Higher-order interactions between hippocampal CA1 neurons are disrupted in amnestic mice.

Across systems, higher-order interactions between components govern emergent dynamics. Here we tested whether contextual threat memory retrieval in mice relies on higher-order interactions between dorsal CA1 hippocampal neurons requiring learning-induced dendritic spine plasticity. We compared population-level Ca2+ transients as wild-type mice (with intact learning-induced spine plasticity and memory) and amnestic mice (TgCRND8 mice with high levels of amyloid-ß and deficits in learning-induced spine plasticity and memory) were tested for memory. Using machine-learning classifiers with different capacities to use input data with complex interactions, our findings indicate complex neuronal interactions in the memory representation of wild-type, but not amnestic, mice. Moreover, a peptide that partially restored learning-induced spine plasticity also restored the statistical complexity of the memory representation and memory behavior in Tg mice. These findings provide a previously missing bridge between levels of analysis in memory research, linking receptors, spines, higher-order neuronal dynamics and behavior.

Excitability mediates allocation of pre-configured ensembles to a hippocampal engram supporting contextual conditioned threat in mice.

Little is understood about how engrams, sparse groups of neurons that store memories, are formed endogenously. Here, we combined calcium imaging, activity tagging, and optogenetics to examine the role of neuronal excitability and pre-existing functional connectivity on the allocation of mouse cornu ammonis area 1 (CA1) hippocampal neurons to an engram ensemble supporting a contextual threat memory. Engram neurons (high activity during recall or TRAP2-tagged during training) were more active than non-engram neurons 3 h (but not 24 h to 5 days) before training. Consistent with this, optogenetically inhibiting scFLARE2-tagged neurons active in homecage 3 h, but not 24 h, before conditioning disrupted memory retrieval, indicating that neurons with higher pre-training excitability were allocated to the engram. We also observed stable pre-configured functionally connected sub-ensembles of neurons whose activity cycled over days. Sub-ensembles that were more active before training were allocated to the engram, and their functional connectivity increased at training. Therefore, both neuronal excitability and pre-configured functional connectivity mediate allocation to an engram ensemble.

Feasibility and impact of ketogenic dietary interventions in polycystic kidney disease: KETO-ADPKD-a randomized controlled trial.

Ketogenic dietary interventions (KDIs) are beneficial in animal models of autosomal-dominant polycystic kidney disease (ADPKD). KETO-ADPKD, an exploratory, randomized, controlled trial, is intended to provide clinical translation of these findings (NCT04680780). Sixty-six patients were randomized to a KDI arm (ketogenic diet [KD] or water fasting [WF]) or the control group. Both interventions induce significant ketogenesis on the basis of blood and breath acetone measurements. Ninety-five percent (KD) and 85% (WF) report the diet as feasible. KD leads to significant reductions in body fat and liver volume. Additionally, KD is associated with reduced kidney volume (not reaching statistical significance). Interestingly, the KD group exhibits improved kidney function at the end of treatment, while the control and WF groups show a progressive decline, as is typical in ADPKD. Safety-relevant events are largely mild, expected (initial flu-like symptoms associated with KD), and transient. Safety assessment is complemented by nuclear magnetic resonance (NMR) lipid profile analyses.

Complement: Functions, location and implications.

The complement system, an arm of the innate immune system plays a critical role in both health and disease. The complement system is highly complex with dual possibilities, helping or hurting the host, depending on the location and local microenvironment. The traditionally known functions of complement include surveillance, pathogen recognition, immune complex trafficking, processing and pathogen elimination. The noncanonical functions of the complement system include their roles in development, differentiation, local homeostasis and other cellular functions. Complement proteins are present in both, the plasma and on the membranes. Complement activation occurs both extra- and intracellularly, which leads to considerable pleiotropy in their activity. In order to design more desirable and effective therapies, it is important to understand the different functions of complement, and its location-based and tissue-specific responses. This manuscript will provide a brief overview into the complex nature of the complement cascade, outlining some of their complement-independent functions, their effects at different locale, and their implication in disease settings.

Formation and fate of an engram in the lateral amygdala supporting a rewarding memory in mice.

Memories allow past experiences to guide future decision making and behavior. Sparse ensembles of neurons, known as engrams, are thought to store memories in the brain. Most previous research has focused on engrams supporting threatening or fearful memories where results show that neurons involved in a particular engram ("engram neurons") are both necessary and sufficient for memory expression. Far less is understood about engrams supporting appetitive or rewarding memories. As circumstances and environments are dynamic, the fate of a previously acquired engram with changing circumstances is unknown. Here we examined how engrams supporting a rewarding cue-cocaine memory are formed and whether this original engram is important in reinstatement of memory-guided behavior following extinction. Using a variety of techniques, we show that neurons in the lateral amygdala are allocated to an engram based on relative neuronal excitability at training. Furthermore, once allocated, these neurons become both necessary and sufficient for behavior consistent with recall of that rewarding memory. Allocated neurons are also critical for cocaine-primed reinstatement of memory-guided behavior following extinction. Moreover, artificial reactivation of initially allocated neurons supports reinstatement-like behavior following extinction even in the absence of cocaine-priming. Together, these findings suggest that cocaine priming after extinction reactivates the original engram, and that memory-guided reinstatement behavior does not occur in the absence of this reactivation. Although we focused on neurons in one brain region only, our findings that manipulations of lateral amygdala engram neurons alone were sufficient to impact memory-guided behavior indicate that the lateral amygdala is a critical hub region in what may be a larger brain-wide engram.

