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Allogeneic mesenchymal stem cell transplantation (MSCT) has been shown to be clinically efficacious in the treatment of various autoimmune diseases. Here, we analyzed the role of allogeneic MSCT to induce renal remission in patients with active and refractory lupus nephritis (LN). This is an open-label and single-center clinical trial conducted from 2007 to 2010 in which 81 Chinese patients with active and refractory LN were enrolled. Allogeneic bone marrow- or umbilical cord-derived mesenchymal stem cells (MSCs) were administered intravenously at the dose of 1 million cells per kilogram of bodyweight. All patients were then monitored over the course of 12 months with periodic follow-up visits to evaluate renal remission, as well as possible adverse events. The primary outcome was complete renal remission (CR) and partial remission (PR) at each follow-up, as well as renal flares. The secondary outcome included renal activity score, total disease activity score, renal function, and serologic index. During the 12-month follow-up, the overall rate of survival was 95 % (77/81). Totally, 60.5 % (49/81) patients achieved renal remission during 12-month visit by MSCT. Eleven of 49 (22.4 %) patients experienced renal flare by the end of 12 months after a previous remission. Renal activity evaluated by British Isles Lupus Assessment Group (BILAG) scores significantly declined after MSCT (mean ± SD, from 4.48 ± 2.60 at baseline to 1.09 ± 0.83 at 12 months), in parallel with the obvious amelioration of renal function. Glomerular filtration rate (GFR) improved significantly 12 months after MSCT (mean ± SD, from 58.55 ± 19.16 to 69.51 ± 27.93 mL/min). Total disease activity evaluated by Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores also decreased after treatment (mean ± SD, from 13.11 ± 4.20 at baseline to 5.48 ± 2.77 at 12 months). Additionally, the doses of concomitant prednisone and immunosuppressive drugs were tapered. No transplantation-related adverse event was observed. Allogeneic MSCT resulted in renal remission for active LN patients within 12-month visit, confirming its use as a potential therapy for refractory LN.

ObjectivesThis study aims to evaluate the safety and efficacy of BCMA-CD19 compound chimeric antigen receptor T cells (cCAR) to dual reset the humoral and B cell immune system in patients with systemic lupus erythematosus (SLE) with lupus nephritis (LN).MethodsThis is a single-arm open-label multicentre phase 1 study of BCMA and CD19-directed cCAR in patients suffering from SLE/LN with autoantibodies produced by B cells and plasma/long-lived plasma cells. In this clinical trial, we sequentially assigned biopsy-confirmed (classes III–V) LN patients to receive 3×106 cCAR cells/kg postcessation of all SLE medications and conditioning. The primary endpoint of safety and toxicity was assessed. Complete immune reset was indicated by B cell receptor (BCR) deep sequencing and flow cytometry analysis. Patient 11 (P11) had insufficient lymphocyte counts and was underdosed as compassionate use.ResultsP1 and P2 achieved symptom and medication-free remission (MFR) from SLE and complete remission from lymphoma. P3–P13 (excluding P11) received an initial dose of 3×106 cCAR cells /kg and were negative for all autoantibodies, including those derived from long-lived plasma cells, 3 months post-cCAR and the complement returned to normal levels. These patients achieved symptom and MFR with post-cCAR follow-up to 46 months. Complete recovery of B cells was seen in 2–6 months post-cCAR. Mean SLE Disease Activity Index 2000 reduced from 10.6 (baseline) to 2.7 (3 months), and renal function significantly improved in 10 LN patients ≤90 days post-cCAR. cCAR T therapy was well tolerant with mild cytokine-release syndrome.ConclusionsData suggest that cCAR therapy was safe and effective in inducing MFR and depleting disease-causing autoantibodies in patients with SLE.

