mycophenolic-acid and Inflammation

To compare the outcomes of mycophenolate mofetil (MMF) versus methotrexate (MTX) in non-infectious ocular inflammatory disease (NIOID).. The study was performed as per the PRISMA Guidelines. A search identified all studies comparing MMF versus MTX in NIOID. Treatment result and side effects were primary outcomes.. Four studies enrolling 905 patients were identified. There was no significant difference between MMF and MTX groups in overall treatment success (OR = 0.97, P = .96), treatment failure (OR = 0.86, P = .85). MTX showed a significantly improved effect in cases involving posterior uveitis and panuveitis (OR = 0.41, P = .003). In addition, MTX was associated with a faster median time to treatment success and had less side effects when compared to MTX, however this was not significant. For secondary outcomes, no significant difference was found in visual acuity and resolution of macular oedema.. MMF is comparable to MTX in the treatment of NIOID.

Topics: Enzyme Inhibitors; Humans; Immunosuppressive Agents; Inflammation; Methotrexate; Mycophenolic Acid; Retrospective Studies; Treatment Outcome

Non-infectious intermediate, posterior, and panuveitis (NIIPPU) represent a heterogenous collection of autoimmune and inflammatory disorders isolated to or concentrated in the posterior structures of the eye. Because NIIPPU is typically a chronic condition, people with NIIPPU frequently require treatment with steroid-sparing immunosuppressive therapy. Methotrexate, mycophenolate, cyclosporine, azathioprine, and tacrolimus are non-biologic, disease-modifying antirheumatic drugs (DMARDs) which have been used to treat people with NIIPPU.. To compare the effectiveness and safety of selected DMARDs (methotrexate, mycophenolate mofetil, tacrolimus, cyclosporine, and azathioprine) in the treatment of NIIPPU in adults.. We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register), MEDLINE, Embase, the Latin American and Caribbean Health Sciences database, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform, most recently on 16 April 2021.. We included randomized controlled trials (RCTs) comparing selected DMARDs (methotrexate, mycophenolate, tacrolimus, cyclosporine, and azathioprine) with placebo, standard of care (topical steroids, with or without oral steroids), or with each other.. We used standard methodological procedures expected by Cochrane.. We included 11 RCTs with a total of 601 participants in this review. DMARDs versus control Two studies compared an experimental DMARD (cyclosporine A or enteric-coated mycophenolate [EC-MPS]) plus oral steroid with steroid monotherapy. We did not pool these results into a meta-analysis because the dose of cyclosporine used was much higher than that used in current clinical practice. The evidence is very uncertain about whether EC-MPS plus low-dose oral steroid results in a higher proportion of participants achieving control of inflammation over steroid monotherapy (risk ratio [RR] 2.81, 95% confidence interval [CI] 1.10 to 7.17; 1 study, 41 participants; very low-certainty evidence). The change in best-corrected visual acuity (BCVA) was reported separately for right and left eyes. The evidence for improvement (lower logarithm of the minimum angle of resolution (logMAR) indicates better vision) between the groups is very uncertain (mean difference [MD] -0.03 and -0.10, 95% CI -0.96 to 0.90 and -0.27 to 0.07 for right and left, respectively; 1 study, 82 eyes; very low-certainty evidence). No data were available for the following outcomes: proportion of participants achieving a 2-line improvement in visual acuity, with confirmed macular edema, or achieving steroid-sparing control. The evidence for the proportion of participants requiring cessation of medication in the DMARD versus control group is very uncertain (RR 2.61, 95% CI 0.11 to 60.51; 1 study, 41 participants; very low-certainty evidence). Methotrexate versus mycophenolate We were able to combine two studies into a meta-analysis comparing methotrexate versus mycophenolate mofetil. Methotrexate probably results in a slight increase in the proportion of participants achieving control of inflammation, including steroid-sparing control, compared to mycophenolate at six months (RR 1.23, 95% CI 1.01 to 1.50; 2 studies, 261 participants; moderate-certainty evidence). Change in BCVA was reported per eye and the treatments likely result in little to no difference in change in vision (MD 0.01 logMAR higher [worse] for methotrexate versus mycophenolate; 2 studies, 490 eyes; moderate-certainty evidence). No data were available for the proportion of participants achieving a 2-line improvement in visual acuity. The evidence is very uncertain regarding the proportion of participants with confirmed macular edema between methotrexate versus mycophenolate (RR 0.49, 95% CI 0.19 to 1.30; 2 studies, 35 eyes; very low-ce. There is a paucity of data regarding which DMARD is most effective or safe in NIIPPU. Studies in general were small, heterogenous in terms of their design and outcome measures, and often did not compare different classes of DMARD with each other. Methotrexate is probably slightly more efficacious than mycophenolate in achieving control of inflammation, including steroid-sparing control (moderate-certainty evidence), although there was insufficient evidence to prefer one medication over the other in the VKH subgroup (very low-certainty evidence). Methotrexate may result in little to no difference in safety outcomes compared to mycophenolate.

Topics: Adult; Antirheumatic Agents; Azathioprine; Cyclosporine; Humans; Immunosuppressive Agents; Inflammation; Macular Edema; Methotrexate; Mycophenolic Acid; Panuveitis; Steroids; Tacrolimus

Mycophenolate mofetil (MMF) and mizoribine (MZR) are increasingly used as immunosuppressive agents for organ transplantation and chronic inflammation. We report a patient with rheumatoid arthritis who had an acute inflammatory syndrome triggered by preoperative immunosuppression therapy with both MMF and MZR.. A 41-year-old woman with IgA nephropathy was referred to our department for living donor renal transplantation. She had rheumatoid arthritis that was adequately treated with prednisolone 5 mg once a day and salazosulfapyridine 2000 mg once a day. MMF 1000 mg twice a day was started for desensitization therapy. Three days later, the patient developed arthritis in the joints of her left hand and elevated inflammatory markers. On day 7, MMF was switched to MZR 150 mg 3 times a day. However, the symptoms extended to both shoulders and the joints of the right foot; MZR was discontinued. The arthritis and inflammatory markers improved. Two months later, the patient was rechallenged with MMF followed by MZR, resulting in a similar clinical course as previously. Tacrolimus (TAC) 3 mg twice a day and everolimus (EVL) 0.5 mg twice a day were introduced as alternative immunosuppressant therapies. No arthritis occurred. ABO-compatible living donor renal transplantation was successfully performed. The patient received TAC, EVL, prednisolone, rituximab, and basiliximab, and her postoperative course was uneventful without arthritis or rejection. At 9 months postoperatively, the serum creatinine was 0.79 mg/dL.. Acute inflammatory syndrome is an extremely rare complication triggered by preoperative immunosuppression therapy. If antimetabolites cannot be used in immunologically high-risk patients, transplantation becomes very difficult. Clinicians should keep in mind this paradoxical reaction.

Topics: Adult; Arthritis; Female; Graft Rejection; Humans; Immunosuppressive Agents; Inflammation; Kidney Transplantation; Mycophenolic Acid; Ribonucleosides; Syndrome

Despite recent developments and treatment successes, the outcome, and prognosis of patients with lupus nephritis (LuN) have not greatly changed since the 1980s. This review covers the application of new concepts to the understanding of renal inflammation and the study of new pharmacologic agents to improve patient outcomes.. Studies have shown that the presence of anti-vimentin antibodies and T follicular helper cells in patient biopsies is associated with more severe interstitial inflammation, which has been tied to faster disease progression and onset of end-stage renal disease. Additionally, data regarding the role of serum IgE antidouble-stranded DNA antibodies in LuN by means of mediating IFN1 production by plasmacytoid dendritic cells are highlighted. Finally, a thorough review of completed and currently open clinical trials of therapeutic agents is provided.. Current management of LuN is guided almost exclusively by glomerular involvement. Based on the data provided in this review, we argue that renal tubulointerstitial inflammation is no less important and represents an overlooked feature in the current clinical approach to patients. Tubulointerstitial inflammation is driven by both adaptive and innate immune mechanisms that are still poorly understood. Studying these pathogenic processes promises to reveal new therapeutic opportunities for those LuN patients with the worst prognosis.. Alternate video abstract introduction (see Video, Supplemental Digital Content 1, with introduction by two of the authors - VL and KT). Abstract Video: http://links.lww.com/COR/A35.

Topics: Abatacept; Antibodies, Monoclonal, Humanized; Autoantibodies; Biopsy; Cyclophosphamide; Dendritic Cells; Disease Progression; Glucocorticoids; Humans; Immunosuppressive Agents; Inflammation; Interferon Type I; Kidney Failure, Chronic; Lupus Nephritis; Maintenance Chemotherapy; Mycophenolic Acid; Prognosis; Quinolones; Recombinant Fusion Proteins; Remission Induction; Ribonucleosides; Severity of Illness Index; T-Lymphocytes, Helper-Inducer; Treatment Outcome; Vimentin

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD). The development and progression of DN might involve multiple factors. Connective tissue growth factor (CCN2, originally known as CTGF) is the one which plays a pivotal role. Therefore, increasing attention is being paid to CCN2 as a potential therapeutic target for DN. Up to date, there are also many drugs or agents which have been shown for their protective effects against DN via different mechanisms. In this review, we only focus on the potential renoprotective therapeutic agents which can specifically abolish CCN2 expression or nonspecifically inhibit CCN2 expression for retarding the development and progression of DN.

Topics: Animals; Anthocyanins; Antibodies, Monoclonal; Connective Tissue Growth Factor; Diabetes Mellitus; Diabetic Nephropathies; Disease Progression; Exenatide; Guanidines; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Kidney; Kidney Failure, Chronic; Mice; Mycophenolic Acid; Oligonucleotides, Antisense; ortho-Aminobenzoates; Peptides; Renin-Angiotensin System; rho-Associated Kinases; Spironolactone; Venoms

Acute renal failure (ARF) is a common cause of mortality and morbidity in hospitalized patients. Ischemia is an important cause of ARF, and ARF caused by ischemic injury is referred to as ischemic acute tubular necrosis (ATN). There is growing evidence from models that ischemic ATN is associated with intrarenal inflammation. Consequently, intrarenal inflammation is an attractive target for the development of novel drug therapies for ARF. This review outlines ischemic ATN models, the pathophysiological roles of inflammatory cells such as T and B cells in ischemic ATN models, and effective T and B cell therapeutic reagents.

Topics: Animals; Anti-Inflammatory Agents; B-Lymphocytes; Cells, Cultured; Disease Models, Animal; Drug Evaluation, Preclinical; Gene Expression Profiling; Gene Expression Regulation; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Ischemia; Kidney; Kidney Tubular Necrosis, Acute; Mycophenolic Acid; Oligonucleotide Array Sequence Analysis; T-Lymphocytes

This article should familiarize the reader with the pharmacokinetics, mechanisms of action, potential toxicities, and current and future applications of mycophenolate mofetil.. The current medical literature.. Mycophenolate mofetil is an immunosuppressive agent that has been used for transplant recipients. More recently, this agent has been used to treat several inflammatory conditions.. Mycophenolate mofetil has the potential to be a useful agent in the treatment of several inflammatory conditions, including systemic lupus erythematosus.

