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Immunosuppressive Drugs (immunosuppressive + drug)
Selected AbstractsSafety and Efficacy of Raltegravir in HIV-Infected Transplant Patients Cotreated with Immunosuppressive DrugsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 8 2009L. Tricot Solid organ transplantations (SOT) are performed successfully in selected HIV-infected patients. However, multiple and reciprocal drug,drug interactions are observed between antiretroviral (ARV) drugs and calcineurin inhibitors (CNIs) through CYP450 metabolization. Raltegravir (RAL), a novel HIV-1 integrase inhibitor, is not a substrate of CYP450 enzymes. We retrospectively reviewed the outcomes of 13 HIV-infected transplant patients treated by an RAL + two nucleosidic reverse transcriptase inhibitor (NRTI) regimen, in terms of tolerability, ARV efficacy (plasma viral load, CD4 cell count), drug interactions, RAL pharmacokinetics and transplant outcome. Thirteen patients with liver (n = 8) or kidney (n = 5) transplantation were included. RAL was initiated (400 mg BID) either at time of transplantation (n = 6), or after transplantation (n = 7). Median RAL trough concentration was 507 ng/mL (176,890), which is above the in vitro IC95 for wild type HIV-1 strains (15 ng/mL). Target trough levels of CNIs were promptly obtained with standard dosages of tacrolimus or cyclosporine. RAL tolerability was excellent. There was no episode of acute rejection. HIV infection remained controlled. After a median follow-up of 9 months (range: 6,14), all patients were alive with satisfactory graft function. The use of an RAL + two NRTI-based regimen is a good alternative in HIV-infected patients undergoing SOT. [source] Everolimus and Basiliximab Permit Suppression by Human CD4+CD25+ Cells in vitroAMERICAN JOURNAL OF TRANSPLANTATION, Issue 3 2005David S. Game Immunosuppressive drugs are essential for the prevention of acute transplant rejection but some may not promote long-term tolerance. Tolerance is dependent on the presence and regulatory function of CD4+CD25+ T cells in a number of animal models. The direct effects of immunosuppressive drugs on CD4+CD25+ cells, particularly those that interfere with IL-2 signaling are uncertain. We studied the effects of the rapamycin derivative everolimus and the anti-CD25 monoclonal antibody basiliximab on the regulatory capacity of human CD4+CD25+ cells in vitro. Both drugs permitted the suppression of proliferation and IFN-, secretion by CD4+CD25, cells responding to allogeneic and other polyclonal stimuli; CTLA-4 expression was abolished on CD4+CD25+ cells without compromising their suppressive ability. Everolimus reduced IFN-, secretion by CD4+CD25, cells before the anti-proliferative effect: this is a novel finding. Exogenous IL-2 and IL-15 could prevent the suppression of proliferation by CD4+CD25+ cells and the drugs could not restore suppression. By contrast, suppression of IFN-, secretion was only slightly impeded with the exogenous cytokines. Finally, CD4+CD25+ cells were more resistant than CD4+CD25, cells to the pro-apoptotic action of the drugs. Together these data suggest that CD4+CD25+ cells may still exert their effects in transplant patients taking immunosuppression that interferes with IL-2 signaling. [source] The present role of corticosteroids in uveitisACTA OPHTHALMOLOGICA, Issue 2009M KHAIRALLAH Corticosteroids are the most widely used anti-inflammatory and immunosuppressant drugs in ophthalmology in general, and remain the mainstay of therapy for patients with uveitis. An infectious etiology for intraocular inflammation should be adequately excluded or appropriately covered with anti-infectious therapy before administration of corticosteroid therapy. Topical corticosteroids alone are usually effective in the management of anterior uveitis and have little activity against intermediate or posterior uveitis. Ocular adverse effects of topical steroid therapy mainly include ocular hypertension and cataract. The use of periocular steroid injections (subconjunctival, anterior or posterior subtenon, orbital floor) are important modalities in the management of anterior uveitis refractory to topical treatment and intermediate or posterior uveitis, particularly unilateral cases. Systemic corticosteroids remain the initial drug of choice for most patients with severe bilateral intermediate or posterior uveitis. Therapy is initiated with 1.0 to 2.0 mg/Kg of oral prednisone or prednisolone as a single morning dose, followed by a slow taper. Use of intravenous pulse steroid therapy is an important option in acute, severe, bilateral posterior segment inflammation. In several cases, the level of systemic steroid required to control the inflammation is too high and unacceptable. Immunosuppressive drugs as steroid-sparing agents are indicated is such cases. Intravitreal injection of triamcinolone acetonide and slow-release intraocular devices are therapeutic options that can be used in selected uveitis cases refractory to conventional therapy and biologic agents. [source] The immunosuppressive drug leflunomide affects mating-pheromone response and sporulation by different mechanisms in Saccharomyces cerevisiaeFEMS MICROBIOLOGY LETTERS, Issue 1 2000Hiro-aki Fujimura Abstract Leflunomide (LFM) is a novel anti-inflammatory and immunosuppressive drug, and inhibits the growth of cytokine-stimulated lymphoid cells in vitro. The effect of LFM on haploid and diploid cells of Saccharomyces cerevisiae was investigated to elucidate the molecular mechanism of action of the drug. Using a halo assay, LFM was shown to enhance the cell cycle arrest of haploid cells induced by mating pheromone ,-factor. LFM also inhibited sporulation of diploid cells completely. S. cerevisiae genes which were cloned to suppress the anti-proliferative effect when present in increased copy number were introduced and examined for their activity to suppress the effect of LFM. Out of them, MLF4/SSH4, was found to suppress the sporulation-inhibitory effect of LFM. However, MLF4 failed to suppress the enhancing effect of LFM on pheromone response. Thus, LFM is suggested to act on haploid and diploid cells by different mechanisms. [source] In vitro effects of tacrolimus on human cytochrome P450FUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 6 2002K. Lecointre Abstract Tacrolimus, a potent immunosuppressive drug, is known to be metabolized predominantly in the liver by cytochrome P450 3A (CYP3A). In order to determine the potential of tacrolimus to inhibit the metabolism of other drugs, we have investigated its inhibitory effects on specific cytochrome reactions. Specific substrates for the seven