Key Points The main purposes of renal biopsy in patients with systemic lupus erythematosus are to confirm the diagnosis of lupus nephritis, to assess disease activity and/or chronicity, guide therapeutic strategy, and provide prognostic information Although the 2003 International Society of Nephrology/Renal Pathology Society (ISN/RPS) lupus nephritis classification system has been widely accepted, some additional lesions reflect the underlying disease pathogenesis and should be included or otherwise recognized The ISN/RPS classification system is based on histology and not necessarily on the underlying pathogenesis, which needs to be the focus of treatment The presence of glomerular crescents, podocyte injury, tubulointerstitial lesions and thrombotic microangiopathy, in particular, are indicative of underlying disease processes and should be considered when assessing patients with lupus nephritis The current management of lupus nephritis is based on steroids and non-selective immunosuppressive drugs; novel agents that specifically interfere with the underlying pathophysiologic mechanisms of lupus nephritis are needed to improve disease outcomes Current treatment recommendations for lupus nephritis are largely guided by the 2003 International Society of Nephrology/Renal Pathology Society classification system. Here, the authors discuss potential approaches by which this classification system could be improved through consideration of underlying disease processes characterized by the presence of glomerular crescents, podocyte injury, tubulointerstitial lesions and vascular injury. Systemic lupus erythematosus (SLE) is associated with a broad spectrum of clinical and immunologic manifestations, of which lupus nephritis is the most common cause of morbidity and mortality. The development of nephritis in patients with SLE involves multiple pathogenic pathways including aberrant apoptosis, autoantibody production, immune complex deposition and complement activation. The 2003 International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification system for lupus nephritis was widely accepted with high intraobserver and interobserver concordance to guide therapeutic strategy and provide prognostic information. However, this classification system is not based on the underlying disease pathophysiology. Some additional lesions that contribute to disease presentation, including glomerular crescents, podocyte injury, tubulointerstitial lesions and vascular injury, should be recognized. Although outcomes for patients with lupus nephritis have improved over the past 30 years, treatment of this disease remains challenging and is best approached on the basis of the underlying pathogenesis, which is only partially represented by the various pathological phenotypes defined by the ISN/RPS classification. Here, we discuss the heterogeneous mechanisms involved in the pathogenesis of lupus nephritis and how improved understanding of underlying disease mechanisms might help guide therapeutic strategies.

Allogeneic mesenchymal stem cells (MSCs) exhibit immunoregulatory function in human autoimmune diseases such as systemic lupus erythematosus (SLE), but the underlying mechanisms remain incompletely understood. Here we show that the number of peripheral tolerogenic CD1c + dendritic cells (DCs) and the levels of serum FLT3L are significantly decreased in SLE patients especially with lupus nephritis, compared to healthy controls. Transplantation of allogeneic umbilical cord-derived MSCs (UC-MSCs) significantly up-regulates peripheral blood CD1c + DCs and serum FLT3L. Mechanistically, UC-MSCs express FLT3L that binds to FLT3 on CD1c + DCs to promote the proliferation and inhibit the apoptosis of tolerogenic CD1c + DCs. Conversely, reduction of FLT3L with small interfering RNA in MSCs abolishes the up-regulation of tolerogenic CD1c + DCs in lupus patients treated with MSCs. Interferon-γ induces FLT3L expression in UC-MSCs through JAK/STAT signaling pathway. Thus, allogeneic MSCs might suppress inflammation in lupus through up-regulating tolerogenic DCs. Promising pilot clinical trials of mesenchymal stem cells (MSCs) therapy of lupus await validation in larger, controlled trials. Here the authors show that MSCs expand CD1c + dendritic cells in cell culture by producing FLT3L, and that in lupus patients, circulating CD1c + dendritic cells and FLT3L are increased following MSCs therapy.

Morbidity and mortality in juvenile-onset systemic lupus erythematosus are higher than adult-onset disease, and children with lupus nephritis have higher scores on the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI).2,3 End-stage renal disease and permanent haemodialysis are severe adverse events than can occur due to juvenile-onset and adult-onset systemic lupus erythematosus, with 15% of all patients with lupus nephritis developing end-stage renal disease.4 The therapeutic goal of complete remission of lupus nephritis is only reached in 60% of patients by conventional therapies, including immunosuppressive drugs and B-cell-depleting antibodies,3 and two-thirds of adults with juvenile-onset systemic lupus erythematosus develop organ damage and impaired health-related quality of life without reaching drug-free remission.5 Due to their high B-cell depletion activity, CD19-targeted chimeric antigen receptor (CAR) T cells are a potentially powerful strategy to treat autoimmune diseases, such as systemic lupus erythematosus.6,7 In a small case series of eight patients aged 18–38 years with treatment-refractory systemic lupus erythematosus, adoptive transfer of CD19-targeted CAR T cells induced a deep reset of B cells leading to abrogation of autoreactive antibodies and durable remission, including abrogation of lupus nephritis with a follow-up time of 6–29 months.8 Herein, we report on a 15-year-old female patient with severe and rapidly progressive systemic lupus erythematosus. Low levels of complement and presence of several autoantibodies including anti-nuclear-antibody anti-double-stranded DNA (anti-dsDNA; 4545 IU/mL [normal range is <100 IU/mL]), anti-nucleosome, and anti-histone antibodies were evident. Because renal function further rapidly worsened under therapy escalation with high-dose methylprednisolone and cyclophosphamide, plasma separation was initiated, leading to a reduction in autoantibody levels. At our site (University Hospital Erlangen, Erlangen, Germany), we initiated CD19-targeted CAR T-cell therapy in an expanded access programme for critically ill patients according to the German Arzneimittelgesetz, §21/2 and the Arzneimittel-Härtefall-Verordnung §2 following a mandatory case review by an independent interdisciplinary board. Despite kidney failure, CAR T-cell therapy was safe and well tolerated due to appropriate dose adjustment of lymphodepletion.