Topics: Autoimmune Diseases; Dose-Response Relationship, Drug; Forecasting; Humans; Immunosuppressive Agents; Inflammation; Mycophenolic Acid; Risk Factors

Topics: Angiotensin II; Animals; Anti-Inflammatory Agents, Non-Steroidal; Fibrosis; Humans; Inflammation; Inflammation Mediators; Kidney Diseases; Models, Biological; Mycophenolic Acid; Nephritis; Renin-Angiotensin System; Transforming Growth Factor beta

Mycophenolate mofetil (MMF) has recently been reported as a useful alternative immunosuppressive drug in autoimmune diseases including in Takayasu arteritis (TA). The aim of this study was to verify the efficacy and tolerability of MMF administration in controlling TA disease activity and allowing glucocorticosteroid reduction. Ten consecutive active TA patients followed at the Vasculitis Clinic were enrolled from January 2003 to 2006 and received oral MMF (2 g/day) for an average of 23.3 months. Disease activity assessed using the National Institutes of Health criteria, clinical features, and inflammatory laboratory findings were evaluated. Five patients had received at least one immunosuppressive drug before administration of MMF (four methotrexate, two azathioprine, and one chlorambucil) but had not achieved clinical and laboratory remission. The other five patients received MMF as their first immunosuppressive drug because of an important disease flare during steroid dose reduction. Clinical activity disappeared in all patients with MMF therapy, except in one patient who abandoned the study because of an important headache, attributed to the drug. Moreover, the MMF therapy allowed significant tapering of the prednisone dose in the rest of the nine patients (24.5 +/- 17.1 vs 5.8 +/- 7.8 mg/day; p = 0.0019). Reinforcing this finding, a significant reduction in inflammatory laboratory parameters, erythrocyte sedimentation rate (24.7 +/- 15.5 vs 12.8 +/- 10.8 mm/h; p = 0.036) and C-reactive protein (24.0 +/- 14.9 vs 11.2 +/- 10.7 mg/l; p = 0.0167), was observed. In summary, MMF therapy reduced clinical and laboratory parameters of TA disease activity, suggesting that this drug is a promising immunosuppressive drug, particularly in refractory cases and as a steroid-sparing agent.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Anti-Inflammatory Agents, Non-Steroidal; Blood Sedimentation; Female; Humans; Immunosuppressive Agents; Inflammation; Male; Mycophenolic Acid; Prospective Studies; Takayasu Arteritis; Time Factors

Evidence that was obtained in several experimental models and in strains of hypertensive rats indicates that infiltration of inflammatory cells and oxidative stress in the kidney play a role in the induction and maintenance of hypertension. Similar evidence is lacking in human hypertension, at least in part, because immunosuppressive treatment is unjustified in patients with hypertension. For addressing this issue, patients who were prescribed by their private physicians mycophenolate mofetil (MMF) for the treatment of psoriasis or rheumatoid arthritis and had, in addition, grade I essential hypertension and normal renal function were studied. Eight patients were studied before MMF was started, during MMF treatment, and 1 mo after MMF treatment had been discontinued. Other treatments and diet were unchanged in the three phases of the study. MMF therapy was associated with a significant reduction in systolic, diastolic, and mean BP. Urinary excretion of TNF-alpha was reduced progressively by MMF treatment and increased after MMF was discontinued. Reduction of urinary malondialdehyde, TNF-alpha, and RANTES excretion during MMF administration did not reach statistical significance but had a direct positive correlation with the BP levels. These data are consistent with the hypothesis that renal immune cell infiltration and oxidative stress play a role in human hypertension.

Topics: Aged; Arthritis, Rheumatoid; Blood Pressure; Chemokine CCL5; Dose-Response Relationship, Drug; Female; Humans; Hypertension; Immunosuppressive Agents; Inflammation; Male; Middle Aged; Mycophenolic Acid; Psoriasis; Tumor Necrosis Factor-alpha

Cardiac allograft vasculopathy (CAV) remains the single most important complication impairing long-term survival after heart transplantation (HTx). Intimal hyperplasia as a response to immunologic and non-immunologic injury is involved in the pathogenesis. Because improved immunosuppressive properties with mycophenolate mofetil (MMF) have been shown within the first year, beneficial effects on intimal hyperplasia and systemic inflammation might be found late after HTx as well.. After a baseline examination with intravascular ultrasound (IVUS, volumetric assessment) 30 patients (2.0 +/- 1.1 years post-HTx) were prospectively randomized to receive either MMF (2 g/day) or to continue with azathioprine (AZA) as part of a triple immunosuppression protocol with cyclosporine and prednisolone. Markers of systemic inflammation and changes in vascular geometry were evaluated by IVUS after 1 year of follow-up.. With regard to inflammation, significantly lower values were found for high-sensitive C-reactive protein (CRP) in the MMF group (AZA 1.8 +/- 1.2 mg/liter. vs MMF 1.0 +/- 4.1 mg/liter, p = 0.02). Tumor necrosis factor (TNF)-alpha, interleukin (IL)-10, IL-6 and transforming growth factor (TGF)-beta did not differ between the groups. IVUS revealed no significant differences between groups. There was a weak trend toward a larger increase in plaque volume (AZA 13 +/- 43 mm(3) vs MMF 27 +/- 41 mm(3), p = 0.33), whereas MMF-treated patients tended to show a small increase in vessel dimensions (AZA +10 +/- 63 mm(3) vs MMF +50 +/- 87 mm(3), p = 0.17).. Changing immunosuppression from a standard AZA-based regimen to MMF resulted in a decrease in systemic inflammatory activity as indicated by levels of high-sensitive CRP. However, progression of intimal hyperplasia did not differ significantly, and the weak trend toward vascular enlargement could indicate some influence on vascular geometry.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Azathioprine; C-Reactive Protein; Cyclosporine; Female; Heart Transplantation; Humans; Hyperplasia; Immunosuppressive Agents; Inflammation; Male; Mycophenolic Acid; Pilot Projects; Prednisolone; Prospective Studies; Ultrasonography

Panniculitis, a type of inflammation of subcutaneous fat, is a relatively uncommon condition that usually presents as inflammatory nodules or plaques, with various proposed etiologic factors. The association between panniculitis and enthesitis-related arthritis has not been described previously.. Herein, we describe a case of a 11-year-old girl who presented with recurrent fever and painful subcutaneous nodules on her extremities and buttocks. Histological examination of the skin biopsy specimen revealed lobular panniculitis. Despite the use of prednisone and mycophenolate mofetil for several months, the patient experienced a relapse of skin lesions and additional symptoms of peripheral joint swelling and inflammatory lumbar pain. She was diagnosed with enthesitis-related arthritis after confirmation by imaging. The panniculitis demonstrated a sustained response when a tumor necrosis factor alpha inhibitor was used for enthesitis-related arthritis. At 2-year follow-up, her skin lesions and arthritis remained stable.. Although rare, panniculitis can be considered an unusual extra-articular manifestation of enthesitis-related arthritis based on clinical and pathological insights.

Topics: Arthritis, Juvenile; Child; Female; Humans; Inflammation; Mycophenolic Acid; Pain; Panniculitis

Schisandra sphenanthera Rehder & E.H. Wilson (S. sphenanthera) is a botanical medicine included in the 2020 edition of the ChP that has a variety of medicinal activities, including hepatoprotective, anticancer, antioxidant and anti-inflammatory properties. Wuzhi capsule (WZ) is a proprietary Chinese medicine made from an ethanolic extract of S. sphenanthera that is commonly used to treat drug-induced liver injury. However, there are no research reports exploring the effects of WZ on the prevention of mycophenolate mofetil (MMF)-induced intestinal injury and its underlying mechanisms.. This experiment aimed to evaluate the ameliorative effect of WZ on MMF-induced intestinal injury in mice and its underlying mechanisms.. A mouse model of MMF-induced intestinal injury was established and treated with WZ during the 21-day experimental period. The pathological characteristics of the mouse ileum were observed. Tight junction (TJ) protein changes were observed after immunofluorescence staining and transmission electron microscopy, and ROS levels were measured by using DHE fluorescent dye and the TUNEL assay for apoptosis. The expression of p65, p-p65, IκBα, p-IκBα, the TJ proteins occludin and ZO-1 and the apoptosis-related proteins Bax, Bcl-2, cleaved caspase-3 and caspase-3 were analysed by Western blot. Levels of DAO, ET, TNF-α, IL-1β, IL-6, IFN-γ, MDA and SOD were analysed by using kits.. MMF activated the NF-κB signaling pathway to cause intestinal inflammation, increased intestinal permeability, changed the expression of TJ protein in the intestinal epithelium, and increased oxidative stress and apoptosis levels. WZ significantly downregulated the expression of p-p65 and p-IκBα to relieve the inflammatory response, reduced intestinal permeability, maintained intestinal TJ protein expression, and reduced intestinal oxidative stress and apoptosis.. Our research suggested that MMF can cause intestinal injury; by contrast, WZ may exert anti-inflammatory, antioxidant and apoptosis-reducing effects to alleviate MMF-induced intestinal injury.

Topics: Animals; Animals, Outbred Strains; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Drugs, Chinese Herbal; Immunosuppressive Agents; Inflammation; Intestinal Diseases; Intestinal Mucosa; Intestines; Male; Mice; Mycophenolic Acid; Oxidative Stress

To characterise the peripheral blood cell (PBC) gene expression changes ensuing from mycophenolate mofetil (MMF) or cyclophosphamide (CYC) treatment and to determine the predictive significance of baseline PBC transcript scores for response to immunosuppression in systemic sclerosis (SSc)-related interstitial lung disease (ILD).. PBC RNA samples from baseline and 12-month visits, corresponding to the active treatment period of both arms in Scleroderma Lung Study II, were investigated by global RNA sequencing. Joint models were created to examine the predictive significance of. 134 patients with SSc-ILD (CYC=69 and MMF=65) were investigated. CYC led to an upregulation of erythropoiesis, inflammation and myeloid lineage-related modules and a downregulation of lymphoid lineage-related modules. The modular changes resulting from MMF treatment were more modest and included a downregulation of plasmablast module. In the longitudinal analysis, none of the baseline transcript module scores showed predictive significance for FVC% course in the CYC arm. In contrast, in the MMF arm, higher baseline lymphoid lineage modules predicted better subsequent FVC% course, while higher baseline myeloid lineage and inflammation modules predicted worse subsequent FVC% course.. Consistent with the primary mechanism of action of MMF on lymphocytes, patients with SSc-ILD with higher baseline lymphoid module scores had better FVC% course, while those with higher myeloid cell lineage activation score had poorer FVC% course on MMF.

Topics: Cyclophosphamide; Gene Expression Profiling; Humans; Immunosuppressive Agents; Inflammation; Lung; Lung Diseases, Interstitial; Mycophenolic Acid; Scleroderma, Systemic; Vital Capacity

Cardiac allograft vasculopathy (CAV) is a major prognosis limiting factor in heart transplantation (HTx). Disease development and progression are influenced by multiple determinants, but the role of remnant cholesterol (RC) in CAV has not yet been investigated. Therefore, the present study aimed to assess the prevalence of CAV in a very long-term follow-up after orthotopic HTx and to examine the role of RC in residual inflammation despite secondary prevention.. Herein, is a retrospective analysis of patient data collected at the last follow-up visit in an outpatient setting. Additionally, RC levels were calculated based upon cholesterol profile.. The study population consisted of 184 patients with a mean follow-up of 15.0 ± 6.8 years. More than 40% of the overall cohort had CAV at last follow-up. The mean RC was 27.1 ± 14.7 mg/dL. Patients with CAV had significantly elevated RC despite intensified statin treatment (p = 0.018). A positive correlation was observed between RC and interleukin-6 as a marker of residual inflammation. Elevated RC and prolonged follow-up emerged as significant factors related to CAV in a multivariate analysis (odds ratio [OR] 2.9, 95% confidence interval [CI] 1.5-5.5, p = 0.001 and OR 3.3, 95% CI 1.4-7.7, p = 0.006, respectively), whereas mycophenolate mofetil was inversely associated with CAV (OR 0.4, 95% CI 0.2-0.9, p = 0.034).. Remnant cholesterol has proinflammatory properties and is associated with CAV development in HTx. Thus, RC should be concerned as an additional tool for risk assessment.