cytochromes (CYPs) 1A2, 2A6, 2C9, 2C19, 2D6, 2E1 and 3A4/5 were incubated with human hepatic microsome preparations with or without specific inhibitors or tacrolimus and the metabolites were detected by high-pressure liquid chromatography (HPLC) or fluorimetric methods. All the specific inhibitors reduced or abolished the specific CYP activity. Tacrolimus had no effect on any CYP at concentrations below 1 µm, while at higher concentrations it had a mild inhibitory effect on CYP3A4 and 3A5. These observations suggest that tacrolimus is unlikely to potentiate the effect of coadministered drugs through inhibition of their metabolism in the liver. [source] Azathioprine-induced suicidal erythrocyte deathINFLAMMATORY BOWEL DISEASES, Issue 8 2008Corinna Geiger Abstract Background: Azathioprine is widely used as an immunosuppressive drug. The side effects of azathioprine include anemia, which has been attributed to bone marrow suppression. Alternatively, anemia could result from accelerated suicidal erythrocyte death or eryptosis, which is characterized by exposure of phosphatidylserine (PS) at the erythrocyte surface and by cell shrinkage. Methods: The present experiments explored whether azathioprine influences eryptosis. According to annexin V binding, erythrocytes from patients indeed showed a significant increase of PS exposure within 1 week of treatment with azathioprine. In a second series, cytosolic Ca2+ activity (Fluo3 fluorescence), cell volume (forward scatter), and PS-exposure (annexin V binding) were determined by FACS analysis in erythrocytes from healthy volunteers. Results: Exposure to azathioprine (,2 ,g/mL) for 48 hours increased cytosolic Ca2+ activity and annexin V binding and decreased forward scatter. The effect of azathioprine on both annexin V binding and forward scatter was significantly blunted in the nominal absence of extracellular Ca2+. Conclusions: Azathioprine triggers suicidal erythrocyte death, an effect presumably contributing to azathioprine-induced anemia. (Inflamm Bowel Dis 2008) [source] Mechanisms and management of gingival overgrowth in paediatric transplant recipients: a reviewINTERNATIONAL JOURNAL OF PAEDIATRIC DENTISTRY, Issue 4 2003D. Chabria Summary. Increasing numbers of children are receiving solid organ transplants namely kidney, liver, heart and lung. Patient survival rates following such transplants are essentially good with much of the success attributable to the development of Cyclosporine A (CyA), an immunosuppressive drug, that minimizes organ rejection. However the gingival overgrowth (GO) associated with the use of CyA is not only disfiguring but in paediatric recipients, may interfere with normal oral development and function. Objective. The aim of this review is to summarize current knowledge concerning the aetiology, pathogenesis and management of gingival overgrowth. Methods. Literature pertaining to gingival overgrowth is reviewed with particular reference to the paediatric population. Emphasis is placed on summarizing the evidence pertaining to the effectiveness of intervention. Conclusion. CyA undoubtedly causes gingival overgrowth, the effects and levels of which appears to be more severe in younger patients. There is conflicting evidence as to the effectiveness of oral hygiene regimes, antibiotics and surgery in reducing overgrowth. The introduction of an alternative immunosuppressive agent (Tacrolimus) offers potential as it does not appear to cause overgrowth, although research to date is limited by the small sample size of many of the studies. This is an area in which multicentre studies would be of great value. [source] Dexamethasone suppresses monocyte chemoattractant protein-1 production via mitogen activated protein kinase phosphatase-1 dependent inhibition of Jun N-terminal kinase and p38 mitogen-activated protein kinase in activated rat microgliaJOURNAL OF NEUROCHEMISTRY, Issue 3 2007Yan Zhou Abstract Microglial cells release monocyte chemoattractant protein-1 (MCP-1) which amplifies the inflammation process by promoting recruitment of macrophages and microglia to inflammatory sites in several neurological diseases. In the present study, dexamethasone (Dex), an anti-inflammatory and immunosuppressive drug has been shown to suppress the mRNA and protein expression of MCP-1 in activated microglia resulting in inhibition of microglial migration. This has been further confirmed by the chemotaxis assay which showed that Dex or MCP-1 neutralization with its antibody inhibits the microglial recruitment towards the conditioned medium of lipopolysaccharide (LPS)-treated microglial culture. This study also revealed that the down-regulation of the MCP-1 mRNA expression by Dex in activated microglial cells was mediated via mitogen-activated protein kinase (MAPK) pathways. It has been demonstrated that Dex inhibited the phosphorylation of Jun N-terminal kinase (JNK) and p38 MAP kinases as well as c-jun, the JNK substrate in microglia treated with LPS. The involvement of JNK and p38 MAPK pathways in induction of MCP-1 production in activated microglial cells was confirmed as there was an attenuation of MCP-1 protein release when microglial cells were treated with inhibitors of JNK and p38. In addition, Dex induced the expression of MAP kinase phosphatase-1 (MKP-1), the negative regulator of JNK and p38 MAP kinases in microglial cells exposed to LPS. Blockade of MKP-1 expression by triptolide enhanced the phosphorylation of JNK and p38 MAPK pathways and the mRNA expression of MCP-1 in activated microglial cells treated with Dex. In summary, Dex inhibits the MCP-1 production and subsequent microglial cells migration to the inflammatory site by regulating MKP-1 expression and the p38 and JNK MAPK pathways. This study reveals that the MKP-1 and MCP-1 as novel mediators of biological effects of Dex may help developing better therapeutic strategies for the treatment of patients with neuroinflammatory diseases. [source] Growth factors and proliferation of cultured rat gingival cells in response to cyclosporin AJOURNAL OF PERIODONTAL RESEARCH, Issue 1 2005Takumasa Yoshida Objective:, The prominent side-effect of cyclosporin A, an immunosuppressive drug, in oral tissues is gingival outgrowth, although the exact mechanism underlying this side-effect is unclear. The main purposes of the present study were to determine whether cyclosporin A induced the gingival outgrowth by promoting proliferation of gingival cells and whether growth factors such as transforming growth factor-,s (TGF-,s), fibroblast growth factor-2 (FGF-2), platelet-derived growth factors (PDGFs), and insulin-like growth factors (IGFs) are involved in the possible changes in