sirolimus and Lupus-Erythematosus--Systemic

Chylous effusion is a rare manifestation of systemic lupus erythematosus (SLE). When it does occur in SLE, it is generally well treated with standard pharmacologic or surgical measures. We present a decade of management in a case of SLE with lung affliction and development of refractory bilateral chylous effusion and pulmonary arterial hypertension (PAH). In the first years, the patient was treated under a Sjogren syndrome diagnose. After few years, her respiratory condition worsened due to chylous effusion and PAH. Immunosuppression therapy (methylprednisolone) was reintroduced, and vasodilator therapy commenced. With this, her cardiac function remained stable, but respiratory function continuously worsened despite several therapy trials with different combinations of immunosuppressant (glucocorticoids, resochin, cyclophosphamide and mycophenolate mofetil). On top of pleural effusion worsening, the patient developed ascites and severe hypoalbuminaemia. Even though albumin loss was stabilized with monthly octreotide applications, the patient remained respiratory insufficient and in need of continuous oxygen therapy. At that point, we decided to introduce sirolimus on top of glucocorticoids and mycophenolate mofetil therapy. Her clinical status, radiological finding, and lung function gradually improved and she became respiratory sufficient at rest. The patient remains in our follow-up and has been stable on given therapy for over 3 years despite overcoming a severe COVID-19 pneumonia in 2021. This case adds to the body of evidence of sirolimus effectiveness in patients with refractory systemic lupus and is, to our best knowledge, the first case to report its successful application in a patient with SLE and refractory chylous effusion.

Topics: COVID-19; Female; Glucocorticoids; Humans; Lupus Erythematosus, Systemic; Mycophenolic Acid; Sirolimus

Pro-inflammatory immune system development, metabolomic defects, and deregulation of autophagy play interconnected roles in driving the pathogenesis of systemic lupus erythematosus (SLE). Lupus nephritis (LN) is a leading cause of morbidity and mortality in SLE. While the causes of SLE have not been clearly delineated, skewing of T and B cell differentiation, activation of antigen-presenting cells, production of antinuclear autoantibodies and pro-inflammatory cytokines are known to contribute to disease development. Underlying this process are defects in autophagy and mitophagy that cause the accumulation of oxidative stress-generating mitochondria which promote necrotic cell death. Autophagy is generally inhibited by the activation of the mammalian target of rapamycin (mTOR), a large protein kinase that underlies abnormal immune cell lineage specification in SLE. Importantly, several autophagy-regulating genes, including ATG5 and ATG7, as well as mitophagy-regulating HRES-1/Rab4A have been linked to lupus susceptibility and molecular pathogenesis. Moreover, genetically-driven mTOR activation has been associated with fulminant lupus nephritis. mTOR activation and diminished autophagy promote the expansion of pro-inflammatory Th17, Tfh and CD3

Topics: Autophagy; Endothelial Cells; Humans; Lupus Erythematosus, Systemic; Lupus Nephritis; Sirolimus; TOR Serine-Threonine Kinases

Systemic lupus erythematosus (SLE) is a typical autoimmune disease characterized by multiorgan involvement and marked variability in clinical presentation. SLE pathogenesis includes regulatory T cell dysfunction and antinuclear antibody production. Mammalian target of rapamycin (mTOR), a serine/threonine kinase in the phosphoinositide 3-kinase (PI3K)-related kinase family, is a therapeutic target for autoimmune diseases such as SLE. Rapamycin, an inhibitor of the mTOR signaling pathway, is a macrolide antibiotic with potent immunosuppressive, antiproliferative and antifibrotic effects. Recently, an increasing number of studies have investigated the role of mTOR in regulatory T (Treg) cells and its impact on SLE pathogenesis. This review aims to systematically summarize the role of the mTOR signaling pathway in SLE pathogenesis, Treg cell dysfunction and SLE treatment.

Topics: Autoimmune Diseases; Humans; Lupus Erythematosus, Systemic; Phosphatidylinositol 3-Kinases; Signal Transduction; Sirolimus; T-Lymphocytes, Regulatory; TOR Serine-Threonine Kinases

Emerging evidence suggested a potential therapeutic role of targeting mTOR in the treatment of SLE. But most studies were observational studies with limited sample size or case reports.. To evaluate the efficacy and safety of sirolimus in treatment of SLE by systematic review and meta-analysis.. Systematic searches of Medline/PubMed, EMBASE, the Cochrane library and Scopus were performed. Original case reports, case series, observational studies and clinical trials reporting the efficacy or safety data on SLE patients treated with sirolimus were included. A random-effects meta-analysis was performed to calculate the pooled efficacy, when possible.. A total of 9 studies comprising 145 patients were identified. The exposure of sirolimus was 245.8 patient-years, with 1-3 mg/day adopted in majority studies. In 111 clinical active patients, the pooled decrease of SLEDAI, BILAG and prednisone dosage was 4.85 (95% CI 3.44-6.25), 1.98 (95% CI 0.23-3.74) and 13.17 mg/day (95% CI 0.71-25.63) respectively. 23 patients initiating sirolimus for active SLE yielded remission in 17 (73.9%) patients. In 22 quiescent lupus nephritis patients, 21 (95.5%) patients sustained remission. Hematological, mucocutaneous abnormalities and dyslipidemia were the most common adverse events. Early cessation due to side effects was reported in 9.28% (13/140) patients, most of the side effects were mild and recovered quickly after cessation.. Summary of the available datasets indicated sirolimus was promising and well-tolerated in the treatment of SLE. Further randomized controlled trials evaluating the potential benefits and risk of sirolimus in SLE are warranted.

Topics: Humans; Lupus Erythematosus, Systemic; Lupus Nephritis; Sirolimus

Autoimmune haemolytic anaemia (AIHA) and autoimmune thrombocytopenia are common complications of childhood-onset lupus, which may be life-threatening. A greater understanding of the pathogenesis of these haematologic manifestations will enhance our understanding of the biology of systemic lupus erythematosus (SLE) and inform the identification of novel treatments.. The mechanisms underlying AIHA and autoimmune thrombocytopenia are incompletely understood and likely multifactorial. Although the development of auto-antibodies is central to the disease process, recent studies have demonstrated the importance of cytokines in the underlying pathologic process. In-vitro and in-vivo evidence points to a role for IL17 in the pathogenesis of AIHA, which involves loss of tolerance to red cell auto-antigens and the development of autoantibodies. Sirolimus, an mTor inhibitor, has benefited patients with primary autoimmune cytopenias, possibly by stimulating T regulatory cells, and may also have efficacy for SLE-associated cytopenias. Similarly, low-dose recombinant human IL-2 therapy has shown promising results for improving platelet counts in patients with autoimmune thrombocytopenia, possibly by restoring the balance between T regulatory, T helper and Th17 cells.. The emergence of new agents directed at restoring immune dysregulation hold promise for the treatment of AIHA and autoimmune thrombocytopenia and should provide better tolerated alternatives to high-dose corticosteroids.