Efficacy and Safety of Low-Dose Interleukin 2 for Primary Sjögren Syndrome: A Randomized Clinical Trial.

Importance: Primary Sjögren syndrome (pSS) is a systemic autoimmune disease associated with dysregulated immune cells, with no efficient therapy. There is a need to study potential therapeutic approaches. Objective: To investigate the efficacy, safety, and immune response of low-dose interleukin 2 (LD-IL-2) in the treatment of pSS. Design, Setting, and Participants: A double-blind, placebo-controlled randomized clinical trial was conducted with a 2-group superiority design from June 2015 to August 2017. Sixty patients, aged 18 to 70 years, were recruited from Peking University People's Hospital. Efficacy analyses were based on the intention-to-treat (ITT) principle. Data were analyzed from December 2018 to March 2020. Interventions: Patients with pSS were treated with LD-IL-2 or placebo for 12 weeks and accompanied by 12 weeks of follow-up. Main Outcomes and Measures: The primary end point was defined as a 3-point or greater improvement on the European League Against Rheumatism Sjögren's Syndrome Disease Activity Index (ESSDAI) by week 24. The secondary end points included other clinical responses, safety, and changes of immune cell subsets at week 12 and 24. Results: Sixty patients with pSS were recruited, with 30 in the LD-IL-2 group (mean [SD] age, 47.6 [12.8] years; 30 [100%] women) and 30 in the placebo group (mean [SD] age, 51.0 [11.9] years; 30 [100%] women), and 57 completed the trial. More patients in the LD-IL-2 group (20 [66.7%]) achieved ESSDAI score reduction of at least 3 points than in the placebo group (8 [26.7%]) at week 24 (P = .004). There were greater resolutions of dryness, pain, and fatigue in the LD-IL-2 group than placebo group at week 12 (dryness: difference, -18.33 points; 95% CI, -28.46 to -8.21 points; P = .001; pain: difference, -10.33 points; 95% CI, -19.38 to -1.29 points; P = .03; fatigue: difference, -11.67 points; 95% CI, -20.65 to -2.68 points; P = .01). No severe adverse events were observed in either group. In addition, the LD-IL-2 group showed a significant decrease in infection compared with the placebo group (1 [3.3%] vs 9 [30.0%]; P = .006). Immunological analysis revealed that LD-IL-2 promoted an expansion of regulatory T cells and regulatory CD24highCD27+ B cells. Conclusions and Relevance: In this randomized clinical trial, LD-IL-2 was effective and well tolerated in patients with pSS, and it restored immune balance, with enhanced regulatory T cells and CD24highCD27+ B cells. Trial Registration: ClinicalTrials.gov Identifier: NCT02464319.

Opto-extinction of a threat memory in mice.

Memories of past experiences guide future behaviour. Sparse ensembles of neurons, known as engrams, are thought to store memories in the brain. Neurons involved in a particular engram ("engram neurons") are necessary for subsequent memory expression as memory retrieval is thought to be initiated by an external sensory cue reactivating engram neurons. However, conditions or environments are dynamic, such that future behaviour should be flexible. The role of engrams in mediating flexible behaviour is not understood. Here we examined this question using one type of flexible behaviour, extinction of a threat response. An initially neutral tone is first paired with an aversive footshock such that the tone alone induces defensive freezing. After subsequent repeated tone presentations without the footshock, rodents no longer freeze to the tone. Because the tone cue is thought to reactivate the engram to induce memory retrieval, we examined whether it is possible to induce an extinction-like behavioural effect by optogenetically reactivating the lateral amygdala component of the engram alone (without tone re-exposure). Similar to tone-induced extinction, mice showed decreased freezing to optogenetic stimulation of the lateral amygdala engram in the "extinction training" session. Moreover, "opto-extinguished" mice showed decreased freezing to the tone when subsequently tested for retrieval of the extinction training in the same context, suggesting that the opto-extinction transferred to the actual sensory stimulus. However, unlike tone extinction, in which mice showed renewal of tone-induced freezing when tested in a novel context, opto-extinguished mice continued to show a deficit in tone-induced freezing. Extinction has been characterized as new learning that inhibits the original memory or a phenomenon in which the original memory is "unlearned". Our findings suggest that opto-extinction may silence the original engram to "unlearn" the original memory.