the proliferation of gingival cells induced by cyclosporin A. Methods:, Cells isolated from rat gingival tissues were cultured with cyclosporin A or IGF-I for 3 days. The effects of cyclosporin A or IGF-I on the proliferation of cultured rat gingival cells were analyzed with a CellTiter 96 proliferation assay kit. The mRNA expression levels for TGF-,s, FGF-2, PDGFs, IGFs, insulin-like growth factor receptors (IGFRs), and insulin-like growth factor binding proteins (IGFBPs) in the rat gingival cells treated with cyclosporin A were measured using competitive reverse transcription,polymerase chain reaction (RT,PCR). Results:, Cyclosporin A induced 23,25% (p < 0.001) increases in the proliferation of rat gingival cells and approximately 130% (p < 0.05) and 60% (p < 0.05) elevations in the mRNA expression levels for TGF-,1 and FGF-2, respectively. On the other hand, exogenous IGF-I induced 8,11% (p < 0.05) increases in the proliferation, but cyclosporin A induced 30,80% (p < 0.05,0.01) reductions in the mRNA expression levels for endogenous IGF-I, IGFR1, IGFBP2, IGFBP3, IGFBP5, and IGFBP6. Conclusions:, Cyclosporin A stimulates the proliferation of rat gingival cells. TGF-,1 and FGF-2 could be involved, but IGFs, IGFRs and IGFBPs could not be directly involved in this cyclosporin A induced-stimulation of the gingival cell proliferation. [source] Melatonin suppresses cyclosporine A-induced autophagy in rat pituitary GH3 cellsJOURNAL OF PINEAL RESEARCH, Issue 3 2010Yeong-Min Yoo Abstract:, Cyclosporine A (CsA) is a powerful immunosuppressive drug with side effects including the induction of chronic nephrotoxicity including endoplasmic reticulum (ER) stress in tubular cells. Recently, it was reported that autophagy is induced by ER stress and serves to alleviate the associated deleterious effects. In the current study, CsA treatment (0,100 ,m) decreased cell survival of rat pituitary GH3 cells in a dose-dependent manner. At concentrations ranging from 1.0 to 10 ,m, CsA induced a dose-dependent increase in the expression of microtubule-associated protein 1 light chain 3 (LC3)-I and LC3-II. Cells treated with 2.5 ,m CsA exhibited cytoplasmic vacuolation, indicating that CsA induces autophagy in rat pituitary GH3 cells. In the presence of 1.0,10 ,m CsA, the expression of catalase decreased while that of the ER stress markers, ER luminal binding protein (BiP) and inositol-requiring enzyme 1 alpha (IRE1,), increased as compared those levels in untreated cells. These results suggested that CsA-induced autophagy is dependent on ER stress. To determine whether melatonin would protect cells against CsA-induced autophagy, we treated rat pituitary GH3 cells with melatonin in the presence of CsA. Melatonin treatment (100 and 200 ,m) suppressed autophagy induced by 2.5 and 5 ,m CsA. Furthermore, co-treatment with 100 ,m melatonin inhibited LC3-II expression, and increased catalase and phosphorylated p-ERK levels in the presence of 2.5 and 5 ,m CsA. BiP and IRE1, expression in melatonin-co-treated cells was superior to that in cells treated with 2.5 and 5 ,m CsA alone. Thus, melatonin suppresses CsA-mediated autophagy in rat pituitary GH3 cells. [source] Treatment of a Myasthenic Dog with Mycophenolate MofetilJOURNAL OF VETERINARY EMERGENCY AND CRITICAL CARE, Issue 3 2000C.W. Dewey DVM, DACVIM (Neurology), DACVS Summary A ten-year-old, male castrated Springer Spaniel was presented for dysphagia, ptyalism, and regurgitation. Evidence of megaesophagus and mild aspiration pneumonia were apparent on thoracic radiographs. A diagnosis of focal acquired myasthenia gravis was suspected and subsequently confirmed with a positive serum acetylcholine (ACh) receptor antibody concentration (3.87 nM/L). A gastrostomy tube was placed shortly after presentation; food and drugs (including azathioprine) were administered through the tube. After transient improvement, the dog suddenly deteriorated clinically, experiencing frequent episodes of regurgitation and developing severe aspiration pneumonia. Mycophenolate mofetil (MMF), a novel immunosuppressive drug with relative specificity for lymphocytes, was instituted every twelve hours via the gastrostomy tube. Within four days of beginning MMF therapy, both clinical evidence of pharyngeal/esophageal dysfunction and radiographic evidence of megaesophagus had resolved. Initially, clinical side-effects of combined MMF/AZA administration were not apparent, but the patient experienced several vomiting episodes during the third week of treatment. The vomiting resolved after decreasing the dose of both drugs. The patient made a full recovery, and a one-month follow-up ACh receptor antibody concentration was normal (0.26 nM/L). After one month of combination therapy, the patient was weaned off of AZA and maintained on MMF as the sole immunosuppressive drug. The dog was subsequently weaned off of MMF on two occasions. Mycophenolate mofetil was reinstituted after the first discontinuation due to the development of profound appendicular muscle weakness two days after stopping MMF; the weakness resolved within 24 hours of reinstituting MMF. A positive ACh receptor antibody concentration (0.89 nM/L) after the second MMF weaning prompted the second reinstitution of MMF. Two months following this second MMF reinstitution, the dog was again serologically negative (0.51 nM/L) for myasthenia gravis. At the time of last followup, the dog remained in clinical remission eight months after initial presentation. The use of MMF to treat acquired myasthenia gravis in dogs has not been reported previously. The literature concerning MMF and its potential use in treating patients with autoimmune diseases is discussed. [source] Mizoribine: Mode of action and effects in clinical usePEDIATRICS INTERNATIONAL, Issue 2 2002Shumpei Yokota Abstract Mizoribine is a new immunosuppressive drug and was authorized by the Japanese Government in 1984. The strong immunosuppressive activity of mizoribine was already demonstrated in various animal models, in renal transplantation and in steriod-resistant nephrotic syndrome. Recently, the remarkable clinical advantages of an imidazole for adults with rheumatoid arthritis, lupus nephritis and other rheumatic diseases were reported. Mizoribine is an imidazole nucleoside and the metabolites, MZ-5-P, exerts its activity through selective inhibition of inosine monophosphate synthetase and guanosine monophosphate synthetase, resulting in the complete inhibition of guanine nucleotide synthesis without incorporation into nucleotides. Thus, mizoribine is superior to azathioprine, in that it may not cause damages to normal cells and normal nucleic acid. [source] ID2-VEGF-related