Topics: Anemia, Hemolytic, Autoimmune; Autoantibodies; Humans; Immunologic Factors; Lupus Erythematosus, Systemic; Purpura, Thrombocytopenic, Idiopathic; Receptors, Thrombopoietin; Rituximab; Sirolimus

The mechanistic target of rapamycin (mTOR) is a central regulator in cell growth, activation, proliferation, and survival. Activation of the mTOR pathway underlies the pathogenesis of systemic lupus erythematosus (SLE). While mTOR activation and its therapeutic reversal were originally discovered in T cells, recent investigations have also uncovered roles in other cell subsets including B cells, macrophages, and "non-immune" organs such as the liver and the kidney. Activation of mTOR complex 1 (mTORC1) precedes the onset of SLE and associated co-morbidities, such as anti-phospholipid syndrome (APS), and may act as an early marker of disease pathogenesis. Six case reports have now been published that document the development of SLE in patients with genetic activation of mTORC1. Targeting mTORC1 over-activation with N-acetylcysteine, rapamycin, and rapalogs provides an opportunity to supplant current therapies with severe side effect profiles such as prednisone or cyclophosphamide. In the present review, we will discuss the recent explosion of findings in support for a central role for mTOR activation in SLE.

Topics: Acetylcysteine; B-Lymphocytes; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Sirolimus; T-Lymphocytes; TOR Serine-Threonine Kinases

Systemic lupus erythematosus (SLE) is a common autoimmune disease with unclear etiology. Treatments for it often provide inadequate control of disease activity or are limited by side effects. Recent studies have shown that rapamycin can be an effective treatment in both murine lupus models and human SLE. We demonstrated that rapamycin could directly alter molecular abnormalities in SLE T cells related to calcium signaling but not mitochondrial function. However, in light of increased knowledge of the role of mammalian target of rapamycin (mTOR) signaling throughout the immune system, several other potential sites of rapamycin action have been revealed. Specifically, mTOR regulates the production of interferon-alpha and the maintenance of immune tolerance at the level of the regulatory T cell and the dendritic cell, and can promote Th2 versus Th1 immune responses. Thus mTOR offers a window into diverse facets of lupus pathogenesis as well as a unifying narrative in our understanding of the therapeutic efficacy of rapamycin in SLE.

Topics: Cell Differentiation; Humans; Interferon-alpha; Intracellular Signaling Peptides and Proteins; Lupus Erythematosus, Systemic; Protein Serine-Threonine Kinases; Signal Transduction; Sirolimus; Th1 Cells; Th2 Cells; TOR Serine-Threonine Kinases

Systemic lupus erythematosus (SLE) is characterized by abnormal T cell activation and death, processes which are crucially dependent on the controlled production of reactive oxygen intermediates (ROI) and of ATP in mitochondria. The mitochondrial transmembrane potential (Deltapsi(m)) has conclusively emerged as a critical checkpoint of ATP synthesis and cell death. Lupus T cells exhibit persistent elevation of Deltapsi(m) or mitochondrial hyperpolarization (MHP) as well as depletion of ATP and glutathione which decrease activation-induced apoptosis and instead predispose T cells for necrosis, thus stimulating inflammation in SLE. NO-induced mitochondrial biogenesis in normal T cells accelerates the rapid phase and reduces the plateau of Ca(2+) influx upon CD3/CD28 co-stimulation, thus mimicking the Ca(2+) signaling profile of lupus T cells. Treatment of SLE patients with rapamycin improves disease activity, normalizes CD3/CD28-induced Ca(2+) fluxing but fails to affect MHP, suggesting that altered Ca(2+) fluxing is downstream or independent of mitochondrial dysfunction. Understanding the molecular basis and consequences of MHP is essential for controlling T cell activation and death signaling in SLE.

Topics: Animals; Calcium Signaling; CD3 Complex; Cell Death; Gene Expression Regulation, Enzymologic; Humans; Lupus Erythematosus, Systemic; Lymphocyte Activation; Membrane Potentials; Mitochondria; Sirolimus; T-Lymphocytes

Immunomodulatory agents represent a unique group of therapies that are not biologics and have relatively specific, noncytotoxic effects on the immune system. Cyclosporine has been the most widely tested of the immunomodulatory agents and shown efficacy in a variety of autoimmune diseases as well as monotherapy in established rheumatoid arthritis. FK-506 and rapamycin, agents similar to cyclosporine, are being tested in human transplantation, with only arthritis studies having been done in animals. Tilomisole, imuthiol, and mycophenolate mofetil have been studied in limited rheumatoid arthritis trials with positive effects. Although more specific and with manageable short-term side effects, this group of therapies requires more studies to establish their efficacy and long-term safety.

Topics: Arthritis, Psoriatic; Arthritis, Rheumatoid; Clinical Trials as Topic; Cyclosporine; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Polyenes; Sirolimus; Tacrolimus

Connective tissue disease-related thrombocytopenia (CTD-TP) is a problematic disorder in clinical practice. Because the first-line therapy of glucocorticoid and/or immunosuppressants is not effective for refractory cases, alternative treatment approaches are urgently needed. The present study investigated the efficacy and safety of sirolimus in refractory CTD-TP patients.. This single-centre, single-arm, phase II study enrolled 20 refractory CTD-TP patients between September 2017 and September 2018 (registered on ClinicalTrials.gov: NCT03688191). Oral sirolimus administration was dose-adjusted to maintain a therapeutic range of 6-15 ng/ml for 6 months. The primary endpoints were partial and complete remission rates at 6 months.. Twelve (60%) patients achieved the primary end point with a 50% complete remission rate after 6 months. Among the 14 SLE patients, the overall response rate was 71.4%, with a complete remission rate of 64.3%. None of the primary Sjögren's syndrome cases responded to sirolimus. There was no significant difference in baseline clinical characteristics or lymphocyte subpopulations between responders and non-responders. No severe side effect was detected during the study.. Sirolimus is an effective and safe treatment option for refractory CTD-TP patients.. https://clinicaltrials.gov, NCT03688191.