Topics: Allografts; Cholesterol; Disease Progression; Follow-Up Studies; Heart Diseases; Heart Transplantation; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Interleukin-6; Mycophenolic Acid; Retrospective Studies

A 45-year-old male with cardiac sarcoidosis verified by cardiac biopsy presented with multiple coexisting arrhythmias, including ventricular tachycardia of more than 1000 episodes per 24 h, paroxysmal atrial fibrillation, and third-degree atrioventricular block. He did not respond to corticosteroids dose of 20-60 mg once daily and mycophenolate mofetil dose of 1 g twice daily for 6 months. Cardiac magnetic resonance (CMR) demonstrated inflammation and late gadolinium enhancement on right ventricular wall and interventricular septum. Positron emission tomography-computed tomography (PET-CT) showed multifocal

Topics: Adalimumab; Arrhythmias, Cardiac; Atrioventricular Block; Cardiomyopathies; Contrast Media; Fluorodeoxyglucose F18; Gadolinium; Humans; Inflammation; Male; Middle Aged; Mycophenolic Acid; Myocarditis; Positron Emission Tomography Computed Tomography; Sarcoidosis

Torasemide is a loop diuretic with a molecule that is chemically similar to the sulphonamides described as eosinophilic granulomatosis with polyangiitis (EGPA) triggering drugs. The presented case is probably the first description of torasemide-induced vascular purpura in the course of EGPA. Any diagnosis of vasculitis should be followed by an identification of drugs that may aggravate the disease. A 74-year-old patient was admitted to the Department of Dermatology with purpura-like skin lesions on the upper, and lower extremities, including the buttocks. The lesions had appeared around the ankles 7 days before admission to the hospital and then started to progress upwards. The patient complained on lower limb paresthesia and pain. Other comorbidities included bronchial asthma, chronic sinusitis, ischemic heart disease, mild aortic stenosis, arterial hypertension, and degenerative thoracic spine disease. The woman had previously undergone nasal polypectomy twice. She was on a constant regimen of oral rosuvastatin 5 mg per day, spironolactone 50 mg per day, metoprolol 150 mg per day, inhaled formoterol 12 μg per day, and ipratropium bromide 20 μg per day. Ten days prior to admission, she was commenced on torasemide at a dose of 50 mg per day prescribed by a general practitioner due to high blood pressure. Doppler ultrasound upon admission to the hospital excluded deep venal thrombosis. The laboratory tests revealed leukocytosis (17.1 thousand per mm3) with eosinophilia (38.6%), elevated plasma level of C-reactive protein (119 mg per L) and D-dimers (2657 ng per mm3). Indirect immunofluorescent test identified a low titer (1:80) of antinuclear antibodies, but elevated (1:160) antineutrophil cytoplasmic antibodies (ANCA) in the patient's serum. Immunoblot found them to be aimed against myeloperoxidase (pANCA). A chest X-ray showed increased vascular lung markings, while high-resolution computed tomography revealed peribronchial glass-ground opacities. Microscopic evaluation of skin biopsy taken from the lower limbs showed perivascular infiltrates consisting of eosinophils and neutrophils, fragments of neutrophil nuclei, and fibrinous necrosis of small vessels. Electromyography performed in the lower limbs because of their weakness highlighted a loss of response from both sural nerves, as well as slowed conduction velocity of the right tibial nerve and in both common peroneal nerves. Both clinical characteristics of skin lesions and histopathology suggested a

Topics: Adolescent; Aged; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Antinuclear; Antihypertensive Agents; Asthma; C-Reactive Protein; Churg-Strauss Syndrome; Eosinophilia; Female; Formoterol Fumarate; Granulomatosis with Polyangiitis; Humans; IgA Vasculitis; Inflammation; Ipratropium; Leukotriene Antagonists; Metoprolol; Mycophenolic Acid; Peroxidase; Prednisone; Purpura; Receptors, Fc; Rosuvastatin Calcium; Sodium Potassium Chloride Symporter Inhibitors; Spironolactone; Sulfanilamides; Torsemide

Topics: Aged; Anemia, Aplastic; Behcet Syndrome; Female; Humans; Immunosuppressive Agents; Inflammation; Mycophenolic Acid

Chronic inflammatory axonal polyneuropathy (CIAP) is defined on the basis of the clinical, electrophysiological and nerve biopsy findings and therapeutic responses of 'immunotherapy responding chronic axonal polyneuropathy (IR-CAP)'.. The diagnosis of IR-CAP was made when all of three of the following mandatory criterion were met: (1) acquired, chronic progressive or relapsing symmetrical or asymmetrical polyneuropathy with duration of progression >2 months; (2) electrophysiological evidence of axonal neuropathy in at least two nerves without any evidence of 'strict criteria of demyelination'; and (3) definite responsiveness to immunotherapy.. Thirty-three patients with IR-CAP showed similar clinical features of chronic inflammatory demyelinating polyneuropathy (CIDP) except 'motor neuropathy subtype'. High spinal fluid protein was found in 27/32 (78%) cases. 'Inflammatory axonal neuropathy' was proven in 14 (45%) of 31 sural nerve biopsies.. IR-CAP could well be 'axonal CIDP' in view of clinical similarity, but not proven as yet. Thus, IR-CAP is best described as CIAP, a distinct entity that deserves its recognition in view of responsiveness to immunotherapy.. Diagnosis of CIAP can be made by additional documentation of 'inflammation' by high spinal fluid protein or nerve biopsy in addition to the first two diagnostic criteria of IR-CAP.

Topics: Adolescent; Adult; Aged; Autoimmune Diseases of the Nervous System; Axons; Azathioprine; Biopsy; Child; Child, Preschool; Chronic Disease; Cyclophosphamide; Cyclosporine; Electromyography; Female; Humans; Immunoglobulins, Intravenous; Immunologic Factors; Inflammation; Male; Middle Aged; Mycophenolic Acid; Neural Conduction; Polyneuropathies; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating; Sural Nerve; Young Adult

Topics: Adrenal Cortex Hormones; Antimetabolites; Humans; Immunosuppressive Agents; Inflammation; Methotrexate; Mycophenolic Acid; Uveitis

Inflammation occurring within the transplanted organ from the time of harvest is an important stimulus of early alloimmune reactivity and promotes chronic allograft rejection. Chronic immune-mediated injury remains the primary obstacle to the long-term success of organ transplantation. However, organ transplantation represents a rare clinical setting in which the organ is accessible

Topics: Animals; Drug Delivery Systems; Female; Graft Rejection; Heart Transplantation; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Male; Mice; Mice, Inbred C57BL; Mycophenolic Acid; Nanomedicine; Nanoparticles; Preoperative Care; Transplants

Blood pressure visit-to-visit variability is a novel risk factor for deleterious long-term cardiac and renal outcomes in the general population. We hypothesized that patients with systemic lupus erythematosus (SLE) have greater blood pressure visit-to-visit variability than control subjects and that blood pressure visit-to-visit variability is associated with a higher comorbidity burden.. We studied 899 patients with SLE and 4172 matched controls using de-identified electronic health records from an academic medical center. We compared blood pressure visit-to-visit variability measures in patients with SLE and control subjects and examined the association between blood pressure visit-to-visit variability and patients' characteristics.. Patients with SLE had higher systolic blood pressure visit-to-visit variability 9.7% (7.8-11.8%) than the control group 9.2% (7.4-11.2%),. Patients with SLE had higher blood pressure visit-to-visit variability than controls, and this increased blood pressure visit-to-visit variability was associated with greater Charlson comorbidity scores, several clinical characteristics and immunosuppressant medications. In particular, hydroxychloroquine prescription was associated with lower blood pressure visit-to-visit variability.

Topics: Adrenal Cortex Hormones; Adult; Blood Pressure; Case-Control Studies; Comorbidity; Cyclophosphamide; Databases, Factual; Female; Humans; Hydroxychloroquine; Hypertension; Inflammation; Logistic Models; Lupus Erythematosus, Systemic; Male; Middle Aged; Multivariate Analysis; Mycophenolic Acid; Risk Factors; Severity of Illness Index

To compare mycophenolate mofetil (MMF) to methotrexate (MTX) as corticosteroid-sparing therapy for ocular inflammatory diseases.. Retrospective analysis of cohort study data.. Participants were identified from the Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study. Demographic and clinical characteristics were obtained via medical record review. The study included 352 patients who were taking single-agent immunosuppression with MTX or MMF at 4 tertiary uveitis clinics. Marginal structural models (MSM)-derived statistical weighting created a virtual population with covariates and censoring patterns balanced across alternative treatments. With this methodological approach, the results estimate what would have happened had none of the patients stopped their treatment. Survival analysis with stabilized MSM-derived weights simulated a clinical trial comparing MMF vs MTX for noninfectious inflammatory eye disorders. The primary outcome was complete control of inflammation on prednisone ≤10 mg/day, sustained for ≥30 days.. The time to success was shorter (more favorable) for MMF than MTX (hazard ratio = 0.68, 95% confidence interval: 0.46-0.99). Adjusting for covariates, the proportion achieving success was higher at every point in time for MMF than MTX from 2 to 8 months, then converges at 9 months. The onset of corticosteroid-sparing success took more than 3 months for most patients in both groups. Outcomes of treatment (MMF vs MTX) were similar across all anatomic sites of inflammation. The incidence of stopping therapy for toxicity was similar in both groups.. Our results suggest that, on average, MMF may be faster than MTX in achieving corticosteroid-sparing success in ocular inflammatory diseases.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; Child, Preschool; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Infant; Inflammation; Male; Methotrexate; Middle Aged; Mycophenolic Acid; Prednisone; Retrospective Studies; Scleritis; Uveitis; Visual Acuity

IgG4-related disease (IgG4-RD) is a systemic fibro-inflammatory disease. This disease may be associated with elevated serum and tissue IgG4 levels. Early treatment prevents fibrosis and organ damage. We retrospectively studied the clinicopathologic correlation and outcome of treatment in IgG4-RD. This single-center retrospective study was done using electronic records of patients subjected to assay of serum IgG4 levels in our laboratory by nephelometry. There were 473 patients with suspected IgG4-RD. Of them, 41 patients fulfilled comprehensive diagnostic criteria for IgG4-RD and 432 had diseases other than IgG4-RD. Clinical and histopathological data including tissue IgG4/IgG ratio, other relevant laboratory findings as well as management data of 41 patients with IgG4-RD were analyzed. There were 29 males and 12 females with mean age of 44.1 ± 2.19 years. Thirteen patients had definite, 19 had probable and 9 had possible IgG4-RD. Male predominance, multiple organ involvement and IgG4 responder Index were significantly higher in definite IgG4-RD as compared to probable and possible IgG4-RD. Serum IgG4 level was elevated in 37 patients (90.2%). Glucocorticoids were used in 35 patients (85.4%) and second-line immunosuppressive agent in 23 patients (65.7%). Of the 21 patients on follow-up, 19 (90.7%) had clinical improvement at the first follow-up visit. Nine (90%) out of the ten patients who were assessed by IgG4 responder index, also had shown improved score with treatment. Patients with IgG4-RD in our series showed favorable responses to treatment with glucocorticoids and addition of steroid sparing immunosuppressive agents (mainly mycophenolate mofetil) helped successful tapering of steroids, while maintaining the improvement.