Pathways in the Pathogenesis of Kaposi's Sarcoma: A Link Disrupted by RapamycinAMERICAN JOURNAL OF TRANSPLANTATION, Issue 3 2009G. Stallone The Id-proteins are a family of four related proteins implicated in the control of differentiation and cell-cycle progression. Down-regulation of Id-gene expression is essential for the differentiation of several cell types. In addition, deregulated Id2 activity inhibits the Rb tumor suppressor pathway and promotes the expression of vascular endothelial growth factor (VEGF). Several members of VEGF family could be involved in Kaposi's sarcoma (KS) development and progression. Lymphatic vascular endothelial hyaluronan receptor-1 (LYVE-1) is the first marker of lymphatic endothelial competence during development in the mature vasculature, and is also expressed on KS spindle cells. Rapamycin (RAPA), an immunosuppressive drug, has been shown to reverse KS growth and to reduce tumor angiogenesis. We evaluate, in transplantation-associated KS and in cultured KS-cells the RAPA effect on Id2 and on de novo lymphangiogenesis. Markers of lymphatic-endothelial-cells (VEGFR-3, LYVE-1) and Id2, expressed at low levels within the normal skin, were up-regulated in KS and returned to normal levels after RAPA introduction. The association between Id2 and lymphangiogenesis is suggested by co-localization of Id2, VEGFR-3 and LYVE-1. RAPA inhibition on Id2 expression was confirmed in vitro in KS-cells, both in basal conditions and upon stimulation with VEGF. In conclusion, our data would suggest a novel molecular mechanism for the antineoplastic effects of RAPA in posttransplant KS. [source] Treatment with rapamycin prevents fibrosis in tight-skin and bleomycin-induced mouse models of systemic sclerosisARTHRITIS & RHEUMATISM, Issue 8 2010Ayumi Yoshizaki Objective Rapamycin, a novel macrolide immunosuppressive drug, is increasingly used as an agent for posttransplant immunosuppression and treatment of autoimmune disease. The molecular mechanism related to rapamycin-mediated immunosuppression is that rapamycin binds to FK-506 binding protein 12, and the formed complex inhibits the function of the mammalian target of rapamycin (mTOR), which in turn reduces protein phosphorylation, cell cycle progression, and cytokine production. The aim of this study was to examine the effect of rapamycin against the development of fibrosis and autoimmunity in 2 different types of systemic sclerosis (SSc) model mice. Methods Tight skin (TSK/+) mice and bleomycin- induced SSc model mice were used to evaluate the effect of rapamycin on fibrosis and immunologic abnormalities. Furthermore, the antifibrotic effect of rapamycin was assessed using TSK/+ mouse fibroblasts. Results Treatment with rapamycin reduced skin fibrosis of TSK/+ mice and skin and lung fibrosis of bleomycin-induced SSc model mice. The production of fibrogenic cytokines, such as interleukin-4 (IL-4), IL-6, IL-17, and transforming growth factor ,1, was attenuated by rapamycin. Hypergammaglobulinemia and anti,topoisomerase I antibody production were also reduced by rapamycin treatment in TSK/+ mice. In addition, mTOR expression levels were increased in TSK/+ mouse fibroblasts compared with those in wild-type mouse fibroblasts. Rapamycin treatment inhibited proliferation and collagen production of TSK/+ mouse fibroblasts in a dose-dependent manner. Conclusion This study is the first to show that rapamycin has a significant inhibitory effect on fibrosis in both TSK/+ and bleomycin-induced SSc model mice. These results suggest that rapamycin might be an attractive candidate for clinical trials in SSc patients. [source] Influence of CYP3A5 and MDR1 polymorphisms on tacrolimus concentration in the early stage after renal transplantationCLINICAL TRANSPLANTATION, Issue 5 2005Xin Zhang Abstract:, Objective:, Tacrolimus is an immunosuppressive drug with a narrow therapeutic range and wide interindividual variation in its pharmacokinetics. Cytochrome P450 (CYP) 3A and P-glycoprotein (P-gp, encoded by MDR1) play an important role in the absorption and metabolism of tacrolimus. The objective of this study was to evaluate whether or not CYP3A5*1/*3 or MDR1 C3435T polymorphisms are associated with the tacrolimus concentration per dose. Methods:, CYP3A5 and MDR1 genotypes were determined by polymerase chain reaction followed by restriction fragment length polymorphism analysis in 118 Chinese renal transplant patients receiving tacrolimus. Whole blood trough tacrolimus concentration was measured by enzyme-linked immunosorbent assay and dose-adjusted concentration (ng/mL per mg/kg/d) was calculated at 1 wk, 1 month, and 3 months after transplantation. Results:, The dose-adjusted concentration of CYP3A5*1/*1 and *1/*3 patients was significantly lower than *3/*3 patients (32.8 ± 17.7 and 41.6 ± 15.8 vs. 102.3 ± 51.2 at 1 wk; 33.1 ± 7.5 and 46.4 ± 12.9 vs. 103 ± 47.5 at 1 month; 35.3 ± 20.9 and 59.0 ± 20.6 vs. 150 ± 85.3 at 3 months after transplantation respectively). At 1 wk, 46% of the CYP3A5*1 allele carriers had a tacrolimus concentration lower than 5 ng/mL and 77% lower than 8 ng/mL, whereas 20% of the *3/*3 patients had a concentration higher than 20 ng/mL. There was a mild difference between *1/*1 homozygotes and *1/*3 heterozygotes at 1 and 3 months after transplantation. No difference was found among the MDR1 genotypes. Conclusion:, CYP3A5*1/*3 polymorphisms are associated with tacrolimus pharmacokinetics and dose requirements in renal transplant recipients. Pharmacogenetic methods could be employed prospectively to help initial dose selection and to individualize immunosuppressive therapy. [source] Islet transplantation: where do we stand now?,DIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 3 2003Boaz Hirshberg Abstract After many years of limited success in islet transplantation, researchers developing this procedure have made great strides, and several centers have now reported that islet transplantation can result in long-term insulin independence for patients with type 1 diabetes mellitus. The improved quality of life achieved in some islet allograft recipients suggests that this important line of investigation should proceed. Yet, several factors limit the technique and these hurdles must be overcome before it can be considered a practical treatment for the millions of individuals with diabetes, be it type 1 or type 2. Most obvious is the gross disparity between the number of islets available for clinical transplantation and the number of patients with diabetes who might benefit. Other important limitations, too often lost in the discussion, include complications associated with the technique itself, the toxicity of