Topics: Administration, Oral; Adolescent; Adult; Connective Tissue Diseases; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Male; Middle Aged; Prednisolone; Prednisone; Prospective Studies; Remission Induction; Sirolimus; Sjogren's Syndrome; Thrombocytopenia; Time Factors; Young Adult

Patients with systemic lupus erythematosus have T-cell dysfunction that has been attributed to the activation of the mammalian target of rapamycin (mTOR). Rapamycin inhibits antigen-induced T-cell proliferation and has been developed as a medication under the generic designation of sirolimus. We assessed safety, tolerance, and efficacy of sirolimus in a prospective, biomarker-driven, open-label clinical trial.. We did a single-arm, open-label, phase 1/2 trial of sirolimus in patients with active systemic lupus erythematosus disease unresponsive to, or intolerant of, conventional medications at the State University of New York Upstate Medical University (Syracuse, NY, USA). Eligible participants (aged ≥18 years) had active systemic lupus erythematosus fulfilling four or more of 11 diagnostic criteria defined by the American College of Rheumatology. We excluded patients with allergy or intolerance to sirolimus, patients with life-threatening manifestations of systemic lupus erythematosus, proteinuria, a urine protein to creatinine ratio higher than 0·5, anaemia, leucopenia, or thrombocytopenia. Patients received oral sirolimus at a starting dose of 2 mg per day, with dose adjusted according to tolerance and to maintain a therapeutic range of 6-15 ng/mL. Patients were treated with sirolimus for 12 months. Safety outcomes included tolerance as assessed by the occurrence of common side-effects. The primary efficacy endpoint was decrease in disease activity, assessed using the British Isles Lupus Assessment Group (BILAG) index and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Blood samples of 56 matched healthy individuals were obtained as controls for immunobiological outcomes monitored at each visit. The primary efficacy endpoint was assessed in all patients who completed 12 months of treatment, and all patients who received at least one dose of treatment were included in the safety analyses. This trial is registered with ClinicalTrials.gov, number NCT00779194.. These data show that a progressive improvement in disease activity is associated with correction of pro-inflammatory T-cell lineage specification in patients with active systemic lupus erythematosus during 12 months of sirolimus treatment. Follow-up placebo-controlled clinical trials in diverse patient populations are warranted to further define the role of mTOR blockade in treatment of systemic lupus erythematosus.. Pfizer, the National Institutes of Health, and the Central New York Community Foundation.

Topics: Adolescent; Adult; Aged; Drug Tolerance; Female; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Male; Middle Aged; Prospective Studies; Sirolimus; Treatment Outcome; Young Adult

Objective To explore the role of autophagy, apoptosis of neutrophils and neutrophils extracellular traps (NET) formation in systemic lupus erythematosus (SLE). Methods Thirty-six patients with SLE were recruited as research subjects, and 32 healthy controls matched accordingly were enrolled as control subjects. The expression levels of microtubule associated protein 1 light chain 3B (LC3B), autophagy-related gene5(ATG5), P62, B-cell lymphoma 2(Bcl2), Bcl2-related X protein (BAX) in neutrophils were detected by Western blot analysis. Flow cytometry was employed to analyze the expression of LC3B on neutrophils. The expression level of myeloperoxidase(MPO) in plasma was estimated by ELISA. Furthermore, neutrophils were cultured in vitro and stimulated by 100 nmol/L rapamycin and 10 μg/mL lipopolysaccharide (LPS) for 6 hours, respectively. And then, the expression levels of LC3B, ATG5, P62, Bcl2 and BAX in neutrophils were detected by Western blot analysis. The level of MPO in culture supernatant was detected by ELISA. The change of fluorescence intensity of NET in culture supernatant was assayed by Sytox

Topics: Autophagy; bcl-2-Associated X Protein; Extracellular Traps; Humans; Lipopolysaccharides; Lupus Erythematosus, Systemic; Neutrophils; Sirolimus

The effectiveness and safety of sirolimus for SLE treatment have been shown in some uncontrolled studies. However, a comparison of sirolimus with other classic immunosuppressants has not been reported. We conducted the study to compare the effectiveness and safety of sirolimus versus tacrolimus for SLE treatment.. A real-world cohort study was conducted. Patients with clinically active SLE who were prescribed sirolimus or tacrolimus were enrolled. Propensity score matching was used to ensure equivalent disease conditions and background medications. SLE disease activity indices, serological parameters, steroid doses, modification of other immunosuppressants, renal effectiveness and adverse events were compared between the two groups at 3-month, 6-month, 9-month and 12-month follow-up visits.. Data from 52 patients in each of the sirolimus and tacrolimus groups were analysed. Indices regarding the effectiveness of sirolimus, including Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) scores, physician's global assessment (PhGA) scores, and proportion of patients with SLEDAI-2K reduction of ≥4 and PhGA increase of <0.3, were equivalent to those of tacrolimus at all follow-up timepoints (all p≥0.05). Greater improvements in complement levels were observed in the sirolimus group at 3 and 6 months. Higher percentages of patients with prednisone doses ≤7.5 mg/day were observed in the sirolimus group at all timepoints. Seventeen adverse events in the sirolimus group were recorded. None was severe or led to drug discontinuation.. Overall, sirolimus was as effective as tacrolimus in the treatment of SLE. Sirolimus had better effects on serological improvement and glucocorticoid tapering. Sirolimus was well tolerated in patients with SLE.

Topics: Cohort Studies; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Sirolimus; Tacrolimus

In antiphospholipid antibody (aPL) nephropathy, activation of the mammalian target of rapamycin (mTOR) contributes to endothelial cell proliferation, a key finding of aPL microvascular disease. Here, we examined mTOR activation in the skin of aPL-positive patients with livedo.. Three patient groups with livedo were studied: (1) persistently aPL-positive with systemic lupus erythematosus (SLE); (2) persistently aPL-positive without SLE; and (3) aPL-negative SLE (control). After collecting aPL-related medical history, two 5-mm skin biopsies of livedo were performed on each patient: (1) peripheral (erythematous-violaceous lesion); and (2) central (nonviolaceous area). We stained specimens for phosphorylated protein kinase B (p-AKT) and phosphorylated S6 ribosomal protein (p-S6RP) as mTOR activity markers, CD31 to identify endothelial cells, and Ki-67 to show cellular proliferation. We counted cells in the epidermis and compared mTOR-positive cell counts between peripheral and central samples, and between patient groups, using Freidman test and Wilcoxon signed-rank test.. Ten patients with livedo reticularis were enrolled: 4 aPL-positive without SLE (antiphospholipid syndrome [APS] classification met, n = 3), 4 aPL-positive SLE (APS classification met, n = 3), and 2 aPL-negative SLE (control). In all aPL-positive patients, epidermal p-AKT and p-S6RP staining were significantly increased in both peripheral and central skin samples when compared to aPL-negative SLE controls; both were more pronounced in the lower basal layers of epidermis.. Our study demonstrates increased mTOR activity in livedoid lesions of aPL-positive patients with or without SLE compared to aPL-negative patients with SLE, with more prominent activity in the lower basal layers of the epidermis. These findings may serve as a basis for further investigating the mTOR pathway in aPL-positive patients.