Topics: Adult; Autoimmune Diseases; Autoimmunity; Biomarkers; Drug Therapy, Combination; Electronic Health Records; Female; Fibrosis; Glucocorticoids; Hospitals, Teaching; Humans; Immunoglobulin G; Immunosuppressive Agents; India; Inflammation; Male; Middle Aged; Mycophenolic Acid; Remission Induction; Retrospective Studies; Tertiary Care Centers; Time Factors; Treatment Outcome

Due to the imbalance between hyper-inflammation and hypo-inflammation, which are characterized by excessive cytokine productions and programmed death 1 (PD-1) upregulation, respectively, sepsis remains a highly lethal inflammatory syndrome with limited effective therapies. Mycophenolate mofetil (MMF), an immunosuppressant, has been reported to attenuate various inflammatory diseases. However, the role of MMF in sepsis therapy remains to be elucidated. C57BL-6J mice underwent cecal ligation and puncture (CLP) and were treated either with or without MMF. Survival rate and organ injuries were compared. Cytokine levels, bacteria clearance, apoptosis of spleen and peritoneal macrophages, and PD-1 expression were assessed. At the beginning of CLP, 60 mg/kg MMF administered by gavage significantly protected septic mice, which was evidenced by improved survival and attenuated organ injuries, decreased cytokines, lower bacterial loads, and alleviated immune cell apoptosis. In addition, immune cells in the MMF mice showed lower PD-1 expression and improved immune response to pathogeny stimuli. MMF protects septic mice via the dual inhibition of cytokine releasing and PD-1 expression.

Topics: Animals; Apoptosis; Bacterial Load; Cytokines; Inflammation; Mice; Mycophenolic Acid; Programmed Cell Death 1 Receptor; Protective Agents; Sepsis; Survival Rate

Topics: Abatacept; Enzyme Inhibitors; Glomerulonephritis, IGA; Humans; Immunosuppressive Agents; Inflammation; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Tendons

Insults to the airway epithelium play a key role in constrictive bronchiolitis after lung transplantation, the typical hallmark of chronic rejection. Our hypothesis is that immunosuppressives might affect airway integrity.. A biculture of human bronchial epithelial cells and lung microvascular endothelial cells was exposed to immunosuppressives (serum through levels) for 24 hours or 4 days. Cytotoxicity, transepithelial electrical resistance (TEER), and permeability was measured after exposure to monotherapies and combination therapies. Apoptosis, oxidative stress, inflammation (IL-8), real-time polymerase chain reaction for epithelial-to-mesenchymal transition and tight junction proteins were assessed in exposed cells.. Mycophenolate mofetil (MMF) and combination therapies including MMF, at serum trough levels and higher, are toxic for the human bronchial epithelial cells after 4-day exposure. Moreover, already after 24 hours, TEER of cells exposed to MMF decreases and permeability increases. MMF did not induce apoptosis, oxidative stress, loss of tight junctions or production of IL-8 after 24 hours, but possibly induces epithelial-to-mesenchymal transition in epithelial cells. MMF was detectable at both sides of the biculture and was also present in bronchoalveolar lavage of lung transplantation patients. Other immunosuppressives were not toxic, neither changed TEER or permeability.. Our findings suggest that MMF is present in the airways of lung transplant patients and might affect the structural integrity of the airway, which needs further investigation and validation in the clinical setting.

Topics: Azathioprine; Bronchiolitis Obliterans; Cyclosporine; Dexamethasone; Endothelial Cells; Epithelial Cells; Epithelial-Mesenchymal Transition; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Inflammation; Interleukin-8; Lung; Lung Transplantation; Microcirculation; Mycophenolic Acid; Permeability; Tacrolimus; Tight Junctions

To evaluate the effectiveness and safety of mycophenolate mofetil (MMF) as first-line therapy combined with systemic corticosteroids in initial-onset acute uveitis associated with Vogt-Koyanagi-Harada (VKH) disease.. This prospective study included 38 patients (76 eyes). The main outcome measures were final visual acuity, corticosteroid-sparing effect, progression to chronic recurrent granulomatous uveitis and development of complications, particularly 'sunset glow fundus'.. The mean follow-up period was 37.0 ± 29.3 (range 9-120 months). Visual acuity of 20/20 was achieved by 93.4% of the eyes. Corticosteroid-sparing effect was achieved in all patients. The mean interval between starting treatment and tapering to 10 mg or less daily was 3.8 ± 1.3 months (range 3-7 months). Twenty-two patients (57.9%) discontinued treatment without relapse of inflammation. The mean time observed off of treatment was 28.1 ± 19.6 months (range 1-60 months). None of the eyes progressed to chronic recurrent granulomatous uveitis. The ocular complications encountered were glaucoma in two eyes (2.6%) and cataract in five eyes (6.6%). None of the eyes developed 'sunset glow fundus', and none of the patients developed any systemic adverse events associated with the treatment.. Use of MMF as first-line therapy combined with systemic corticosteroids in patients with initial-onset acute VKH disease prevents progression to chronic recurrent granulomatous inflammation and development of 'sunset glow fundus'.

Topics: Acute Disease; Administration, Oral; Adolescent; Adult; Child; Disease Progression; Drug Therapy, Combination; Enzyme Inhibitors; Female; Fundus Oculi; Glucocorticoids; Humans; Inflammation; Injections, Intravenous; Male; Methylprednisolone; Mycophenolic Acid; Prednisone; Prospective Studies; Recurrence; Uveitis; Uveomeningoencephalitic Syndrome; Visual Acuity

Biochemical remission is widely considered a satisfactory treatment end point in autoimmune hepatitis (AIH). The significance of persisting histological activity despite biochemical remission is unknown. We aimed to assess the frequency and prognostic significance of persisting histological inflammation in patients with AIH who had achieved biochemical remission with treatment.. We studied 120 patients (median age at diagnosis 57 years; 81% female) with AIH by International Criteria (59% definite), who received immunosuppressive treatment and underwent a follow-up liver biopsy after at least 6 months of sustained biochemical remission (defined as normal serum ALT and globulin).. Fifty-five patients (46%) had persisting histological activity (Ishak histological activity index (HAI) ≥4). These patients had higher serum ALT (24 vs. 18 IU/l, P=0.003) and AST (27 vs. 23 IU/l, P=0.03) at the time of follow-up biopsy, compared with patients who achieved histological remission (HAI ≤3). They had less frequent regression of fibrosis on follow-up biopsy compared with those achieving histological remission (32 vs. 60%, P=0.004) and had excess mortality (standardized mortality ratio 1.4 vs. 0.7, P<0.05). The excess mortality was due to liver disease. On multivariate analysis, persisting histological activity was independently associated with all-cause death/transplantation (HR 3.1 (95% CI 1.2-8.1); P=0.02); an association with liver-related death/transplantation fell short of significance (HR 9.7 (95% CI 0.84-111.6; P=0.07).. Persisting histological activity, despite biochemical remission, is frequent in patients with treated AIH and is associated with lower rates of fibrosis regression and reduced long-term survival.

Topics: Adult; Aged; Anti-Inflammatory Agents; Azathioprine; Biomarkers; Biopsy; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Inflammation; Kaplan-Meier Estimate; Liver Cirrhosis; Male; Middle Aged; Mycophenolic Acid; Predictive Value of Tests; Prednisolone; Prognosis; Proportional Hazards Models; Retrospective Studies; Time Factors

Mycophenolate mofetil (MMF) has beneficial effects in cardiac transplant patients beyond the suppression of tissue rejection. Moreover, mycophenolic acid (MPA), its active metabolite, has been associated with positive effects on atherosclerosis in animal models. The attachment of leukocytes to the vascular endothelium and the subsequent migration of these cells into the vessel wall are early events in inflammation and atherosclerosis. The aim of this study was to investigate the effects of MPA on tumour necrosis-α (TNF-α)-induced, endothelial cell proinflammatory responses and the underlying mechanisms.. Human aortic endothelial cells (HAECs) were treated with different concentrations (primarily 50 μM) of MPA before treatment with TNF-α. The surface protein and mRNA expressions of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were determined by flow cytometry and real-time RT-PCR, respectively. Adhesion of leukocytes to TNF-α-treated HAECs was evaluated by an adhesion assay. Activation of mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) was evaluated by measuring the levels of their phosphorylation using flow cytometry. NF-κB p65 translocation was detected by Western blotting. The production of reactive oxygen species (ROS) was determined by reduction in fluorescent 2',7'-dichlorofluorescein diacetate (H2 DCFH-DA). MPA significantly inhibits TNF-α-induced ICAM-1, VCAM-1 surface protein and mRNA expression as well as adhesion of mononuclear leukocytes to HAEC. ICAM-1 and VCAM-1 expressions were also reduced by antioxidants such as pyrrolidine dithiocarbamate, diphenylene iodonium and apocynin. MPA inhibited TNF-α-stimulated ROS generation similarly to apocynin. TNF-α increased ICAM-1 and VCAM-1 expression via c-Jun NH2 -terminal kinase (JNK), extracellular signal-regulated kinase (ERK1/2) and p38 MAPK. MPA and apocynin inhibited TNF-α-induced phosphorylation of all three MAP kinases. Furthermore, TNF-α-induced NF-κB activation was attenuated by SP600125 (JNK inhibitor), PD98059 (ERK1/2 inhibitor, SB203580 (p38 MAPK inhibitor) and MPA. MPA also inhibited TNF-α-induced nuclear translocation of NF-κB p65.. These results suggest that, in addition to the prevention of rejection, MPA may be a promising approach for the treatment of inflammatory vascular disease.

Topics: Cell Line; Endothelial Cells; Enzyme Inhibitors; Humans; Inflammation; Mitogen-Activated Protein Kinases; Mycophenolic Acid; NF-kappa B; Phosphorylation; Reactive Oxygen Species; Signal Transduction; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1

Macrophages are involved in the development and progression of kidney fibrosis. The aim of this study was to analyse the phenotype of circulating monocytes and their ability to predict kidney allograft dysfunction in living kidney transplant recipients. Whole blood samples from 25 kidney recipients and 17 donors were collected at five time-points. Monocyte phenotype was analysed by flow cytometry, and interleukin (IL)-10 and soluble CD163 by enzyme-linked immunosorbent assay. One week after transplantation, surface CD163 and IL-10 levels increased significantly from baseline [2·99 ± 1·38 mean fluorescence intensity (MFI) to 5·18 ± 2·42 MFI for CD163; 4·5 ± 1·46 pg/ml to 6·7 ± 2·5 pg/ml for IL-10]. This CD163 increase correlated with 4-month creatinine levels (r = 0·4394, P = 0·04). However, soluble CD163 decreased significantly from baseline at 1 week (797·11 ± 340·45 ng/ml to 576·50 ± 293·60 ng/ml). CD14(+) CD16(-) monocytes increased at 4 months and correlated positively with creatinine levels at 12 and 24 months (r = 0·6348, P = 0·002 and r = 0·467, P = 0·028, respectively) and negatively with Modification of Diet in Renal Disease (MDRD) at 12 months (r = 0·6056, P = 0·003). At 4 months, IL-10 decreased significantly (P = 0·008) and correlated positively with creatinine at 2 years (r = 0·68, P = 0·010) and with CD14(+) CD16(-) monocytes at 4 months (r = 0·732, P = 0·004). At 24 h, levels of human leucocyte antigen D-related declined from 12·12 ± 5·99 to 5·21 ± 3·84 and CD86 expression decreased from 2·76 ± 1·08 to 1·87 ± 0·95. Both markers recovered progressively until 12 months, when they decreased again. These results indicate that monitoring monocytes could be a promising new prognostic tool of graft dysfunction in renal transplant patients.