currently available immunosuppressive drugs, and the imperfect glycemia control achieved in most patients. In fact, our ongoing analysis as to whether transplantation-based therapy improves survival for patients with type 1 diabetes suggests that, for many at least, the opposite may be true. Two variables, as yet undefined, also need to be considered: (1) can the procedure, when done well, prevent or reverse diabetes-associated complications and (2) what are the long-term consequences of intrahepatic islets? Published in 2003 by John Wiley & Sons, Ltd. [source] Increased levels of serum IL-31 in chronic spontaneous urticaria,EXPERIMENTAL DERMATOLOGY, Issue 5 2010Ulrike Raap Please cite this paper as: Increased levels of serum IL-31 in chronic spontaneous urticaria. Experimental Dermatology 2010; 19: 464,466. Abstract:, IL-31 represents a novel cytokine involved in pruritic skin diseases including atopic dermatitis (AD). We, therefore, aimed at investigating IL-31 levels in chronic spontaneous urticaria (CU). We included 46 patients with CU, 26 non-atopic skin healthy subjects as negative and 28 patients with AD as positive controls. IL-31 serum levels were analysed using commercial ELISA kit. IL-31 serum levels were higher in patients with CU compared to healthy controls (P < 0.001), but lower compared to patients with AD (P < 0.001). There was no difference in IL-31 serum levels in autologous serum skin test positive or negative CU patients and patients with infectious trigger factors including helicobacter pylori infection. IL-31 serum levels may play a role in the pathophysiology of CU. This is supported by the finding that not all patients with CU respond to antihistamine treatment but to the treatment with immunosuppressive drugs. [source] Prevalence rate of Cryptosporidium infection in hemodialysis patients in IranHEMODIALYSIS INTERNATIONAL, Issue 4 2006Shiva SEYRAFIAN Abstract Cryptosporidium is one of the most common causes of diarrhea in the world, which can be severe and prolonged in immunocompromised patients. We compared the prevalence rate of Cryptosporidium infection in hemodialysis patients and 2 control groups (i.e., their healthy family members and normal population). Stool specimens of 104 adult outpatient chronic hemodialysis patients, their 91 healthy family members, and 140 healthy individuals were examined for the presence of Cryptosporidium oocysts by using a modified acid-fast staining method. Twelve (11.5%) dialysis patients were infected with Cryptosporidium. This was significantly higher than 4 (4.4%), and 5 (3.6%) cases in the 2 control groups, respectively (p<0.05). There was no significant difference between the 2 control groups. The prevalence rate of Cryptosporidium infection did not correlate with patients' sex, age, duration of dialysis, history of kidney transplantation, or history of taking immunosuppressive drugs. However, it was significantly higher in diabetics vs. nondiabetics (19.4% vs. 8.3%, respectively, p<0.05). Our results indicate that the prevalence rate of Cryptosporidium infection is considerably higher in dialysis patients than in the general population. Moreover, dialyzed diabetic patients had the highest rate of infection. As hemodialysis patients are candidates for renal transplantation, general preventive measures against acquiring Cryptosporidium infection must be considered. [source] THIS ARTICLE HAS BEEN RETRACTED STEALTH matters: a novel paradigm of durable primate allograft toleranceIMMUNOLOGICAL REVIEWS, Issue 1 2001J. M. Thomas Summary: We review a novel strategy for tolerance induction developed in rhesus macaques and termed STEALTH. We summarize the evolution of the STEALTH model, the results of successful trials in inducing long-term, stable transplant tolerance in rhesus kidney and diabetic islet recipients and discuss information related to the mechanism by which durable tolerance is induced. STEALTH tolerance is induced by a 3-day treatment course of CD3, immunotoxin (IT) combined with a 14-day treatment with deoxyspergualin (DSG). IT causes profound depletion of sessile lymph node T cells as well as the more accessible circulating T cells. DSG, an inhibitor of HSC 70-mediated NF-,B nuclear translocation, arrests maturation of myeloid dendritic cells, blocks production of proinflammatory cytokines induced by IT administration, and promotes systemic production of Th2 type cytokines that persist indefinitely. Such Th2 cytokine deviation has not been reported in NHP transplant recipients. These studies provide proof of principle in a preclinical model that prevention of both acute and chronic allograft rejection, for at least 2.2,4.9 years of follow-up, can be achieved in NHP in the absence of chronic immunosuppressive drugs or other interventions. This strategy for inducing NHP tolerance is discussed in relation to current tolerance paradigms. [source] Primary biliary cirrhosis: an orchestrated immune response against epithelial cellsIMMUNOLOGICAL REVIEWS, Issue 1 2000M. Eric Gershwin Summary: Primary biliary cirrhosis (PBC) is an organ-specific autoimmune disease that predominantly affects women and is characterized by chronic progressive destruction of small intrahepatic bile ducts with portal inflammation and ultimately fibrosis. The serologic hallmark of PBC is the presence of antibodies to mitochondria, especially to the E2 component of the pyruvate dehydrogenase complex. The mechanisms by which (and if) such antibodies produce liver tissue injury are unknown. However, the presence of these antibodies has allowed detailed immunological definition of the antigenic epitopes, the nature of reactive autoantibodies and the characterization of T-cell responses. Several mechanisms may now be proposed regarding the immune-mediated bile duct damage in PBC, including the possible role of T-cell-mediated cytotoxicity and intracellular interaction between the IgA class of antimitochondrial antibodies and mitochondrial autoantigens. There are major questions which remain unanswered, including, of course, etiology, but also the reasons for female predominance, the absence of PBC in children, the relative ineffectiveness of immunosuppressive drugs, and the specific role of mitochondrial antigens. The data so far provide suggestive evidence that PBC is a mucosal disease; this thesis provides a basis for discussion of etiology via the enterohepatic circulation of toxins and/or infection. [source] Could immunosuppressive drugs reduce recurrence rate after second resection for crohn disease?INFLAMMATORY BOWEL DISEASES, Issue 5 2004Arnaud Alves MD Abstract Background: The aim of this study was to assess the possible benefit of