Topics: Antibodies, Antiphospholipid; Antiphospholipid Syndrome; Endothelial Cells; Humans; Ki-67 Antigen; Livedo Reticularis; Lupus Erythematosus, Systemic; Proto-Oncogene Proteins c-akt; Ribosomal Proteins; Sirolimus; TOR Serine-Threonine Kinases

Topics: Animals; B-Lymphocytes; CD40 Ligand; Cell Communication; Delayed-Action Preparations; Inducible T-Cell Co-Stimulator Protein; Lupus Erythematosus, Systemic; Mice; Nanoparticles; Sirolimus; T-Lymphocytes; TOR Serine-Threonine Kinases

The present study aimed to predict the effect of sirolimus on disease activity in patients with systemic lupus erythematosus (SLE) using machine learning and to recommend appropriate sirolimus dosage regimen for patients with SLE.. The E. This study was the first time to predict the effect of sirolimus on disease activity in patients with SLE and in order to achieve better therapeutic effect maintaining a concentration of 8-10 ng/ml sirolimus for at least 6.12 months was necessary.

Topics: Humans; Lupus Erythematosus, Systemic; Machine Learning; Sirolimus

To investigate the effectiveness and safety of sirolimus in childhood-onset systemic lupus erythematosus in a real world. This is a retrospective real world clinical study. All childhood-onset systemic lupus erythematosus patients treated with sirolimus in Children's Hospital of Hebei Province China were analyzed. They were treated with sirolimus and followed up regularly. The patients had systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score, levels of antidouble-stranded DNA antibody, complement components C3 and C4, 24-hour proteinuria and corticosteroid reduction were recorded at baseline and at 6, 12, and 18 months. Adverse events were also collected. Thirty-two patients were enrolled in the study. SLEDAI-2K were improved on all time-points (P < .05). Complement levels increased and the levels of antidouble-stranded DNA antibody decreased during treatment. The mean dose of prednisone tapered and achieved significant reduction after 12 months therapy (15.4 ± 5.8 mg/d to 4.8 ± 2.1 mg/d; P < .05). Sirolimus was well tolerated and only 5 patients (15.6%) experienced adverse events, all of which were classified as infections (2 bacterial infection and 3 viral infections). No deaths, severe infusion reactions, or hypersensitivity reactions were found. Sirolimus use was associated with a decrease in disease activity and ability to tolerate tapering of oral glucocorticoid dose with a favorable risk-benefit profile.

Topics: Antibodies, Antinuclear; Child; DNA; Humans; Lupus Erythematosus, Systemic; Retrospective Studies; Sirolimus; Treatment Outcome

This study aimed to explore the therapeutic effect and mechanism of rapamycin (RAPA) on systemic lupus erythematosus (SLE) in BALB/C mice induced by pristane. The mice were randomly divided into 5 groups (n = 6): control, model, saline, RAPA (1 mg/kg) and RAPA (2 mg/kg). All groups were injected with pristane except control. HE staining revealed 1 mg/kg and 2 mg/kg RAPA treatments obviously alleviated pathological changes in the kidney of SLE mice such as glomeruli enlargement, hyperplasia of mesangial cells, epithelial and endothelial cells, infiltration of inflammatory cells, and edema-like degeneration of renal tubules. Compared with control group, body weights and anti-ribosomal P-protein antibody (ARPA) level of the mice in model group and saline group decreased (P < 0.05), while immune complex deposition and levels of anti-dsDNA antibody, anti-smRNP antibody and urine protein in model group and saline group increased (P < 0.05). However, compared with model group and saline group, body weights of the mice in RAPA (1 mg/kg) group and RAPA (2 mg/kg) group increased (P < 0.05), while immune complex deposition and levels of anti-dsDNA antibody, anti-smRNP antibody, ARPA, and urine protein in RAPA (1 mg/kg) group and RAPA (2 mg/kg) group decreased (P < 0.05). Compared with control group, the proportion of dentritic cells (DC) in the kidney and peripheral blood decreased while the proportion of Th1, Th2 and Th17 cells in the spleen, kidney and peripheral blood increased in model group and saline group (P < 0.05). Compared with model group and saline group, 1 mg/kg and 2 mg/kg RAPA treatments boosted the proportion of DC in the kidney and peripheral blood, reduced the proportion of Th1 and Th17 cells in the spleen, kidney and peripheral blood, and lessened the proportion of Th2 cells in the kidney and peripheral blood (P < 0.05). In conclusion, RAPA alleviated renal damage in SLE mice through improving immune response and function.

Topics: Animals; Antibodies, Antinuclear; Antigen-Antibody Complex; Dendritic Cells; Disease Models, Animal; Female; Immunosuppressive Agents; Kidney; Lupus Erythematosus, Systemic; Lupus Nephritis; Mice, Inbred BALB C; Sirolimus; T-Lymphocytes, Helper-Inducer; Terpenes

The safety, tolerance, and selected renal and non-renal outcome measures were evaluated in 73 SLE patients who received sirolimus therapy for more than 3 months in our institution over the past 21 years. In 12 patients who had lupus nephritis, proteinuria (p = 0.0287), hematuria (p = 0.0232), anti-DNA antibody levels (p = 0.0028) and steroid use were reduced (p = 0.0200). In the non-renal cohort of 61 patients, anti-DNA antibody levels (p = 0.0332) and steroid use were reduced (p = 0.0163). Both in the renal and non-renal cohorts, C3 (renal p = 0.0070; non-renal p = 0.0021) and C4 complement levels were increased (renal p = 0.0063; non-renal p = 0.0042) Adverse effects of mouth sores (2/73), headaches (1/73), and gastrointestinal discomfort were noted in a minority of patients (6/73). Sirolimus was only discontinued in two of 73 patients due to headache and recurrent infections, respectively. This study suggests that sirolimus is well tolerated and exerts long-term therapeutic efficacy in controlling renal and non-renal manifestations of SLE.