Background Systemic lupus erythematosus, characterized by persistent inflammation, is a complex autoimmune disorder with no known cure. Immunosuppressants used in treatment put patients at a higher risk of infections. New knowledge of disease modulators, such as symbiotic bacteria, can enable fine-tuning of parts of the immune system, rather than suppressing it altogether. Results Dysbiosis of gut microbiota promotes autoimmune disorders that damage extraintestinal organs. Here we report a role of gut microbiota in the pathogenesis of renal dysfunction in lupus. Using a classical model of lupus nephritis, MRL/ lpr , we found a marked depletion of Lactobacillales in the gut microbiota. Increasing Lactobacillales in the gut improved renal function of these mice and prolonged their survival. We used a mixture of 5 Lactobacillus strains ( Lactobacillus oris , Lactobacillus rhamnosus , Lactobacillus reuteri , Lactobacillus johnsonii , and Lactobacillus gasseri ), but L. reuteri and an uncultured Lactobacillus sp. accounted for most of the observed effects. Further studies revealed that MRL/ lpr mice possessed a “leaky” gut, which was reversed by increased Lactobacillus colonization. Lactobacillus treatment contributed to an anti-inflammatory environment by decreasing IL-6 and increasing IL-10 production in the gut. In the circulation, Lactobacillus treatment increased IL-10 and decreased IgG2a that is considered to be a major immune deposit in the kidney of MRL/ lpr mice. Inside the kidney, Lactobacillus treatment also skewed the Treg-Th17 balance towards a Treg phenotype. These beneficial effects were present in female and castrated male mice, but not in intact males, suggesting that the gut microbiota controls lupus nephritis in a sex hormone-dependent manner. Conclusions This work demonstrates essential mechanisms on how changes of the gut microbiota regulate lupus-associated immune responses in mice. Future studies are warranted to determine if these results can be replicated in human subjects.

ObjectiveTo update the 2012 EULAR/ERA–EDTA recommendations for the management of lupus nephritis (LN).MethodsFollowing the EULAR standardised operating procedures, a systematic literature review was performed. Members of a multidisciplinary Task Force voted independently on their level of agreeement with the formed statements.ResultsThe changes include recommendations for treatment targets, use of glucocorticoids and calcineurin inhibitors (CNIs) and management of end-stage kidney disease (ESKD). The target of therapy is complete response (proteinuria <0.5–0.7 g/24 hours with (near-)normal glomerular filtration rate) by 12 months, but this can be extended in patients with baseline nephrotic-range proteinuria. Hydroxychloroquine is recommended with regular ophthalmological monitoring. In active proliferative LN, initial (induction) treatment with mycophenolate mofetil (MMF 2–3 g/day or mycophenolic acid (MPA) at equivalent dose) or low-dose intravenous cyclophosphamide (CY; 500 mg × 6 biweekly doses), both combined with glucocorticoids (pulses of intravenous methylprednisolone, then oral prednisone 0.3–0.5 mg/kg/day) is recommended. MMF/CNI (especially tacrolimus) combination and high-dose CY are alternatives, for patients with nephrotic-range proteinuria and adverse prognostic factors. Subsequent long-term maintenance treatment with MMF or azathioprine should follow, with no or low-dose (<7.5 mg/day) glucocorticoids. The choice of agent depends on the initial regimen and plans for pregnancy. In non-responding disease, switch of induction regimens or rituximab are recommended. In pure membranous LN with nephrotic-range proteinuria or proteinuria >1 g/24 hours despite renin–angiotensin–aldosterone blockade, MMF in combination with glucocorticoids is preferred. Assessment for kidney and extra-renal disease activity, and management of comorbidities is lifelong with repeat kidney biopsy in cases of incomplete response or nephritic flares. In ESKD, transplantation is the preferred kidney replacement option with immunosuppression guided by transplant protocols and/or extra-renal manifestations. Treatment of LN in children follows the same principles as adult disease.ConclusionsWe have updated the EULAR recommendations for the management of LN to facilitate homogenization of patient care.