postoperative immunosuppressive drugs administration (ie, azathioprine, 6-mercaptopurine, or methotrexate) on long-term surgical recurrence rate after second anastomotic ileocolonic resection. Methods: From 1984 to 2000, 26 patients with CD underwent second resection for ileocolonic anastomotic recurrence. There were 14 women and 12 men (mean age ± SD: 34 ± 9 years). Two groups of patients were compared according to the postoperative treatment: immunosuppressive (IS) drugs group was composed of 14 patients, and control group was composed of 12 patients receiving either salicylates (n = 5) or no treatment (n = 7). Results: Clinical recurrence rate at 3 years was significantly lower in the IS group than in the control group (3/12, 25% vs 6/10, 60%; P < 0.05). Although not significant, after a mean follow-up of 80 ± 46 months (extr. 17,178 months) after the second resection, clinical recurrence rate at follow-up was also lower in IS group (6/14, 43%) than in control group (9/12, 75%). The mean delay of recurrence was similar in both groups (27 ± 13 months vs 28 ± 21; NS). A third intestinal resection was performed less frequently in the IS group than in control group (2/14, 17% vs 7/12, 58%; P < 0.02). Conclusions: In patients treated with IS drugs, the rate of postoperative recurrence after second ileocolonic CD resection is lower than in untreated patients. Our results suggest that IS drugs should be evaluated prospectively for prevention of second postoperative CD recurrence. [source] Systemic lupus erythematosus complicated with posterior reversible encephalopathy syndrome and intracranial vasculopathyINTERNATIONAL JOURNAL OF RHEUMATIC DISEASES, Issue 4 2010Hung-An CHEN Abstract Posterior reversible encephalopathy syndrome (PRES) is a neurotoxic condition characterized by reversible vasogenic edema on neuroimaging. It is associated with various neurological manifestations, including headaches, vomiting, seizures, visual loss, altered mental status and focal neurological deficits. PRES mainly occurs in the setting of eclampsia, hypertension, uremia, malignancy, transplantation, autoimmune diseases and/or use of immunosuppressive drugs. This syndrome has been described in patients with systemic lupus erythematosus (SLE). PRES is a potentially reversible clinical,radiological entity; however, it can be complicated with vasculopathy, infarction or hemorrhage. Vasculopathy has been demonstrated to be a common finding in patients with SLE. We report the case of a woman with lupus nephritis and PRES whose diffuse vasculopathy was present on initial neuroimaging. Subsequent brain computed tomography scan demonstrated interval development of intraparenchymal hemorrhage and subarachnoid hemorrhage. To our knowledge, this unique brain image pattern has not been reported in SLE patients. [source] Intravenous dexamethasone-cyclophosphamide pulse therapy in comparison with oral methylprednisolone-azathioprine therapy in patients with pemphigus: Results of a multicenter prospectively randomized studyJOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, Issue 3 2005Intravenöse Dexamethason-Cyclophosphamid-Pulstherapie im Vergleich zu einer oralen Methylprednisolon-Azathioprin-Therapie bei Patienten mit Pemphigus-Erkrankungen: Ergebnisse einer multizentrischen, prospektiven, randomisierten Studie Azathioprin; Cyclophosphamid; Pemphigus; Pulstherapie Summary Background: Pemphigus is a potentially life-threatening autoimmune blistering skin disease usually treated with high-dose corticosteroids in combination with immunosuppressive drugs. In a multicenter, prospectively randomized study we compared efficacy and side effects of a dexamethasone-cyclophosphamide (D/C) pulse therapy with a methylprednisolone-azathioprine (M/A) therapy in 22,patients with newly diagnosed pemphigus vulgaris and pemphigus foliaceus. Patients and methods: The 11,patients of the M/A group were treated with daily doses of methylprednisolone (initially 2,mg/kg body weight) and azathioprine (2,,,2,5,mg/kg body weight) which were subsequently tapered. D/C pulse therapy in 11,patients consisted of intravenous administration of 100,mg dexamethasone/d on 3 consecutive days along with cyclophosphamide (500,mg) on day one. Pulses were initially repeated every 2,,,4 weeks and then at increasing intervals. In between the pulses, oral cyclophosphamide (50,mg) was given daily for 6,months. Results: Within 24,months after treatment initiation, 5/11,patients of the D/C group had a remission (complete remissions after discontinuation of therapy in 3,patients) and 6/11,patients had a progression. In the M/A group, there were remissions in 9/11,patients (complete remissions after discontinuation of therapy in 3,patients) and progression in 1/11,patients. There were more relapses in M/A therapy after remission than in D/C therapy. Side effects were more common in the M/A group. These differences were not significant (p > 0,05). Conclusion: Because of the high number of progressions in patients treated with D/C therapy, we can not confirm the encouraging results of earlier reports about pulse D/C therapy. Nevertheless D/C therapy seemed to be better tolerated and, in case of primary efficacy, was associated with fewer recurrences than M/A therapy. Zusammenfassung Hintergrund: Pemphiguserkrankungen sind potentiell lebensbedrohliche blasenbildende Autoimmunerkrankungen, die üblicherweise mit hochdosierten Kortikosteroiden in Kombination mit Immunsuppressiva behandelt werden. In einer multizentrischen, prospektiven, randomisierten Studie verglichen wir die Wirksamkeit und Nebenwirkungen einer Dexamethason-Cyclophosphamid (D/C)-Pulstherapie mit einer Methylprednisolon-Azathioprin (M/A)-Therapie bei 22,Patienten mit neu diagnostiziertem Pemphigus vulgaris und Pemphigus foliaceus. Patienten und Methoden: 11,Patienten der M/A-Gruppe wurden kontinuierlich oral mit Methylprednisolon (initial 2,mg/kg Körpergewicht/Tag) und Azathioprin (2,,,2,5,mg/kg Körpergewicht/Tag) behandelt; die Dosen wurden schrittweise reduziert. Die Therapie bei den 11,Patienten der D/C-Gruppe erfolgte durch intravenöse Gabe von 100,mg Dexamethason/Tag an 3 aufeinander folgenden Tagen und 500,mg Cyclophosphamid am ersten Tag. Die Pulstherapie wurde zunächst alle 2,,,4 Wochen, dann in längeren Abständen wiederholt. Im Intervall wurden 50,mg Cyclophosphamid/Tag oral für 6,Monate verabreicht. Ergebnisse: Innerhalb von 24,Monaten nach Therapiebeginn kam es bei 5 von 11,Patienten der D/C-Gruppe zu einer Remission (komplette Remission nach Absetzen der Therapie bei 3,Patienten); bei 6 der 11,Patienten verlief die Erkrankung progredient. In der M/A-Gruppe kam es bei 9 von 11,Patienten zu