Topics: Adult; Aged; Antibodies, Antinuclear; Cohort Studies; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lupus Nephritis; Male; Middle Aged; Outcome Assessment, Health Care; Sirolimus; Treatment Outcome

Topics: Animals; Antibodies; Disease Models, Animal; Hippocampus; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Mice; Ribosomal Proteins; Sirolimus; Social Behavior

Increased IFNα is important in the pathogenesis of SLE. Plasmacytoid dendritic cells are considered the main producer of IFNα upon Toll-like receptor pathway activation. However, which cells produce IFNα following stimulation with cyclic GMP-AMP synthase (cGAS) and stimulator of IFN genes (STING) in SLE remains unknown. We investigated the IFNα producing capacity of myeloid cells under cGAS-STING pathway stimulation.. IFNα levels in peripheral blood mononuclear cells from SLE patients and healthy controls stimulated with 2'3'c-GAMP, a stimulator of cGAS-STING, were measured by intracellular cytokine staining and flow cytometry. STING expression and its co-localization with TBK1 were examined by flow cytometry or confocal microscopy. The effects of in vitro exposure to IFNα on IFNα production and STING expression, and in vitro rapamycin treatment on IFNα production and STING, pTBK1 and IRF3 expression were examined.. IFNα was produced by monocytes, conventional dendritic cells and plasmacytoid dendritic cells upon cGAS-STING pathway activation. The frequency of IFNα-producing monocytes positively correlated with SLE disease activity. STING expression and its co-localization with TBK1 were increased in lupus monocytes. Prior exposure to IFNα enhanced the IFNα-producing capacity of monocytes. Inhibition of the mechanistic target of the rapamycin (mTOR) pathway suppressed IFNα production from monocytes and downregulated enhanced STING expression and its downstream molecules.. Enhanced IFNα from lupus monocytes induced by augmented STING pathway activation is associated with SLE pathogenesis. Suppression of the mTOR pathway downregulated the enhanced STING expression and the subsequent IFNα production by monocytes.

Topics: Adult; Case-Control Studies; Dendritic Cells; Down-Regulation; Female; Flow Cytometry; Humans; Immunosuppressive Agents; Interferon-alpha; Lupus Erythematosus, Systemic; Male; Membrane Proteins; Microscopy, Confocal; Middle Aged; Monocytes; Nucleotides, Cyclic; Protein Serine-Threonine Kinases; Sirolimus; TOR Serine-Threonine Kinases; Young Adult

The development of Systemic lupus erythematosus (SLE) has been associated with the balance of Th17 and Treg cells. IL-2 and rapamycin can influence the populations of both Th17 and Treg cells. However, it is unclear whether low dose of IL-2 and rapamycin can relieve the symptoms of SLE patients and what is the mechanisms. In this study, we aim to analyze the effect of low dose of IL-2 plus rapamycin on the number of Tregs, Th17 cells and the ratio of Th17/Treg cells, as well as to evaluate its therapeutic efficacy in refractory SLE patients.. Fifty refractory SLE patients and 70 healthy controls were enrolled and followed up for 24 weeks. We found that compared with HC, the refractory SLE patients had a lower number of Tregs, a similar number of Th17 cells, but an increased ratio of Th17/Treg. After the treatment, the number of Tregs of the patients at 12th and 24th week was significantly increased. While the number of Th17 cells was unchanged, the ratio of Th17/Treg was significantly decreased at both 6 weeks and 24 weeks. After 6, 12 and 24 weeks of treatment, the SLEDAI score was significantly reduced. The prednison dosage at 6th,12th and 24th week post treatment was significantly decreased.. Our results support that the reduction of Tregs and the imbalance of Th17/Treg cells were correlated with the occurrence and development of refractory SLE. Low dose of IL-2 combined with rapamycin was able to restore the number of Tregs and the balance of Th17/Treg cells. As a result, this approach was able to induce immune tolerance and promote disease remission, allowing for the reduction in prednisone dosage.. ChiCTR-IPR-16009451 Registration date: 2016/10/16.

Topics: Adult; Biomarkers; Drug Synergism; Drug Therapy, Combination; Female; Humans; Interleukin-2; Leukocytes, Mononuclear; Lupus Erythematosus, Systemic; Lymphocyte Count; Male; Middle Aged; Severity of Illness Index; Sirolimus; T-Lymphocyte Subsets; T-Lymphocytes, Regulatory; Th17 Cells; Treatment Outcome

Recent studies suggest that defects in macroautophagy/autophagy contribute to the pathogenesis of systemic lupus erythamatosus (SLE), especially in adaptive immunity. The occurrence and progression of lupus nephritis (LN) is the end result of complex interactions between regulation of immune responses and pathological process by renal resident cells, but there is still a lot of missing information for establishing the role of autophagy in the pathogenesis of LN, and as a therapy target. In our recent study, we observed that autophagy is activated in LN, especially in podocytes. Based on in vitro assays, many of the most important mediators of the disease - patients' sera, patients' IgG and IFNA/IFN-α - can induce autophagy in both murine and human podocytes, by reactive oxygen species production or MTORC1 inhibition; autophagy activation negatively associates with podocyte injury. With regard to intervention, autophagy activators can protect against podocyte injury, whereas autophagy inhibitors aggravate injury. Taken together, our findings suggest that podocyte autophagy is involved in lupus renal protection and may be a therapeutic target. These data shed new light on the role of rapamycin and autophagy inducers in the treatment of SLE. Abbreviations: ALB: albumin; ARHGDIB: Rho GDP dissociation inhibitor beta; APOL1: apolipoprotein L1; ATG5: autophagy related 5; ATG7: autophagy related 7; ATG16L2: autophagy related 16 like 2; BECN1: beclin 1; CDKN1B: cyclin dependent kinase inhibitor 1B; CLEC16A, C-type lectin domain containing 16A; CYBB: cytochrome b-245 beta chain; DC: dendritic cell; DRAM1: DNA damage regulated autophagy modulator 1; eQTL: expression quantitative trait loci; GWAS: genome-wide association study; IFNA: interferon alpha; IRGM: immunity related GTPase M; LRRK2: leucine rich repeat kinase 2; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; MTMR3: myotubularin related protein 3; LAP" LC3-associated phagocytosis; LN: lupus nephritis; NOD: non-obese diabetic; NPHS2: NPHS2, podocin; PBMC: peripheral blood mononuclear cell; RUBCN: rubicon autophagy regulator; SLE: systemic lupus erythematosus.

Topics: Animals; Autophagy; Autophagy-Related Protein 5; Humans; Inflammation; Kidney; Lupus Erythematosus, Systemic; Lupus Nephritis; Mice; Microtubule-Associated Proteins; Molecular Targeted Therapy; Phagocytosis; Podocytes; Sirolimus