Topics: Allografts; Antigens, CD; Antigens, Differentiation, Myelomonocytic; B7-2 Antigen; Creatinine; Female; Fibrosis; HLA-DR Antigens; Humans; Immunosuppressive Agents; Inflammation; Interleukin-10; Kidney; Kidney Transplantation; Lipopolysaccharide Receptors; Macrophages; Male; Middle Aged; Monocytes; Mycophenolic Acid; Phenotype; Prednisone; Primary Graft Dysfunction; Prospective Studies; Receptors, Cell Surface; Receptors, IgG; Spain; Tacrolimus

GPB are often performed in PRT to detect subclinical acute rejection or IF/TA. Reducing immunosuppression side effects without increasing rejection is a major concern in PRT. We report the results of GPB in children transplanted with a steroid-sparing protocol adapted to immunological risk. Children under 18 yr who received a renal transplantation between April 1, 2009 and May 31, 2012 were included. Immunosuppression consisted of an antibody induction therapy, tacrolimus, and MMF for all recipients. CSs were administered to children under five yr old, or receiving a second allograft. Twenty-eight children were included, 50% were CSs free. GPB were performed between three and six months. IF/TA was documented in seven biopsies; four of these seven children were CS free. One child, with CSs, presented a borderline rejection, and another child, steroid free, with significant inflammatory interstitial infiltrate, considered as a subclinical rejection, was treated with CSs pulses. The median eGFR was stable (74, 67.5, and 82 mL/min/1.73 m² at, respectively, seven days, three months, and one yr). Patient and graft survival were 100%. These results have to be confirmed in a larger cohort, with long-term follow-up.

Topics: Antibiotics, Antineoplastic; Biopsy; Child; Child, Preschool; Cohort Studies; Female; Graft Rejection; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Inflammation; Kidney Transplantation; Male; Mycophenolic Acid; Renal Insufficiency; Steroids; Tacrolimus

It was demonstrated that human natural killer (NK) cells, via antibody-dependent cellular cytotoxicity (ADCC)-like mechanism, increase IFNγ production after exposure to alloantigens. This finding was associated with an increased risk for antibody-mediated rejection (ABMR). Although the effects of various immunosuppressive drugs on T cells and B cells have been extensively studied, their effects on NK cells are less clear. This study reports the effect of immunosuppressive agents on antibody-mediated NK cell activation in vitro.. Whole blood from normal individuals was incubated with irradiated peripheral blood mononuclear cells (PBMCs) pretreated with anti-HLA antibody+ sera (in vitro ADCC), with or without immunosuppressive agents. The %IFNγ+ and CD107a+ (degranulation marker) in CD56+ NK cells were enumerated by flow cytometry.. Cyclosporine A and tacrolimus significantly reduced IFNγ production in a dose-dependent manner (53%-83%), but showed minimal effect on degranulation (20%). Prednisone significantly reduced both IFNγ production and degranulation (50%-66% reduction at maximum therapeutic levels). Calcineurin inhibitors (CNIs) in combination with prednisone additively suppressed IFNγ production and degranulation. The effect of sirolimus or mycophenolate mofetil on NK cells was minimal.. These results suggest that potent suppressive effects of CNIs and prednisone on antibody-mediated NK cell activation may contribute to the reduction of ADCC in sensitized patients and possibly reduce the risk for ADCC-mediated ABMR. These further underscore the importance of medication compliance in prevention of ABMR and possibly chronic rejection, and suggest that ADCC-mediated injury may increase in strategies aimed at CNI or steroid minimization or avoidance.

Topics: Antibodies; Antibody-Dependent Cell Cytotoxicity; Calcineurin Inhibitors; CD56 Antigen; Cyclosporine; Dose-Response Relationship, Drug; Flow Cytometry; Gene Expression Regulation; HLA Antigens; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Inflammation; Interferon-gamma; Killer Cells, Natural; Leukocytes, Mononuclear; Lysosomal-Associated Membrane Protein 1; Mycophenolic Acid; Risk; Sirolimus; Tacrolimus

Topics: Antibodies, Monoclonal; Basiliximab; Cytomegalovirus; Cytomegalovirus Infections; Female; Ganciclovir; Glomerulonephritis, IGA; HIV Seronegativity; Humans; Immunosuppression Therapy; Inflammation; Kidney Transplantation; Middle Aged; Mycophenolic Acid; Prednisolone; Recombinant Fusion Proteins; Renal Dialysis; Renal Insufficiency; Sinusitis; Tacrolimus; Valganciclovir

In human, autoimmune uveitis is a leading cause of visual disability and ranks with diabetic retinopathy as a major source of blind registrations in developed countries. Since most cases of non-infectious uveitis are considered to be autoimmune or at least immune-mediated, the management of such patients has rested on appropriate immunosuppression. Some patients, however, despite maximal immunotherapy, fail to respond or are seriously intolerant of the drug therapies. Since its establishment 20 years ago, the model of experimental autoimmune uveoretinitis has served as a useful template for novel therapeutic approaches. The aim of our study was to compare the efficacy of mycophenolate mofetil and cyclophosphamide and golimumab treatment in the mouse model of experimental autoimmune uveitis. The intensity of intraocular inflammation was evaluated histologically in the treatment and control groups. Experimental autoimmune uveitis has been induced in mouse strain C57BL/6 by subcutaneous application of interphotoreceptor retinoid binding protein in complete Freund's adjuvant and pertussis toxin. The treatment was commenced on the day of uveitis induction. Cyclophosphamide was applied intraperitoneally in a single dose (100 mg/kg), mycophenolate mofetil intraperitoneally daily (30 mg/kg or 50 mg/kg), golimumab subcutaneously weekly (70 mg/kg). Sham intraperitoneal injection of a placebo (aqua pro injectione) and untreated mice with experimental autoimmune uveitis served as controls. The results show statistically significant suppression of experimental uveitis both with mycophenolate mofetil and with cyclophosphamide, and thus support its use in human medicine.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Cyclophosphamide; Disease Models, Animal; Inflammation; Mice; Mice, Inbred C57BL; Mycophenolic Acid; Uveitis

Clinical studies suggest that the immunosuppressant MPA is associated with impaired wound healing. It is believed that the main cause of impairment is the inhibition of inflammatory response. However, it is unknown whether MPA may directly affect epidermal cells. The aim of our study was to examine the direct influence of mycophenolic acid, the selective blocker of de novo purine synthesis, on human epidermal keratinocyte morphology, proliferation, motile activity, and differentiation in in vitro culture. The number of keratinocytes cultured in the presence of MPA was counted and cell motility was measured by a time-lapse computer-aided method. Cell morphology was determined by flow and image cytometry methods. Real-time RT-PCR analysis was employed to investigate the expression of markers of differentiation. We showed that MPA induces irreversible inhibition of cell proliferation, causes cell enlargement and impairs cell locomotion in a time-dependent manner. The level of expression of differentiation markers was significantly reduced by MPA treatment. All these effects were reversed by the addition of guanine. Our results indicated that MPA impairs basic functions of human skin keratinocytes via intracellular guanosine nucleotide depletion, which may be directly reflected in wound healing problems in patients treated with this immunosuppressant.

Topics: Adolescent; Adult; Cell Differentiation; Cell Movement; Cell Proliferation; Cells, Cultured; Child; Enzyme Inhibitors; Female; Guanine; Guanine Nucleotides; Humans; Immunosuppression Therapy; Immunosuppressive Agents; IMP Dehydrogenase; Inflammation; Keratinocytes; Male; Mycophenolic Acid; Wound Healing

Septic shock is a systemic inflammatory response syndrome, and it is the leading cause of death in intensive care units. Mycophenolate mofetil (MMF) is an immunosuppressant that has been shown to be effective in the treatment of various inflammatory diseases. In this study, the anti-inflammatory effect of MMF in a mouse model of acute lung injury (ALI) induced by lipopolysaccharide (LPS) was evaluated. ALI was induced by intrapleural injection of LPS (250 ng/cavity). The leukocyte migration, exudation, myeloperoxidase and adenosine deaminase activities, nitric oxide products, tumor necrosis factor alpha (TNF-α), and interleukin 1 beta (IL-1β) levels, as well as mRNA expression of TNF-α and IL-1β, were evaluated. This study showed that MMF significantly decreased all parameters studied in a manner comparable to treatment with dexamethasone. In conclusion, MMF has important anti-inflammatory effects that may be useful as an auxiliary treatment for septic shock.

Topics: Acute Lung Injury; Adenosine Deaminase; Animals; Anti-Inflammatory Agents; Cell Movement; Dexamethasone; Disease Models, Animal; Immunosuppressive Agents; Inflammation; Interleukin-1beta; Leukocytes; Lipopolysaccharides; Lung; Mice; Mycophenolic Acid; Nitric Oxide; Peroxidase; RNA, Messenger; Shock, Septic; Tumor Necrosis Factor-alpha

Topics: Acute Pain; Aged; Arthritis, Rheumatoid; Calcitonin; Calcitonin Gene-Related Peptide; Humans; Inflammation; Interleukin-6; Male; Mycophenolic Acid; Protein Precursors; Withholding Treatment

A promising therapeutic approach to reducing inflammation is to inhibit the production of proinflammatory cytokines (e.g., tumor necrosis factor alpha [TNF-α], interleukin 1 beta [IL-1β], vascular endothelial growth factor alpha (VEGF-α), and, as shown more recently, interleukin-17 [IL-17]). In the present study, the authors have demonstrated the anti-inflammatory effects of mycophenolate mofetil (MMF) in in vivo experiments and have investigated the mechanism of action underlying those effects. Oral administration of MMF significantly inhibited leukocyte influx during the first (4 hours) and second (48 hours) phases of inflammation in a mouse model of pleurisy caused by carrageenan (P < .01). As expected, MMF suppressed protein levels of TNF-α, IL-1β, VEGF-α, and IL-17A (P < .01). This inhibitory effect was due to down-regulation of mRNA expression for these proinflammatory cytokines (P < .01). These results provide evidence of MMF-mediated inhibition of proinflammatory cytokines, and these anti-inflammatory effects are assumed to result mainly from the inhibition of the synthesis and release of TNF-α, IL-1β, VEGF-α, and IL-17A from activated leukocytes. These findings suggest that MMF might be an applicable therapeutic in the regulation of the inflammatory response-a response in which the humoral system plays a pivotal role.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Cytokines; Immunosuppressive Agents; Inflammation; Interleukin-17; Interleukin-1beta; Leukocytes; Mice; Mycophenolic Acid; Pleurisy; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

To assess the long-term efficacy and tolerability of mycophenolate mofetil (MMF) in the therapy of ocular mucous membrane pemphigoid (OcMMP).. Ten patients (19 eyes) with OcMMP treated with MMF, who had a follow-up of at least 4 years, were retrospectively analyzed. Main outcome measures were inflammatory control, progression of cicatrization, and side effects.. Control of inflammation was achieved in 11 eyes (58%) of 6 patients (rate: 0.11/PY). Mild inflammatory activity was observed in 8 eyes (42%) of 4 patients (rate: 0.07/PY). Progression of conjunctival cicatrization was prevented in 47% (9/19) of the eyes. Mild progression of cicatrization was found in 42% (8/19) of the eyes. Conjunctival cicatrization had progressed to stage IV in 1 patient (11%). Treatment-related side effects occurred in 7 patients (rate: 0.12/PY).. MMF is an effective agent for treatment of OcMMP. However, the drug cannot always prevent disease progression.