einer Remission (komplette Remission nach Absetzen der Therapie bei 3,Patienten) und bei einem Patienten zu einer Progression. In der M/A-Gruppe traten häufiger Rezidive nach Remission auf als in der D/C-Gruppe. Therapienebenwirkungen kamen in der M/A-Gruppe häufiger vor. Diese Unterschiede waren nicht signifikant (p > 0,05). Schlußfolgerungen: Aufgrund der hohen Anzahl von Progressionen bei Patienten der D/C-Gruppe können wir die positiven Ergebnisse früherer Berichte über die D/C-Pulstherapie nicht bestätigen. Dennoch scheint die D/C-Therapie, beim einzelnen Patienten einmal erfolgreich, seltener zu Rezidiven zu führen und möglicherweise auch besser verträglich zu sein als die M/A-Therapie. [source] Disorders Associated With Acute Rapid and Severe Bone Loss,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 12 2003Solomon Epstein We describe a constellation of bone diseases characterized by the common feature of acute, rapid, and severe bone loss accompanied by dramatic fracture rates. These disorders are poorly recognized, resulting mainly from systemic diseases, frailty, immobilization, and immunosuppressive drugs, such as glucocorticoids and the calcineurin inhibitors. The opportunity to prevent or treat fractures is commonly missed because they are often not detected. Ideally, patients need to be identified early and preventative therapy initiated promptly to avoid the rapid bone loss and fractures. The most effective therapy at present seems to be the bisphosphonates, particularly when bone resorption is predominant. However, more severe forms of bone loss that result from an osteoblastic defect and reduced bone formation may benefit potentially more from newer anabolic agents, such as recombinant human parathyroid hormone (rhPTH). [source] The effects of immunosuppressive drugs on CD4+CD25+ regulatory T cells: a systematic review of clinical and basic researchJOURNAL OF EVIDENCE BASED MEDICINE, Issue 2 2010Chuntao Zhang Abstract Objective To review the effects of different immunosuppressive drugs on proliferation and function of regulatory T cells (Tregs). Methods We searched MEDLINE, Embase (from inception to September 2009), and the Cochrane Library (Issue 4, 2009) for clinical and basic research about the effects of various immunosuppressive drugs on Tregs. Data were extracted and methodological quality was assessed by two independent reviewers. Outcome measures for clinical research included blood Tregs levels, acute rejection episodes, and graft function. Outcomes for basic research included percentage of Tregs proliferation, function, Tregs phenotype, and evidence for possible mechanisms. We analyzed data qualitatively. Results Forty-two studies, including 19 clinical trials and 23 basic studies, were included. The immunosuppressive drugs studied were calcineurin inhibitors (CNIs), Rapa, anti-metabolism drugs, IL-2 receptor-blocking antibodies, T-cell depleting antibodies, and co-stimulation blockade antibodies. Most of the studies were on Rapa and CNIs. Eight basic studies on Rapa and CNIs showed that Rapa could promote the proliferation and function of Tregs, while CNIs could not. Five clinical trials involving a total of 158 patients showed that patients taking Rapa had higher blood concentration of Tregs than patients taking CNIs, but no difference was found in graft function (6,42 months follow-up). Conclusion There is substantial evidence that Rapa favors Tregs survival and function. However, the higher numbers of blood Tregs in patients treated with Rapa do not show any association with better graft function. Larger clinical studies with longer follow-up are needed to more thoroughly assess the efficacy of immunosuppressive drugs on Tregs, and reveal whether a relationship exists between Tregs and graft function. [source] Neuroimaging in Posterior Reversible Encephalopathy SyndromeJOURNAL OF NEUROIMAGING, Issue 2 2004C. Lamy ABSTRACT The terms posterior reversible leukoencephalopathy, reversibleposterior cerebral edema syndrome, and posterior reversibleencephalopathy syndrome(PRES) all refer to a clinicoradiologic entity characterized by headaches, confusion, visual disturbances, seizures, and posterior transient changes on neuroimaging. Clinical findings are not sufficiently specific to readily establish the diagnosis; in contrast, magnetic resonance imaging pattern is often characteristic and represents an essential component of the diagnosis of PRES. Typical lesions predominate in the posterior white matter, with some involvement of the overlying cortex; are hyperintense on T2-weighted images; and are usually hypointense or isointense on diffusion-weighted images, with an increase of the apparent diffusion coefficient, indicating vasogenic edema. The pathogenesis is incompletely understood, although it seems to be related to the breakthrough of autoregulation and endothelial dysfunction. Since its initial description, this syndrome has been subsequently described in an increasing number of medical conditions, including hypertensive encephalopathy, eclampsia, and the use of cytotoxic and immunosuppressive drugs. The diagnosis has important therapeutic and prognostic implications because the reversibility of the clinical and radiologic abnormalities is contingent on the prompt control of blood pressure and/or discontinuing the offending drug. On the contrary, when unrecognized, conversion to irreversible cytotoxic edema may occur. [source] Matrix metalloproteinase-3 gene polymorphism in renal transplant patients with gingival overgrowthJOURNAL OF PERIODONTAL RESEARCH, Issue 1 2010A. Drozdzik Drozdzik A, Kurzawski M, Lener A, Kozak M, Banach J, Drozdzik M. Matrix metalloproteinase-3 gene polymorphism in renal transplant patients with gingival overgrowth. J Periodont Res 2009; doi: 10.1111/j.1600-0765.2009.01221.x. © 2009 The Authors. Journal compilation © 2009 Blackwell Munksgaard Background and Objective:, Gingival enlargement frequently occurs in transplant patients receiving immunosuppressive drugs. It was hypothesized that gingival enlargement associated with cyclosporine use results from reduced degradation of extracellular matrix in the gingiva. Matrix metalloproteinase-3 (MMP-3) is involved in biodegradation of the extracellular matrix, and its inhibition may contribute to an abnormal accumulation of fibronectin and proteoglycans, which are MMP-3 substrates. The aim of this study was to investigate whether an association exists between MMP-3 genotypes and gingival enlargement in kidney transplant patients medicated with cyclosporine A. Material and Methods:, Sixty-four unrelated kidney transplant patients suffering from gingival overgrowth, as well as 