The mechanistic target of rapamycin (mTOR) has become a therapeutic target in systemic lupus erythematosus (SLE). In T cells, mTOR plays a central role in lineage specification, including development of regulatory cells (Treg cells). This study sought to investigate whether mTOR is activated within Treg cells and whether this contributes to the depletion and dysfunction of Treg cells in patients with SLE.. Activities of mTOR complexes 1 (mTORC1) and 2 (mTORC2) were examined by quantifying phosphorylation of translation initiation factor 4E-binding protein 1, S6 kinase, and Akt in SLE patients relative to age- and sex-matched female healthy control subjects. Polarization of Treg cells from naive CD4+ T cells was assessed in the presence of interleukin-6 (IL-6), IL-17, and IL-21. The suppressor function of sorted CD4+CD25+ Treg cells was measured by determining their impact on the proliferation of autologous CD4+CD25- responder T cells. Treg cell expression of FoxP3, GATA-3, and CTLA-4 was monitored by flow cytometry. Autophagy was assessed using immunoblotting of light chain 3 lipidation. The effect of mTOR blockade was evaluated by testing the impact of rapamycin treatment on Treg cell function.. SLE Treg cells exhibited increased activities of mTORC1 and mTORC2, whereas autophagy, the expression of GATA-3 and CTLA-4, and the suppressor function of Treg cells were diminished. IL-21, but not IL-6 or IL-17, blocked the development of Treg cells. IL-21 stimulated mTORC1 and mTORC2, and it abrogated the autophagy, differentiation, and function of Treg cells. Moreover, IL-21 constrained the expression of GATA-3 and CTLA-4 selectively in Treg cells. In turn, blockade of mTORC1 by 3-day rapamycin treatment enhanced transforming growth factor β production, while dual blockade of mTORC1 and mTORC2 by 4-week rapamycin treatment induced autophagy, restored the expression of GATA-3 and CTLA-4, and corrected Treg cell function.. IL-21-driven mTOR activation is a pharmacologically targetable checkpoint of the deficient autophagy that underlies Treg cell dysfunction in SLE.

Topics: Adult; Autophagy; Cell Differentiation; Female; Flow Cytometry; Humans; Immunoblotting; Interleukins; Lupus Erythematosus, Systemic; Male; Middle Aged; Signal Transduction; Sirolimus; T-Lymphocytes, Regulatory; TOR Serine-Threonine Kinases

Topics: Humans; Lupus Erythematosus, Systemic; Sirolimus

Topics: Humans; Lupus Erythematosus, Systemic; Sirolimus

We have shown that bone marrow (BM)-derived mesenchymal stem cells (BM-MSCs) from SLE patients exhibit senescent behavior and are involved in the pathogenesis of SLE. The aim of this study was to investigate the effects of rapamycin (RAPA) on the senescences and immunoregulatory ability of MSCs of MRL/lpr mice and SLE patients and the underlying mechanisms. Cell morphology, senescence associated β-galactosidase (SA-β-gal) staining, F-actin staining were used to detect the senescence of cells. BM-MSCs and purified CD4+ T cells were co-cultured indirectly. Flow cytometry was used to inspect the proportion of regulatory T (Treg) /T helper type 17 (Th17). We used small interfering RNA (siRNA) to interfere the expression of mTOR, and detect the effects by RT-PCR, WB and immunofluorescence. Finally, 1x106 of SLE BM-MSCs treated with RAPA were transplanted to cure the 8 MRL/lpr mice aged 16 weeks for 12 weeks. We demonstrated that RAPA alleviated the clinical symptoms of lupus nephritis and prolonged survival in MRL/lpr mice. RAPA reversed the senescent phenotype and improved immunoregulation of MSCs from MRL/lpr mice and SLE patients through inhibition of the mTOR signaling pathway. Marked therapeutic effects were observed in MRL/lpr mice following transplantation of BM-MSCs from SLE patients pretreated with RAPA.

Topics: Animals; beta-Galactosidase; Cell Shape; Cells, Cultured; Cellular Senescence; Disease Models, Animal; Female; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lupus Nephritis; Mesenchymal Stem Cells; Mice; Mice, Inbred MRL lpr; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Liver disease (LD), defined as ≥ 2-fold elevation of aspartate aminotransferase (AST) or alanine aminotransferase (ALT), was examined in a longitudinal study of systemic lupus erythematosus (SLE) patients. Among 435 patients, 90 (20.7%) had LD with a greater prevalence in males (15/39; 38.5%) than females (75/396; 18.9%; p = 0.01). SLE disease activity index (SLEDAI) was greater in LD patients (7.8 ± 0.7) relative to those without (5.8 ± 0.3; p = 0.0025). Anti-smooth muscle antibodies, anti-DNA antibodies, hypocomplementemia, proteinuria, leucopenia, thrombocytopenia, and anti-phospholipid syndrome were increased in LD. An absence of LD was noted in patients receiving rapamycin relative to azathioprine, cyclosporine A, or cyclophosphamide. An absence of LD was also noted in patients treated with N-acetylcysteine. LFTs were normalized and SLEDAI was diminished with increased prednisone use in 76/90 LD patients over 12.1 ± 2.6 months. Thus, LD is attributed to autoimmunity and disease activity, it responds to prednisone, and it is potentially preventable by rapamycin or N-acetylcysteine treatment.

Topics: Acetylcysteine; Adult; Alanine Transaminase; Antibodies, Antinuclear; Aspartate Aminotransferases; Azathioprine; Biomarkers; Cohort Studies; Complement System Proteins; Cyclosporine; Diabetes Mellitus; Female; Free Radical Scavengers; Humans; Immunosuppressive Agents; Liver Diseases; Longitudinal Studies; Lupus Erythematosus, Systemic; Male; Middle Aged; Mycophenolic Acid; Prednisone; Prevalence; Retrospective Studies; Severity of Illness Index; Sex Distribution; Sirolimus

The mechanistic target of rapamycin (mTOR) is recognized as a sensor of mitochondrial dysfunction and effector of T cell lineage development; however, its role in autoimmunity, including systemic lupus erythematosus, remains unclear. In this study, we prospectively evaluated mitochondrial dysfunction and mTOR activation in PBLs relative to the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) during 274 visits of 59 patients and 54 matched healthy subjects. Partial least square-discriminant analysis identified 15 of 212 parameters that accounted for 70.2% of the total variance and discriminated lupus and control samples (p < 0.0005); increased mitochondrial mass of CD3(+)/CD4(-)/CD8(-) double-negative (DN) T cells (p = 1.1 × 10(-22)) and FOXP3 depletion in CD4(+)/CD25(+) T cells were top contributors (p = 6.7 × 10(-7)). Prominent necrosis and mTOR activation were noted in DN T cells during 15 visits characterized by flares (SLEDAI increase ≥ 4) relative to 61 visits of remission (SLEDAI decrease ≥ 4). mTOR activation in DN T cells was also noted at preflare visits of SLE patients relative to those with stable disease or healthy controls. DN lupus T cells showed increased production of IL-4, which correlated with depletion of CD25(+)/CD19(+) B cells. Rapamycin treatment in vivo blocked the IL-4 production and necrosis of DN T cells, increased the expression of FOXP3 in CD25(+)/CD4(+) T cells, and expanded CD25(+)/CD19(+) B cells. These results identify mTOR activation to be a trigger of IL-4 production and necrotic death of DN T cells in patients with SLE.