Topics: Aged; Cicatrix; Disease Progression; Female; Humans; Immunosuppressive Agents; Inflammation; Male; Middle Aged; Mycophenolic Acid; Pemphigoid, Benign Mucous Membrane; Retrospective Studies; Treatment Outcome

This protocol describes microsphere-based protease assays for use in flow cytometry and high-throughput screening. This platform measures a loss of fluorescence from the surface of a microsphere due to the cleavage of an attached fluorescent protease substrate by a suitable protease enzyme. The assay format can be adapted to any site or protein-specific protease of interest and results can be measured in both real time and as endpoint fluorescence assays on a flow cytometer. Endpoint assays are easily adapted to microplate format for flow cytometry high-throughput analysis and inhibitor screening.

Topics: Animals; Biotinylation; Flow Cytometry; Fluorescence Resonance Energy Transfer; Green Fluorescent Proteins; High-Throughput Screening Assays; Humans; Inflammation; Kinetics; Microspheres; Peptide Hydrolases; Peptides; Reproducibility of Results; Temperature

Bronchiolitis obliterans syndrome (BOS) is still the main complication after lung transplantation. Besides other improvements in post-operative management, newer immunosuppressive regimens might decrease the devastating sequelae of this complication.. We compared the prospectively collected data of lung transplant recipients treated either with azathioprine (AZA; n = 48) or mycophenolate mofetil (MMF; n = 108), who underwent regular monthly surveillance bronchoscopies for at least 6 post-operative months.. Patients on MMF had significantly fewer acute (P < 0.001) and recurrent (P < 0.001), as well as less severe rejection episodes (P = 0.01). In addition, MMF significantly reduced the number of alveolar lymphocytes, eosinophils and neutrophils (P < 0.001), and decreased the hemosiderin score reflecting non-specific alveolar-capillary damage (P < 0.001). Although there was no change in the three stages of BOS, there was a trend towards improved survival (P = 0.062) and a significant decrease in graft loss due to BOS (P = 0.049) in patients receiving MMF.. Immunosuppression with MMF significantly decreased the incidence, severity and recurrence of acute rejection episodes in lung transplant recipients. Parameters of alveolar inflammation and alveolar-capillary damage were also decreased. As a potential consequence, MMF significantly reduced graft loss due to BOS and tended to improve overall survival in these patients.

Topics: Adult; Azathioprine; Bronchiolitis Obliterans; Bronchoalveolar Lavage Fluid; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Inflammation; Lung Transplantation; Macrophages, Alveolar; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Pulmonary Alveoli; Treatment Outcome

Lupus nephritis (LN) is an immune inflammation of kidneys caused by systemic lupus erythematosus (SLE), a chronic inflammatory disease that affects the body's immune system. Aim of this study was to analyze clinical manifestation and treatment results of patients with LN. Forty one patients with clinical signs of LN were included in the study. Mean age of patients was 31.9+/-12.1 years in the moment of first diagnosis of LN, with female-male ratio 8:1. Renal disease was pathohistologically (PTH) verified in 53.7% of patients (4 pts with class III, 17 pts with class IV, one pt with class V of lupus nephrites). Patients with high nephrotic proteinuria were treated with pulse dose of methylprednisolone and pulse doses of cyclophosphamide (CYC) in induction therapy. Corticosteroid and CYC were continued according to treatment protocol. The other group of LN patients with lower nephrotic proteinuria was treated with mycophenolate mofetil (MMF) in induction therapy at a dose of 2x1 g/day for six months, and than in maintenance 2x0.5 g/day. The patients with non-nephrotic proteinuria and normal renal function were treated with oral prednisolone 0.75-1 mg/kg/day in a single morning dose, and then gradually reduced to the dose of maintenance. The mean time of patient's follow-up was 10.9+/-4.1 years. Partial renal remission was accomplished in 29.2% pts, and complete remission in 60.9% pts for period of 17.2+/-13.3 months from the beginning of the treatment. Duration of complete renal remission was 30.1+/-19.1 months. During the period of follow-up, 29.3% pts developed at least one nephritic flare and were treated again. These results confirmed that the aggressive form of lupus nephritis should be treated associating cyclophosphamide with corticosteroids therapeutical regiment. MMF is a new promising immunosuppressive drug for a treatment of this serious disease.

Topics: Adult; Cyclophosphamide; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Inflammation; Lupus Nephritis; Male; Methylprednisolone; Mycophenolic Acid; Proteinuria; Remission Induction; Time Factors; Treatment Outcome

Nucleotide depletion induced by the immunosuppressant mycophenolate mofetil (MMF) has been shown to exert neuroprotective effects. It remains unclear whether nucleotide depletion directly counteracts neuronal demise or whether it inhibits microglial or astrocytic activation, thereby resulting in indirect neuroprotection.. Effects of MMF on isolated microglial cells, astrocyte/microglial cell co-cultures and isolated hippocampal neurones were analysed by immunocytochemistry, quantitative morphometry, and elisa.. We found that: (i) MMF suppressed lipopolysaccharide-induced microglial secretion of interleukin-1β, tumour necrosis factor-α and nitric oxide; (ii) MMF suppressed lipopolysaccharide-induced astrocytic production of tumour necrosis factor-α but not of nitric oxide; (iii) MMF strongly inhibited proliferation of both microglial cells and astrocytes; (iv) MMF did not protect isolated hippocampal neurones from excitotoxic injury; and (v) effects of MMF on glial cells were reversed after treatment with guanosine.. Nucleotide depletion induced by MMF inhibits microglial and astrocytic activation. Microglial and astrocytic proliferation is suppressed by MMF-induced inhibition of the salvage pathway enzyme inosine monophosphate dehydrogenase. The previously observed neuroprotection after MMF treatment seems to be indirectly mediated, making this compound an interesting immunosuppressant in the treatment of acute central nervous system lesions.

Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Astrocytes; Cell Proliferation; Coculture Techniques; Guanosine; Hippocampus; Immunosuppressive Agents; Inflammation; Interleukin-1beta; Microglia; Microscopy, Confocal; Mycophenolic Acid; Neurons; Neuroprotective Agents; Nitric Oxide; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

To critically assess potentially carcinogenic effects of immunosuppressive therapy in the ocular inflammation setting.. Focused evidence assessment.. Relevant publications were identified by MEDLINE and EMBASE queries and reference list searches.. Extrapolation from transplant, rheumatology, skin disease, and inflammatory bowel disease cohorts to the ocular inflammation setting suggest that: 1) alkylating agents increase hematologic malignancy risk and cyclophosphamide increases bladder cancer risk, but less so with < or =18 months' duration of therapy and hydration, respectively; 2) calcineurin inhibitors and azathioprine probably do not increase total cancer risk to a detectable degree, except perhaps some other risk factors (uncommon in ocular inflammation patients) might interact with the former to raise risk; 3) tumor necrosis factor (TNF) inhibitors may accelerate diagnosis of cancer in the first six to 12 months, but probably do not increase long-term cancer risk; and 4) changes in risk with methotrexate, mycophenolate mofetil, and daclizumab appear negligible, although nontransplant data are limited for the latter agents. Immunosuppression in general may increase skin cancer risk in a sun exposure-dependent manner.. Use of alkylating agents for a limited duration seems justifiable for severe, vision-threatening disease, but otherwise cancer risk may be a relevant constraint on use of this approach. Antimetabolites, daclizumab, TNF inhibitors, and calcineurin inhibitors probably do not increase cancer risk to a degree that outweighs the expected benefits of therapy. Monitoring for skin cancer may be useful for highly sun-exposed patients. Data from ocular inflammation patients are needed to confirm the conclusions made in this analysis by extrapolation.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antimetabolites; Azathioprine; Daclizumab; Databases, Factual; Humans; Immunoglobulin G; Immunosuppressive Agents; Inflammation; Longitudinal Studies; Methotrexate; Mycophenolic Acid; Neoplasms; Risk Factors; Tumor Necrosis Factor-alpha; Uveitis

To compare the relative effectiveness and side effect profiles of antimetabolite drugs in the treatment of noninfectious ocular inflammation.. Retrospective cohort study.. A total of 257 patients with inflammatory eye disease seen in a single-center, academic practice and treated with an antimetabolite as a first-line immunosuppressive agent from 1984 to 2006.. Data recorded included demographics, antimetabolite and prednisone doses, use of other immunosuppressive drugs, response to therapy, and side effects associated with drug use.. Ability to control ocular inflammation and to taper prednisone to

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antimetabolites; Azathioprine; Child; Female; Glucocorticoids; Humans; Inflammation; Male; Methotrexate; Middle Aged; Mycophenolic Acid; Prednisone; Retrospective Studies; Scleritis; Uveitis

To investigate the effect of mycophenolate mofetil(MMF) on early inflammatory reaction of renal lesion in streptozotocin(STZ)-induced diabetic rats.. Thirty-six male Sprague-Dawley rats were randomly divided into 3 groups after uninephrectomy: normal control group, diabetic model group, and MMF-treated group. Six rats in each group were sacrificed at the 4th week and 14th week after STZ injection. Twenty-four hour urinary protein (24 h Upro) count was measured before death. The expressions of regulated on activation of normal T expressed and secreted (RANTES),ectodermal dysplasia (ED-1)and Col-IV protein in the renal tissue were detected by immunohistochemistry. The expression of RANTES mRNA in the renal tissue was detected by RT-PCR.. MMF prevented the increasing of 24h Upro in diabetic rats,and the expressions of RANTES,ED-1,Col-IV protein and RANTES mRNA in the kidney of MMF-treated rats were significantly decreased.. MMF plays an early renal protective role in diabetic nephropathy, possibly through inhibition of early inflammatory reaction.

Topics: Animals; Chemokine CCL5; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Ectodysplasins; Inflammation; Kidney; Male; Mycophenolic Acid; Random Allocation; Rats; Rats, Sprague-Dawley; RNA, Messenger

Topics: Acute Disease; Adult; Female; Humans; Immunosuppressive Agents; Inflammation; Lupus Erythematosus, Systemic; Mycophenolic Acid; Syndrome

The authors describe a young patient affected by long-standing polymyositis refractory to conventional treatment who showed a rapid and striking response to mycophenolate mofetil treatment.

Topics: Adult; Biopsy; Female; Humans; Immunoglobulins; Immunosuppressive Agents; Inflammation; Mycophenolic Acid; Polymyositis; Treatment Outcome

Hypertension is a likely consequence of chronic lead exposure in humans, especially in association with reduced renal function and in high risk populations. Numerous studies have demonstrated that oxidative stress plays an important role in the pathogenesis of experimental lead-induced hypertension and we have shown recently that tubulointerstitial immune cell infiltration is a feature of chronic low-dose lead exposure. Since oxidative stress, renal inflammation, and angiotensin activity are closely linked characteristics in experimental models of hypertension, we decided to investigate whether lead-induced hypertension would be ameliorated by suppressing renal inflammation with the immunosuppressive drug mycophenolate mofetil (MMF). We studied rats exposed for 14 wk to lead acetate (100 ppm in the drinking water) that, in addition, received either MMF, 20 mg.kg(-1).day(-1) by gastric gavage (Pb.MMF group, n = 12) or vehicle (Pb group, n = 12). Control rats received MMF alone (n = 5) or neither lead nor MMF (n = 6). All rats were killed at the end of the experiment. Low-dose lead exposure resulted in mild to moderate tubular cell damage and a progressive increment in blood pressure, oxidative stress, interstitial accumulation of lymphocytes and macrophages, NF-kappaB activation, and increased renal angiotensin II level. The administration of MMF suppressed the tubulointerstitial accumulation of lymphocytes and macrophages and prevented the hypertension, oxidative stress, and NF-kappaB activation and reduced the heightened renal angiotensin content associated with chronic lead exposure. We conclude that interstitial inflammation plays an important role in lead-induced hypertension.