111 control transplant patients without gingival overgrowth, were enrolled in the study. Gingival overgrowth was assessed 6 mo after transplantation. During the post-transplant period all patients were given cyclosporine A as a principal immunosuppressive agent. MMP-3 polymorphism was determined using a PCR restriction fragment length polymorphism assay. Results:, In kidney transplant patients suffering from gingival overgrowth the mean gingival overgrowth score was 1.35 ± 0.57, whereas in control subjects the mean gingival overgrowth score was 0.0. The distribution of MMP-3 -1178A/*dupA alleles among all kidney transplant patients, as well as in the two study subgroups, did not differ significantly from Hardy,Weinberg equilibrium. The frequency of the MMP-3-1171*A/*A genotype (28.1% for gingival overgrowth vs. 26.1% for controls) and of the MMP-3-1171*dupA/*dupA genotype (32.8% for gingival overgrowth vs. 22.5% for controls) was similar for both study groups. The risk of gingival overgrowth was lowest among patients carrying the MMP-3-1171*A/*dupA genotype (odds ratio 0.52), but this did not differ markedly from the other genotypes. Conclusion:, No association between MMP-3 gene polymorphism and gingival overgrowth was revealed in kidney transplant patients administered cyclosporine A. [source] Treatment of hepatitis DJOURNAL OF VIRAL HEPATITIS, Issue 1 2005G. A. Niro Summary., Delta virus related chronic hepatitis is difficult to treat. The response to , -interferon (IFN), which still represents the only therapy for chronic hepatitis D, varies widely and occurs at different times from the beginning of treatment. The rate of response is proportional to the dose of IFN, with 9 million units (MU) three times a week being more effective than 3 MU thrice weekly. Sustained responses are unusual and are accompanied by the clearance of serum hepatitis B virus surface antigen (HBsAg), seroconversion to anti-HBs and improvement of liver histology. Although disease of a short-standing may respond better to therapy, clear predictors of response are still unidentified. Besides IFN, other therapeutic approaches such as immunosuppressive drugs, acyclovir, ribavirin and thymosin, have been unhelpful. Available evidence does not support the use of deoxynucleotide analogues. Famciclovir has no effect on disease activity and hepatitis D virus (HDV)-RNA levels. Twelve- or 24-month lamivudine treatment does not significantly affect biochemical, virological or histological parameters. Pegylated-IFN could represent a reasonable therapeutic option in the long-term treatment required for chronic hepatitis D. Antisense oligonucleotides and prenylation inhibitors hold promise as therapeutic agents of the future. Liver transplantation provides a valid option for end-stage HDV liver disease; the risk of re-infection is lower for HDV than for HBV under long-term administration of hyperimmune serum against HBsAg. Molecularly tailored drugs capable of interfering with crucial viral replicative processes of HDV appear to be the best prospect in the treatment of hepatitis D. [source] Older age and liver transplantation: A reviewLIVER TRANSPLANTATION, Issue 8 2004Rajesh N. Keswani Patients older than 60 are undergoing transplantation with increasing frequency. Reports from several transplant centers document that overall short-term patient survival rates in seniors undergoing liver transplantation are comparable to survival rates of younger adults. However, specific subgroups of older patients may not fare as well. Seniors with far-advanced end-stage liver disease are high-risk for liver transplantation and have poor survival rates. In addition, seniors older than 65 have worse outcomes than those who are 60 to 65, and studies have shown increased mortality with increasing age as a continuous variable. On the other hand, the majority of seniors who survive liver transplantation have full or only minimally limited functional status. Preoperative evaluation of older patients for transplantation requires careful screening to exclude cardiopulmonary disease, malignancy, and other diseases of the aged. Paradoxically, seniors may benefit from a senescent immune system, which results in decreased requirements for immunosuppressive drugs, and possibly a lower rate of acute allograft rejection. Despite good overall short-term survival in the elderly, long-term survival may be worse because of an increased rate of long-term complications, such as malignancy and heart disease. In conclusion, although advanced age is a negative risk factor, advanced age alone should not exclude a patient from liver transplantation; however, it mandates thorough pretransplant evaluation and careful long-term follow-up with attention to usual health maintenance issues in the elderly. (Liver Transpl 2004;10:957,967.) [source] Management of drug-to-drug interactions between cyclosporine A and the protease-inhibitor lopinavir/ritonavir in liver-transplanted HIV-infected patientsLIVER TRANSPLANTATION, Issue 7 2004Martin Vogel Highly active antiretroviral therapy (HAART) has improved the life expectancy of HIV-infected patients, allowing orthotopic liver transplantation as a reasonable treatment option for selected patients with terminal liver disease. Both non-nucleoside reverse transcriptase inhibitors and protease inhibitors, key elements of HAART, give rise to substantial drug-to-drug interactions with immunosuppressive drugs such as tacrolimus and cyclosporine A. After studying 12-hour pharmacokinetic profiles in 3 HIV-positive patients after liver transplantation, we describe how dosing of cyclosporine A can be adjusted to maintain effective immunosuppressive drug levels on a daily dosing schedule when ritonavir-boosted indinavir or lopinavir-based antiretroviral therapy is given. To avoid toxic drug levels, we used an orally available cyclosporine A formulation prepared from the commercial available intravenous solution, which enabled dose adjustments in 1-mg increments. Under ritonavir-boosted HAART, cyclosporine A levels showed markedly altered absorption/elimination characteristics with more or less constant blood-levels throughout the dosing interval and prolonged elimination half-lives up to 38 hours. To obtain equivalent areas under the curve of cyclosporine A, daily doses were reduced to 5,20% of the individual standard doses given before initiation of ritonavir-boosted HAART. Because of the flat absorption/elimination profiles under ritonavir-boosted HAART cyclosporine A, dosing could be reliably monitored long term by measuring cyclosporine A trough-levels. (Liver Transpl 2004;10:939,944.) [source] | ||||||||||||||||||||||||||||||||||