Topics: Adult; Aged; Clinical Trials as Topic; Female; Flow Cytometry; Humans; Immunosuppressive Agents; Interleukin-4; Lupus Erythematosus, Systemic; Male; Middle Aged; Necrosis; Sirolimus; T-Lymphocytes; TOR Serine-Threonine Kinases; Young Adult

We report a case of a sirolimus eluting (Cypher, Johnson-Johnson) stent fracture (SF) incidentally depicted 3 years post PCI in an asymptomatic female with systemic lupus erythematosus (SLE). The vessel was assessed with intravascular ultrasound (IVUS) and optical coherence tomography (OCT). Different imaging modalities results are presented. OCT may offer superior imaging of SF compared to fluoroscopy and IVUS and might prove useful for the detailed assessment and tailored treatment of this rare complication.

Topics: Adult; Drug-Eluting Stents; Equipment Failure; Female; Humans; Lupus Erythematosus, Systemic; Radiography; Sirolimus; Time Factors

Persistent mitochondrial hyperpolarization (MHP) and enhanced calcium fluxing underlie aberrant T cell activation and death pathway selection in systemic lupus erythematosus. Treatment with rapamycin, which effectively controls disease activity, normalizes CD3/CD28-induced calcium fluxing but fails to influence MHP, suggesting that altered calcium fluxing is downstream or independent of mitochondrial dysfunction. In this article, we show that activity of the mammalian target of rapamycin (mTOR), which is a sensor of the mitochondrial transmembrane potential, is increased in lupus T cells. Activation of mTOR was inducible by NO, a key trigger of MHP, which in turn enhanced the expression of HRES-1/Rab4, a small GTPase that regulates recycling of surface receptors through early endosomes. Expression of HRES-1/Rab4 was increased in CD4(+) lupus T cells, and in accordance with its dominant impact on the endocytic recycling of CD4, it was inversely correlated with diminished CD4 expression. HRES-1/Rab4 overexpression was also inversely correlated with diminished TCRzeta protein levels. Pull-down studies revealed a direct interaction of HRES-1/Rab4 with CD4 and TCRzeta. Importantly, the deficiency of the TCRzeta chain and of Lck and the compensatory up-regulation of FcepsilonRIgamma and Syk, which mediate enhanced calcium fluxing in lupus T cells, were reversed in patients treated with rapamcyin in vivo. Knockdown of HRES-1/Rab4 by small interfering RNA and inhibitors of lysosomal function augmented TCRzeta protein levels in vitro. The results suggest that activation of mTOR causes the loss of TCRzeta in lupus T cells through HRES-1/Rab4-dependent lysosomal degradation.

Topics: Adolescent; Adult; Blotting, Western; CD4-Positive T-Lymphocytes; Female; Flow Cytometry; Gene Expression; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Microscopy, Confocal; Middle Aged; Nitric Oxide; Oligonucleotide Array Sequence Analysis; Protein Kinases; rab4 GTP-Binding Proteins; rab5 GTP-Binding Proteins; Receptors, Antigen, T-Cell; Reverse Transcriptase Polymerase Chain Reaction; RNA, Small Interfering; Sirolimus; TOR Serine-Threonine Kinases; Transfection

Sirolimus and everolimus belong to the novel class of immunosuppressant agents known as proliferation signal inhibitors (PSIs). They act by preventing antigen-driven T cell proliferation. While PSIs are widely used in transplantation, there are few reports of PSI usage in the treatment of autoimmune rheumatic diseases. The author has presented a series in the APLAR 2006 conference. This report summarizes the clinical experience with PSIs in the treatment of resistant or relapsed rheumatic diseases where conventional immunosuppressive agents have failed. This is a retrospective review of patients with various autoimmune rheumatic diseases who had sirolimus and everolimus treatment from the rheumatological clinics of Changi Hospital or the Arthritis and Rheumatism Specialist Medical Centre. The period of review was from April 2006 to April 2008. A total of 46 patients were reviewed, 39 females and 7 males. The racial distribution was 33 Chinese, 7 Malays, and 6 Indians. Their disease conditions were as follows: 26 (57%) rheumatoid arthritis, 7 psoriatic arthritis, 4 systemic lupus erythematosus, 3 scleroderma, 2 anti-Jo-1 syndrome, 2 spondyloarthropathy, 1 MCTD, and 1 vasculitis. All patients had failed at least three DMARDs or immunosuppressants. Twenty-eight patients received sirolimus and 28 patients received everolimus. Overall positive response rate was 48.2%. Twenty-seven percent had adverse events. 20% had no response. 7% relapsed after initial response. PSIs, namely sirolimus and everolimus, are a novel class of immunosuppressants that can be added to the armamentarium of rheumatologists for the treatment of patients with refractory autoimmune rheumatic diseases.

Topics: Adult; Aged; Arthritis, Psoriatic; Arthritis, Rheumatoid; Autoimmune Diseases; Drug Resistance; Everolimus; Female; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Male; Middle Aged; Molecular Structure; Retrospective Studies; Rheumatic Diseases; Scleroderma, Systemic; Sirolimus; Spondylarthropathies; Treatment Outcome; Vasculitis

Topics: Adult; Anticoagulants; Coronary Angiography; Drug Delivery Systems; Echocardiography; Female; Humans; Lupus Erythematosus, Systemic; Metals; Myocardial Infarction; Patient Compliance; Sirolimus; Stents

Though B cells play key roles in lupus pathogenesis, the molecular circuitry and its dysregulation in these cells as disease evolves remain poorly understood. To address this, a comprehensive scan of multiple signaling axes using multiplexed Western blotting was undertaken in several different murine lupus strains. PI3K/AKT/mTOR (mTOR, mammalian target of rapamycin), MEK1/Erk1/2, p38, NF-kappaB, multiple Bcl-2 family members, and cell-cycle molecules were observed to be hyperexpressed in lupus B cells in an age-dependent and lupus susceptibility gene-dose-dependent manner. Therapeutic targeting of the AKT/mTOR axis using a rapamycin (sirolimus) derivative ameliorated the serological, cellular, and pathological phenotypes associated with lupus. Surprisingly, the targeting of this axis was associated with the crippling of several other signaling axes. These studies reveal that lupus pathogenesis is contingent upon the activation of an elaborate network of signaling cascades that is shared among genetically distinct mouse models and raise hope that targeting pivotal nodes in these networks may offer therapeutic benefit.