Topics: Angiotensin II; Animals; Blood Pressure; Body Weight; Creatinine; Hypertension; Immunosuppressive Agents; Inflammation; Kidney Diseases; Lead; Lymphocytes; Macrophages; Male; Malondialdehyde; Mycophenolic Acid; Oxidative Stress; Proteinuria; Rats; Rats, Sprague-Dawley; Superoxides; Transcription Factor RelA

Anomalous inflammatory responses triggered by the metabolic syndrome cause renal injury. This discovery links renal lipid accumulation with lipotoxicity to inflammation and may explain the insidious fibrosis and cellular decay characteristic of nephropathy in the metabolic syndrome. However, it is not clear whether control of inflammation protects the kidney independently of lipid accumulation, which is a required step for lipotoxicity in hyperglycemia and dyslipidemia. We hypothesized that in rats with the metabolic syndrome, and overt nephropathy, treatment with mycophenolate mofetil (MMF; 10 mg.kg(-1).day(-1) ip for 14 wk) would reduce the abnormal renal lipid depots and limit renal inflammation and injury. We studied groups of lean and obese F1 hybrid Zucker fatty diabetic/spontaneous hypertensive heart failure (ZS) rats. MMF did not affect lean rats. In obese ZS rats, MMF did not change severe hyperglycemia or the higher kidney loads of unutilized lipid and peroxidation products. Nonetheless, MMF dramatically reduced diabetes/obesity-derived systemic and renal inflammation, limited renal size, hyperfiltration, and fibrosis. These data indicate that in rats, anti-inflammatory therapy presumably acting downstream, and independently of lipotoxicity, can effectively limit renal injury and fibrosis.

Topics: Aging; Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Glucose; Cholesterol; Inflammation; Kidney; Kidney Diseases; Male; Metabolic Syndrome; Mycophenolic Acid; Obesity; Phenotype; Rats; Triglycerides

Immunosuppressive therapies allow long-term patient and transplant survival, but are associated with increased development of UV-induced skin cancers, particularly squamous cell carcinomas. The mechanisms by which CsA, MMF, tacrolimus (TAC) or sirolimus (SRL), alone or in dual combinations, influence tumor development and progression are not completely understood. In the current study, chronically UV-exposed mice treated with SRL alone or in combination with CsA or TAC developed more tumors than mice treated with vehicle or other immunosuppressants, but the tumors were significantly smaller and less advanced. Mice treated with CsA or TAC developed significantly larger tumors than vehicle-treated mice, and a larger percentage in the CsA group were malignant. The addition of MMF to CsA, but not to TAC, significantly reduced tumor size. Immunosuppressant effects on UVB-induced inflammation and tumor angiogenesis may explain these findings. CsA enhanced both UVB-induced inflammation and tumor blood vessel density, while MMF reduced inflammation. Addition of MMF to CsA reduced tumor size and vascularity. SRL did not affect inflammation, but significantly reduced tumor vascularity. Thus the choice of immunosuppressants has important implications for tumor number, size and progression, likely due to the influence of immunosuppressants on UVB-induced inflammation and angiogenesis.

Topics: Animals; Blood Vessels; Carcinoma, Squamous Cell; Cyclosporine; Disease Models, Animal; Drug Therapy, Combination; Female; Immunosuppressive Agents; Inflammation; Mice; Mice, Hairless; Mycophenolic Acid; Neoplasms, Radiation-Induced; Neovascularization, Pathologic; Sirolimus; Skin Neoplasms; Tacrolimus; Ultraviolet Rays

The aim of this experimental study was to investigate the effect of mycophenolate mofetil (MMF) during the three phases of colonic anastomosis healing and specifically to check the effect of MMF on the expression of transforming growth factor-beta1 (TGF-beta1), one of the most important growth factors contributing to mechanical stability of colonic anastomosis.. Sixty male Wistar rats underwent colonic resection and end-to-end anastomosis. The animals were divided into two groups, a study group given MMF 40 mg/kg, intraduodenally and a control group given vehicle. The rats were sacrificed at 3, 7, and 14 days (10 animals in each group). The anastomoses were tested by measuring bursting pressure and hydroxyproline content. Histological examination and immunohistochemical expression of TGF-beta1 also were assessed.. The mean bursting pressure in the study group was significantly lower on day 3 and 7, but there was no statistical significance on day 14. The mean hydroxyproline content was lower in the study group on days 3, 7, and 14. Histology showed decreased number of macrophages and fibroblasts on days 3 and 7 but no difference on day 14. The expression of TGF-beta1 was significantly reduced in the study group, with the difference being more pronounced on days 3 and 7.. MMF weakens the integrity of colonic anastomosis, and this effect is more significant during the inflammatory phase of healing. MMF has a negative effect on macrophages and TGF-beta1 expression, resulting in decreased collagen accumulation at the anastomosis.

Topics: Anastomosis, Surgical; Animals; Colon; Fibroblasts; Hydroxyproline; Immunohistochemistry; Immunosuppressive Agents; Inflammation; Macrophages; Male; Mycophenolic Acid; Pressure; Rats; Rats, Wistar; Rupture; Time Factors; Transforming Growth Factor beta; Transforming Growth Factor beta1; Wound Healing

The aim of this study was to assess the effects of tacrolimus in combination with either sirolimus (n = 10) or mycophenolate mofetil (n = 7) on renal function and renal histopathologic factors 6 and 12 months after kidney transplantation.. Renal function was assessed by the glomerular filtration rate (as measured by the inulin clearance rate) and by determining renal functional reserve. A renal allograft biopsy was performed at the time of transplantation and 6 and 12 months later.. Serum creatinine levels tended to be higher in the sirolimus group 12 months after transplantation. In contrast, inulin clearance and renal functional reserve were similar in both groups 6 and 12 months after transplantation. With respect to histopathologic findings, only mononuclear-cell interstitial inflammation was significantly higher in the sirolimus group than in the mycophenolate mofetil group 12 months after transplantation. However, the progression of tubular atrophy, interstitial fibrosis, and vascular fibrous intimal thickening within the first postoperative year was significantly greater in the sirolimus group.. In the long term, the addition of sirolimus to treatment with tacrolimus in de novo renal transplant patients might more adversely affect renal allograft survival than might the addition of mycophenolate mofetil to tacrolimus therapy.

Topics: Adult; Biopsy; Creatinine; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Inflammation; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Sirolimus; Tacrolimus; Transplantation, Homologous

Septic arthritis (SA) typically occurs in young children, often from Staphylococcus. With chronic immunosuppression, however, pathogens may be atypical. A 15-year-old African-American female developed Mycoplasma hominis SA in her right hip 2 months following cadaveric renal transplant (Tx). Her presentation was subtle and indolent, without fever or leukocytosis. Although reported in adult Tx recipients, M. hominis infections have not been described in pediatric recipients. Early immunosuppression (basiliximab, prednisone, tacrolimus, mycophenolate mofetil and Thymoglobulin) may have increased her susceptibility to M. hominis. Optimal therapy for M. hominis SA is not well established and relapses occur. This patient underwent joint incision and drainage, treatment for 8 weeks with doxycycline and levofloxacin guided by in vitro sensitivities, and a reduction in immunosuppression. She has been free of ongoing infection for 3 years with stable graft function (Cr 1.1 mg/dL) on moderate immunosuppression with prednisone, tacrolimus and MMF.

Topics: Adolescent; Arthritis, Infectious; Doxycycline; Edema; Female; Graft Survival; Hip; Humans; Immunocompromised Host; Immunosuppressive Agents; Inflammation; Kidney Transplantation; Levofloxacin; Magnetic Resonance Imaging; Mycophenolic Acid; Mycoplasma hominis; Ofloxacin; Pelvis; Prednisone; Radiography; Tacrolimus; Treatment Outcome

In vitro and in vivo studies have shown that building-associated Penicillium spores and spore extracts can induce significant inflammatory responses in lung cells and animal models of lung disease. However, because spores and spore extracts comprise mixtures of bioactive constituents often including toxins, it is impossible to resolve which constituent mediates inflammatory responses. This study examined dose-response (0.5 nM, 2.5 nM, 5.0 nM, 12.5 nM/g body weight (BW) animal) and time-course (3, 6, 24 and 48 h post instillation (PI)) relationships associated with inflammatory and cytotoxic responses in mouse lungs intratracheally instilled with pure brevianamide A, mycophenolic acid, and roquefortine C. High doses (5.0 nM and/or 12.5 nM/g BW animal) of brevianamide A and mycophenolic acid, the dominant metabolites of P. brevicompactum, and roquefortine C, the dominant metabolite of P. chrysogenum, induced significant inflammatory responses within 6 h PI, expressed as differentially elevated macrophage, neutrophil, MIP-2, TNF, and IL-6 concentrations in the bronchioalveolar lavage fluid (BALF) of intratracheally exposed mice. Macrophage and neutrophil numbers were maximal at 24 h PI; responses of the other inflammatory markers were maximal at 6 h PI. Except for macrophage numbers in mycophenolic acid-treatment animals, cells exhibited significant dose-dependent-like responses; for the chemo-/cytokine markers, dose dependency was lacking except for MIP-2 concentration in brevianamide A-treatment animals. It was also found that brevianamide A induced cytotoxicity expressed as significantly increased LDH concentration in mouse BALF, at concentrations of 12.5 nM/g BW animal and at 6 and 24 h PI. Albumin concentrations, measured as a nonspecific marker of vascular leakage, were significantly elevated in the BALF of mice treated with 12.5 nM/g nM brevianamide A/animal from 6 to 24 h PI and in > or =5.0 nM/g mycophenolic acid-treated animals at 6 to 24 h PI. These results suggest that these three toxins from Penicillium species common on damp materials in residential housing provoke compound-specific toxic responses with different toxicokinetics. Moreover, that these toxins can stimulate significant inflammatory responses in vivo might help explain some of the indoor effects associated with Penicillium spore exposures in indoor environments.