Lupus nephritis (LN) is a severe and common manifestation of systemic lupus erythematosus (SLE) that is frequently identified with a poor prognosis. Macrophages play an important role in its pathogenesis. Different macrophage subtypes have different effects on lupus-affected kidneys. Based on their origin, macrophages can be divided into monocyte-derived macrophages (MoMacs) and tissue-resident macrophages (TrMacs). During nephritis, TrMacs develop a hybrid pro-inflammatory and anti-inflammatory functional phenotype, as they do not secrete arginase or nitric oxide (NO) when stimulated by cytokines. The infiltration of these mixed-phenotype macrophages is related to the continuous damage caused by immune complexes and exposure to circulating inflammatory mediators, which is an indication of the failure to resolve inflammation. On the other hand, MoMacs differentiate into M1 or M2 cells under cytokine stimulation. M1 macrophages are pro-inflammatory and secrete pro-inflammatory cytokines, while the M2 main phenotype is essentially anti-inflammatory and promotes tissue repair. Conversely, MoMacs undergo differentiation into M1 or M2 cells in response to cytokine stimulation. M1 macrophages are considered pro-inflammatory cells and secrete pro-inflammatory mediators, whereas the M2 main phenotype is primarily anti-inflammatory and promotes tissue repair. Moreover, based on cytokine expression, M2 macrophages can be further divided into M2a, M2b, and M2c phenotypes. M2a and M2c have anti-inflammatory effects and participate in tissue repair, while M2b cells have immunoregulatory and pro-inflammatory properties. Further, memory macrophages also have a role in the advancement of LN. Studies have demonstrated that the polarization of macrophages is controlled by multiple metabolic pathways, such as glycolysis, the pentose phosphate pathway, fatty acid oxidation, sphingolipid metabolism, the tricarboxylic acid cycle, and arginine metabolism. The changes in these metabolic pathways can be regulated by substances such as fish oil, polyenylphosphatidylcholine, taurine, fumaric acid, metformin, and salbutamol, which inhibit M1 polarization of macrophages and promote M2 polarization, thereby alleviating LN. Highlights Macrophages are the main infiltrating cells in lupus nephritis (LN) kidneys. Different macrophage subtypes have different effects on the development and progression of LN. M1-type macrophages possess pro-inflammatory functions, participating in the onset and progression of LN. In contrast, M2-type macrophages primarily exhibit anti-inflammatory and tissue repair-promoting functions, which are beneficial for the remission of LN. The infiltration of mixed phenotype macrophages reflects a failure in the resolution of inflammation and correlates with poor prognostic outcomes in LN. Multiple metabolic pathways, such as glycolysis, pentose phosphate pathway, amino sugar and nucleotide sugar metabolism, fatty acid oxidation, sphingolipid metabolism, tricarboxylic acid cycle, arginine metabolism, and tryptophan metabolism, regulate macrophage polarization. Compounds such as omega-3 fatty acids, polyunsaturated phospholipids, taurine, fumarate, metformin, salbutamol, and others can modulate metabolic pathways, suppressing M1 polarization and promoting M2 polarization in macrophages, thereby ameliorating LN symptoms.

The 2003 International Society of Nephrology/Renal Pathology Society (ISN/RPS) pathological classification system of lupus nephritis specified the importance of vascular damage and indicated this should be included in the diagnostic summary. Few pathological studies of lupus nephritis, however, focus on the patterns of renal vascular involvement. Here we assessed renal vascular lesions in lupus nephritis based on the 2003 ISN/RPS classification system and evaluated their association with clinical and pathological data in a large cohort from a single center in China. Among 341 patients with lupus nephritis, 279 were diagnosed with single or multiple renal vascular lesions that included 253 with vascular immune complex deposits, 82 with atherosclerosis, 60 with thrombotic microangiopathy, 13 with noninflammatory necrotizing vasculopathy, and 2 with true renal vasculitis. Patients with thrombotic microangiopathy had the poorest renal outcome. In multivariate Cox hazard analysis after inclusion of renal vascular lesions, the new chronicity index score became a significantly better independent risk factor for renal outcome (hazard ratio 2.32). Thus, renal vascular lesions are common in lupus nephritis and closely correlate with clinical disease activity and renal outcome. Inclusion of a detailed description of renal vascular lesions in the ISN/RPS classification of lupus nephritis may strengthen its predictive value for renal outcome.