found. Twenty-seven months later, we performed repeat follow-up angiography. Intravascular ultrasound still showed vessel malapposition. A previous report showed that aneurysmal dilatation of the stented segment with severe localized hypersensitivity reaction could be a potential cause of late thrombosis after DES implantation. If LSM is related to hypersensitivity of the DES, it may have a potential risk of adverse events. Although there is a paucity of data regarding malapposition as the cause of adverse events, careful long-term follow-up of patients with vessel enlargement after DES placement is recommended.

Topics: Aged; Angioplasty, Balloon, Coronary; Cardiovascular Agents; Coronary Angiography; Coronary Artery Disease; Drug-Eluting Stents; Female; Humans; Hypersensitivity; Metals; Prosthesis Design; Severity of Illness Index; Sirolimus; Stents; Time Factors; Treatment Outcome; Ultrasonography, Interventional

Topics: Aged; Coronary Restenosis; Drug-Eluting Stents; Female; Humans; Hypersensitivity; Male; Manganese; Metals; Sirolimus; Syndrome

Topics: Coronary Vessels; Drug Hypersensitivity; Humans; Hypersensitivity; Paclitaxel; Sirolimus; Stents

We report on a 30-year-old man, with type 1 diabetes mellitus, who developed generalized allergy to insulin consisting of several bouts of tremor, tachycardia, breathlessness and syncope. Strong positive reactions to protamine and metacresol were demonstrated by skin-prick testing. Symptoms persisted despite the use of antihistamine therapy, Actrapid HM Paraben and Monotard (insulin without protamine and metacresol) and immunosuppression (tacrolimus). He underwent a cadaver pancreas transplantation with portal-enteric drainage in June 2003. Following the antithymocyte globulin induction, immunosuppression consisted in tacrolimus and sirolimus without steroids. The patient subsequently reported a complete resolution of his symptoms and excellent glycaemic control. Thirteen months after transplantation, the patient developed oral ulcerations and severe leucopoenia initially attributed to sirolimus, which was subsequently stopped. A hyperglycaemic episode following corticosteroid therapy for acute rejection therapy required the reintroduction of insulin. Allergic manifestations reappeared promptly. Currently, 2 years after transplantation, the patient is euglycaemic without insulin (glycated haemoglobin 5.8%) and he is free of allergic reactions.

Topics: Adult; Diabetes Mellitus, Type 1; Homeostasis; Humans; Hypersensitivity; Hypersensitivity, Immediate; Immunosuppressive Agents; Insulin; Insulin Resistance; Male; Pancreas Transplantation; Protamines; Sirolimus; Tacrolimus

The US Food and Drug Administration recently issued a warning of subacute thrombosis and hypersensitivity reactions to sirolimus-eluting stents (Cypher). The cause and incidence of these events have not been determined.. We present findings of a 58-year-old man who died of late stent thrombosis 18 months after receiving 2 Cypher stents for unstable angina. Although angiographic and intravascular ultrasound results at 8 months demonstrated the absence of neointimal formation, vessel enlargement was present. An autopsy showed aneurysmal dilation of the stented arterial segments with a severe localized hypersensitivity reaction consisting predominantly of T lymphocytes and eosinophils.. The known pharmacokinetic elution profile of Cypher stents and the presence of polymer fragments surrounded by giant cells and eosinophils suggest that a reaction to the polymer may have caused late stent thrombosis. Careful long-term follow-up of patients with vessel enlargement after Cypher stent placement is recommended.

Topics: Angina, Unstable; Coronary Angiography; Coronary Thrombosis; Drug Delivery Systems; Fatal Outcome; Humans; Hypersensitivity; Male; Middle Aged; Myocardial Infarction; Sirolimus; Stents; Ultrasonography