Topics: Albumins; Alkaloids; Animals; Body Weight; Bronchoalveolar Lavage Fluid; Cytokines; Dose-Response Relationship, Drug; Heterocyclic Compounds, 4 or More Rings; Indoles; Inflammation; L-Lactate Dehydrogenase; Lung; Male; Mice; Mycophenolic Acid; Piperazines; Spiro Compounds

Lung ischemia-reperfusion injury (LIRI) is associated with an increased incidence of both primary graft failure and obliterative bronchiolitis. The immunosuppressant mycophenolate mofetil (MMF) has recently been shown to attenuate inflammatory injury in acute ischemia-reperfusion models via a mechanism that is presently unclear. These experiments studied the effects of MMF in a warm, in situ LIRI model, focusing on transcriptional regulation of pro-inflammatory mediators.. Left lungs of rats were rendered ischemic for 90 minutes and reperfused for up to 4 hours. Treated animals received 10 mg/kg of intravenous MMF at 2 hours before ischemia. Left lung injury was quantitated by myeloperoxidase (MPO) content, permeability indices and bronchoalveolar lavage (BAL) inflammatory cell counts. Lungs were analyzed by electrophoretic mobility shift assay (EMSA) for transcription factor transactivation and by enzyme-linked immunoassay for BAL chemokine protein content.. MMF significantly reduced lung vascular permeability indices, MPO content and alveolar leukocyte counts at 4 hours of reperfusion. There was significant attenuation of activator protein 1 (AP-1) and early growth response 1 (EGR-1) transactivation, whereas nuclear factor-kappaB (NF-kappaB) was unaffected. Reductions in bronchoalveolar lavage monocyte chemoattractant protein 1 (MCP-1) and cytokine-induced neutrophil chemoattractant (CINC) protein content were found at 4 hours of reperfusion.. MMF limits lung ischemia-reperfusion-induced increases in vascular permeability and inflammatory cell sequestration in lung parenchyma and alveolar spaces. The protection is mediated at the transcriptional level via an attenuation of early EGR-1 and AP-1 transactivation, which was found to be associated with reduced late MCP-1 and CINC protein secretion. The use of MMF in concert with an agent that affects NF-kappaB activation may provide even further protection against lung reperfusion injury as multiple inflammatory pathways are inhibited.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Bronchiolitis Obliterans; Bronchoalveolar Lavage Fluid; Chemokines; Electrophoretic Mobility Shift Assay; Enzyme-Linked Immunosorbent Assay; Graft Rejection; Inflammation; Lung; Lung Transplantation; Male; Mycophenolic Acid; Permeability; Peroxidase; Postoperative Complications; Rats; Rats, Long-Evans; Reperfusion Injury; Transcription Factors; Transcription, Genetic

Myositis is a rare complication following renal transplantation and is most commonly the result of drug-mediated myotoxicity. Other causative disorders include viral infection, electrolyte imbalance and myositis of autoimmune origin. We describe a 60-year-old patient who developed acute polymyositis 4 weeks after a 000 human leukocyte antigen (HLA) mismatch cadaveric renal transplant. Following an uncomplicated transplant course with maintenance triple immunosuppression (prednisolone, mycophenolate mofetil and cyclosporine), the patient presented with severe symmetrical proximal muscle weakness associated with a rise in serum creatine kinase to 46800 U/L. Electromyography confirmed myopathic changes and muscle biopsy demonstrated extensive muscle-fiber necrosis with an inflammatory infiltrate. There were no obviously culpable drugs and viral studies were negative. Prompt initiation of high-dose steroid therapy led to clinical and biochemical recovery. Acute polymyositis may occur following renal transplantation. Potential mechanisms include viral antigen transmission or a localized form of graft vs. host disease.

Topics: Acute Disease; Anti-Inflammatory Agents; Antigens; Creatine Kinase; Cyclosporine; Electrolytes; Electromyography; HLA Antigens; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Inflammation; Kidney Transplantation; Male; Middle Aged; Muscles; Mycophenolic Acid; Myositis; Polymyositis; Prednisolone; Time Factors

To evaluate the outcomes of patients with chronic ocular inflammatory disease treated with mycophenolate mofetil as an immunosuppressive and steroid-sparing agent.. Retrospective noncomparative interventional case series.. All patients with ocular inflammatory disease treated with mycophenolate mofetil at a single institution between 1998 and 2001.. Charts of patients seen on the Ocular Immunology and Uveitis Service at the Massachusetts Eye and Ear Infirmary were reviewed. Patients with chronic ocular inflammatory disease were included in the study.. Control of inflammation, steroid-sparing effect, visual acuity, and adverse reactions were measured.. A total of 54 patients were evaluated. Control of ocular inflammation with mycophenolate mofetil as monotherapy was achieved in 35 patients (65%) and in 67 eyes (62%), and a steroid-sparing effect was achieved in 29 (54%) patients. Visual acuity was maintained or improved in 51 patients (94%) and in 97 eyes (90%). Side effects requiring discontinuation of medication occurred in 10 patients (18%). There was neither long-term morbidity nor mortality due to mycophenolate mofetil.. Mycophenolate mofetil is effective in the treatment of patients with steroid-dependent or -resistant chronic ocular inflammatory disorders that fail to respond to conventional steroid treatment. It is a safe and effective steroid-sparing immunomodulatory agent and can be considered an important addition to our armamentarium in the care of patients with ocular inflammatory disease.

Topics: Adolescent; Adult; Chronic Disease; Endophthalmitis; Female; Humans; Immunosuppressive Agents; IMP Dehydrogenase; Inflammation; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; Visual Acuity

Angiotensin (Ang) II promotes renal infiltration by immunocompetent cells in double-transgenic rats (dTGRs) harboring both human renin and angiotensinogen genes. To elucidate disease mechanisms, we investigated whether or not dexamethasone (DEXA) immunosuppression ameliorates renal damage. Untreated dTGRs developed hypertension, renal damage, and 50% mortality at 7 weeks. DEXA reduced albuminuria, renal fibrosis, vascular reactive oxygen stress, and prevented mortality, independent of blood pressure. In dTGR kidneys, p22phox immunostaining co-localized with macrophages and partially with T cells. dTGR dendritic cells expressed major histocompatibility complex II and CD86, indicating maturation. DEXA suppressed major histocompatibility complex II+, CD86+, dendritic, and T-cell infiltration. In additional experiments, we treated dTGRs with mycophenolate mofetil to inhibit T- and B-cell proliferation. Reno-protective actions of mycophenolate mofetil and its effect on dendritic and T cells were similar to those obtained with DEXA. We next investigated whether or not Ang II directly promotes dendritic cell maturation in vitro. Ang II did not alter CD80, CD83, and MHC II expression, but increased CCR7 expression and cell migration. To explore the role of tumor necrosis factor (TNF)-alpha on dendritic cell maturation in vivo, we treated dTGRs with the soluble TNF-alpha receptor etanercept. This treatment had no effect on blood pressure, but decreased albuminuria, nuclear factor-kappaB activation, and infiltration of all immunocompetent cells. These data suggest that immunosuppression prevents dendritic cell maturation and T-cell infiltration in a nonimmune model of Ang II-induced renal damage. Ang II induces dendritic migration directly, whereas in vivo TNF-alpha is involved in dendritic cell infiltration and maturation. Thus, Ang II may initiate events leading to innate and acquired immune response.

Topics: Angiotensin II; Angiotensinogen; Animals; Animals, Genetically Modified; Antigens, CD; B7-2 Antigen; Blood Pressure; Dendritic Cells; Dexamethasone; Etanercept; Histocompatibility Antigens Class II; Humans; Immunoglobulin G; Immunosuppressive Agents; Inflammation; Kidney; Kidney Diseases; Kinetics; Macrophage Migration-Inhibitory Factors; Male; Membrane Glycoproteins; Membrane Transport Proteins; Mycophenolic Acid; NADPH Dehydrogenase; NADPH Oxidases; NF-kappa B; Phosphoproteins; Protective Agents; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Receptors, Tumor Necrosis Factor; Renin; T-Lymphocytes

Mycophenolate mofetil (MMF) is increasingly used for prevention of allograft rejection and to treat immune disorders. We report the development of an acute inflammatory syndrome in two patients with Wegener's granulomatosis after MMF was introduced, because of persistent renal and systemic disease activity despite cyclophosphamide treatment. Within 1 week both patients developed an acute inflammatory syndrome, characterized by fever, arthralgias and muscle pain. No infection could be detected and no indications for increased Wegener's activity were present. MMF was stopped resulting in a rapid and complete resolution of the syndrome. A rechallenge with 2 g of MMF in the second patient resulted in a relapse of the syndrome within 4 days. There was an association between symptoms and increased levels of mycophenolic acid (MPA) acyl glucuronide and serum interleukin-6, suggesting the induction of inflammatory cytokines by MPA acyl glucuronide as the cause of the syndrome. Therefore, special attention should be given to side effects such as fever, arthralgias and muscle pain when treating patients with Wegener's granulomatosis during the active phase. Because this side effect of MMF may also occur after solid organ transplantation and in other immune disorders, pharmacokinetic profiling of MPA and MPA acyl glucuronide is needed in future studies with MMF.

Topics: Acute Disease; Arthralgia; Female; Fever; Granulomatosis with Polyangiitis; Humans; Immunosuppressive Agents; Inflammation; Male; Middle Aged; Muscles; Mycophenolic Acid; Pain; Syndrome

Evidence of autoimmunity in primary biliary cirrhosis (PBC) provides a rationale for treatment with an immunosuppressant. Such a drug should be sufficiently free from serious toxicities to enable patients with asymptomatic, but progressive, disease to be treated longterm. Mycophenolate mofetil (MMF) mediates immunosuppression by selectively and reversibly inhibiting lymphocyte function, and has a more acceptable safety profile than other immunosuppressants that have been used in the treatment of this disease. Two patients, whose response to long-term treatment with ursodeoxycholic acid (UDCA) had been inadequate, were treated with a combination of MMF 2 g daily and UDCA 1 g daily for 12 months. In both patients this regimen was associated with no clinically significant adverse events, a decrease in elevated serum alkaline phosphatase levels to values close to the upper limit of normal, and an almost complete disappearance of the chronic inflammatory cell infiltrate that had been present in pre-combination treatment liver biopsies. MMF may be an appropriate immunosuppressive drug for use in the long-term treatment of patients with PBC, including asymptomatic patients.

Topics: Alkaline Phosphatase; Cholagogues and Choleretics; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Inflammation; Liver; Liver Cirrhosis, Biliary; Liver Function Tests; Middle Aged; Mycophenolic Acid; Ursodeoxycholic Acid

Topics: Animals; Biopsy, Needle; Graft Rejection; Graft Survival; Immunosuppressive Agents; Inflammation; Liver Transplantation; Lymphocytes; Macrophages; Mycophenolic Acid; Rats; Rats, Inbred BN; Rats, Inbred Strains

To investigate the impact of mycophenolate mofetil (MMF) on allograft arteriosclerosis (chronic rejection) in rat aortic allograft model, we administrated MMF 20 mg/kg/day from the day of transplantation and sacrificed the rats at 1-12 months afterwards. MMF significantly suppressed all major histological manifestations of allograft arteriosclerosis, i.e. adventitial inflammation, media necrosis and intimal thickening and cellularity. There was a significant decrease in the replication rate (3H-thymidine incorporation) of inflammatory cells in the adventitia and of smooth muscle cells (SMC) in the media. MMF did not have any major effect on mRNA expression of several growth factors, (determined by polymerase chain reaction with inbuilt glyceraldehyde-3-phosphate dehydrogenase control), which have previously been demonstrated to be elevated in nonimmunosuppressed allografts. Immunoperoxidase staining showed a 40% reduction in the number of adventitial interleukin-2 receptors expressing lymphoid cells in MMF-treated allografts. The intensity of SMC alpha-actin staining was also significantly reduced. As the results suggested that MMF may have a direct antiproliferative effect on SMC, this possibility was investigated in primary SMC cultures in vitro and using the carotid denudation model in vivo. Both approaches showed inhibition of SMC proliferation by MMF. Our results indicate that MMF inhibits histopathological changes of chronic rejection by reducing the immune response and possible replication of SMC.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Aorta; Base Sequence; Cell Division; Immunosuppressive Agents; Inflammation; Molecular Sequence Data; Muscle, Smooth; Mycophenolic Acid; Polymerase Chain Reaction; Rats; Rats, Inbred WF; Transplantation, Homologous