Topics: Age Factors; Animals; B-Lymphocytes; Disease Models, Animal; Gene Dosage; Immunosuppressive Agents; Lupus Erythematosus, Systemic; MAP Kinase Kinase 1; Mice; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; NF-kappa B; Phenotype; Phosphatidylinositol 3-Kinases; Protein Kinases; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Sirolimus is a new immunosuppressive drug used to avoid allograft rejection. The immunosuppressive effect of sirolimus is due to inhibition of the mammalian target of rapamycin, necessary for the proliferation and clonal expansion of activated T-cells. Because T-cells play a central role in the pathogenesis of autoimmune disease developed in (NZBxNZW)F1 mice, we evaluated the therapeutic use of sirolimus in such mice. (NZBxNZW)F1 female mice received 1mg/kg/day of sirolimus from 12 to 37 weeks of age. The development of autoimmune disease was evaluated by measuring the serum levels of auto-antibodies (autoAbs) and their immunoglobulin isotypes, prevalence of glomerulonephritis and mortality rates. Sirolimus directly inhibited production of autoAbs, glomerular deposits of immunoglobulins and development of proteinuria; also the survival of these mice was prolonged. Our results demonstrate the beneficial effects of sirolimus in preventing the development of lupus disease in (NZBxNZW)F1 female mice.

Topics: Animals; Autoantibodies; Autoimmune Diseases; Female; Immunoglobulin Isotypes; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lupus Nephritis; Mice; Mice, Inbred NZB; Proteinuria; Sirolimus; Survival Rate; Treatment Outcome

Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown origin. Current treatment options are often ineffective or poorly tolerated. Recent observations have revealed mitochondrial hyperpolarization and enhanced Ca2+ fluxing in T cells from SLE patients. Rapamycin, a lipophilic macrolide antibiotic that regulates mitochondrial transmembrane potential and Ca2+ fluxing, has been used safely and effectively to treat renal transplant rejection since 1999. In addition, rapamycin has been shown to ameliorate T cell function and to prolong survival in lupus-prone MRL/lpr mice. We therefore undertook the present study to investigate whether rapamycin is beneficial in patients with SLE.. Nine patients with clinically active SLE that had been treated unsuccessfully with other immunosuppressive medications began therapy with rapamycin, 2 mg/day orally. Disease activity was assessed with the British Isles Lupus Assessment Group (BILAG) score, SLE Disease Activity Index (SLEDAI), and requirement for prednisone therapy. Mitochondrial transmembrane potential and Ca2+ fluxing were assessed by flow cytometry.. In patients treated with rapamycin, the BILAG score was reduced by a mean +/- SEM of 1.93 +/- 0.9 (P = 0.0218), the SLEDAI by 5.3 +/- 0.8 (P = 0.00002), and concurrent prednisone use by 26.4 +/- 6.7 mg/day (P = 0.0062) compared with pre-rapamycin treatment. While mitochondrial hyperpolarization persisted, pretreatment cytosolic and mitochondrial Ca2+ levels and T cell activation-induced rapid Ca2+ fluxing were normalized in rapamycin-treated patients.. Rapamycin appears to be a safe and effective therapy for SLE that has been refractory to traditional medications. Mitochondrial dysfunction and Ca2+ fluxing could serve as biomarkers to guide decisions regarding future therapeutic interventions in SLE.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Calcium Signaling; Cell Culture Techniques; Flow Cytometry; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lymphocyte Activation; Male; Membrane Potentials; Middle Aged; Mitochondrial Membranes; Sirolimus; T-Lymphocytes

Avascular necrosis (AVN) after renal transplantation has been largely attributed to the use of corticosteroids. However, other risk factors such as microvascular thrombosis and hyperlipidemia have been well described and may be of increased importance in the era of early steroid cessation and avoidance. We hypothesized that maintenance immunosuppressive medications known to be associated with these risk factors for AVN would also be associated with a higher risk of AVN.. By using the U.S. Renal Data System database, we studied 27,772 primary patients on Medicare who received a solitary kidney transplant between January 1, 1996, and July 31, 2000. Cox proportional hazards regression models were used to calculate adjusted hazard ratios (AHRs) for patient- and transplant-related factors (including allograft rejection) with Medicare claims for AVN. The intensity and duration of corticosteroid use could not be assessed.. Among patients who were prescribed sirolimus at discharge, 3.5% of patients who received the combination of sirolimus-cyclosporine A (CsA) demonstrated AVN, compared with 1.4% of patients who received the combination of sirolimus-tacrolimus (P=0.06 by chi). In Cox regression, CsA use (vs. tacrolimus) (AHR 1.36, 95% confidence interval, 1.09-1.71) was independently associated with an increased risk of AVN. Sirolimus use showed a trend toward significance (AHR 1.59, 95% confidence interval, 0.99-2.56), with no significant interaction with CsA.. Compared with other maintenance immunosuppression, AVN was significantly more common after use of CsA prescribed at the time of discharge for renal transplantation. Whether this increased risk of AVN was directly attributable to hyperlipidemia, microvascular thrombosis, or differences in corticosteroid dosing could not be determined.

Topics: Adult; Cyclosporine; Diabetes Mellitus; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Lupus Erythematosus, Systemic; Male; Medicare; Middle Aged; Necrosis; Postoperative Complications; Regression Analysis; Sirolimus; Survival Analysis; United States

Topics: Animals; Cyclosporine; Enzyme-Linked Immunosorbent Assay; Female; Immunosuppressive Agents; Interleukin-2; Lupus Erythematosus, Systemic; Mice; Mice, Inbred Strains; Polyenes; Sirolimus; Spleen

To evaluate the effects of oral rapamycin (RAPA), a macrolide immunosuppressant that has been shown to interfere with T cell activation events, on the course of spontaneous disease progression in the MRL/MpJ/lpr/lpr (MRL/l) mouse model of lupus.. RAPA treatment (6, 12, or 25 mg/kg 3 times per week) was evaluated by monitoring survival rates, autoantibody levels, and urinary albumin levels. Additionally, concanavalin A responsiveness, interleukin-2 (IL-2) production, lymphoid organ size, and histopathology were evaluated ex vivo.. RAPA prevented the typical rise in anti-double-stranded DNA antibody and urinary albumin levels and prolonged survival. Spleen and lymph node sizes were significantly decreased, inflammatory changes in the lung, liver, kidney, spleen, lymph node, and thymus were significantly reduced, and T cell mitogen-stimulated splenocyte proliferation and IL-2 production were restored.. Data from 3 independent experiments demonstrated that RAPA significantly reduced or prevented many pathologic features of lupus normally seen in the MRL/l mouse, and suggest that RAPA may be useful as a therapeutic agent in SLE in humans.

Topics: Administration, Oral; Albuminuria; Animals; Antibodies, Antinuclear; Cyclosporine; Female; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Mice; Mice, Mutant Strains; Polyenes; Sirolimus; Survival Analysis

Topics: Administration, Oral; Animals; Arthritis; Arthritis, Experimental; Autoimmune Diseases; Blood Glucose; Diabetes Mellitus, Type 1; Drinking; Encephalomyelitis, Autoimmune, Experimental; Female; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Male; Mice; Mice, Inbred DBA; Mice, Inbred NOD; Polyenes; Rats; Rats, Inbred Lew; Sirolimus