Cohort profile: The PreEclampsia, Angiogenesis, Cardiac dysfunction and Hypertension (PEACH) Study.

BACKGROUND: Hypertensive disorders of pregnancy (HDP) remain a leading cause of maternal morbidity and mortality worldwide, with implications for maternal and neonatal well-being in the short term and for long-term maternal cardiovascular health. Although the mechanisms behind HDP remain incompletely understood, evidence suggests that preeclampsia in particular is a syndrome with more than one distinct subtype. OBJECTIVES: The PEACH (PreEclampsia, Angiogenesis, Cardiac dysfunction, Hypertension) Study was established to identify new HDP subtyping systems reflecting aetiology and prognosis and to find markers of later cardiovascular disease risk associated with preeclampsia. POPULATION: The PEACH Study recruited pregnant women referred to two Copenhagen-area hospitals with suspected preeclampsia (mean gestational age at enrolment: 36.7 weeks) and a group of frequency-matched pregnant women planning delivery at the same hospitals and healthy when enrolled mid-pregnancy. DESIGN: Prospective, longitudinal pregnancy cohort. METHODS: Participants underwent repeated third-trimester blood sample collection, longitudinal cardiac function assessments using the USCOM-1A during the third trimester and at 1 year postpartum and collection of placental samples immediately after delivery. Medical information was abstracted from medical records and hospital databases. PRELIMINARY RESULTS: During 2016-2018, we recruited 1149 pregnant women, of whom 1101 were followed to delivery. Among 691 women enrolled with suspected preeclampsia, 310 and 172 developed preeclampsia and gestational hypertension respectively. Among 410 women with healthy pregnancies when enrolled mid-pregnancy, 37 later developed hypertensive disorders of pregnancy. Of 1089 women still in the cohort 1 year postpartum, 578 (53.1%) participated in the follow-up assessment. CONCLUSIONS: The PEACH Study's rich data from women with and without HDP will enable us to identify new, clinically useful HDP subtypes to aid in decision-making regarding monitoring and treatment. Continued postpartum follow-up will help us develop algorithms to identify women at risk of persistent postpartum cardiac dysfunction and later cardiovascular disease after pregnancies complicated by HDP.

Rebozo and External Cephalic Version in breech presentation (RECEIVE): A randomised controlled study.

OBJECTIVE: To investigate if a hospital-initiated home-based rebozo intervention performed by the pregnant woman and her partner before external cephalic version (ECV) would increase the rate of cephalic presentations at birth. DESIGN: A multicentre randomised controlled trial. SETTING: Three university hospitals in Copenhagen, Denmark. POPULATION: Pregnant women with a breech or transverse presentation at 35 weeks or more of gestation eligible for ECV. METHODS: We compared rebozo before ECV with ECV alone. The randomisation was computer-generated in blocks and stratified by parity. The woman and her partner were instructed in the technique by a project midwife and performed the technique at home three times daily for 3-5 days before the scheduled ECV. Analyses were by intention-to-treat. MAIN OUTCOME MEASURE: The number of cephalic presentations at the time of birth. Odds ratios (OR) and 95% confidence intervals (CI) were calculated. RESULTS: A total of 372 women were randomly assigned (1:1) to either rebozo intervention (n = 187) or control (n = 185). At birth, 95 (51%) in the intervention group versus 112 (62%) in the control group had a fetus in cephalic presentation (OR 0.61; 95% CI 0.40-0.95). No adverse events were observed in relation to the intervention. CONCLUSIONS: In breech or transverse presentation, home-based rebozo exercise before ECV lowered the overall rate of cephalic presentation at birth. TWEETABLE ABSTRACT: Home-based rebozo for breech presentation before external version reduces the rate of cephalic presentation at birth.

Macrophage Depletion Reduces Disease Pathology in Factor H-Dependent Immune Complex-Mediated Glomerulonephritis.

Complement factor H (FH) is a key regulator of the alternative pathway of complement, in man and mouse. Earlier, our studies revealed that the absence of FH causes the C57BL6 mouse to become susceptible to chronic serum sickness (CSS) along with an increase in the renal infiltration of macrophages compared to controls. To understand if the increased recruitment of macrophages (Mϕs) to the kidney was driving inflammation and propagating injury, we examined the effect of Mϕ depletion with clodronate in FH knockout mice with CSS. Eight-week-old FHKO mice were treated with apoferritin (4 mg/mouse) for 5 wks and with either vehicle (PBS) or clodronate (50 mg/kg ip, 3 times/wk for the last 3 weeks). The administration of clodronate decreased monocytes and Mϕs in the kidneys by >80%. Kidney function assessed by BUN and albumin remained closer to normal on depletion of Mϕs. Clodronate treatment prevented the alteration in cytokines, TNFα and IL-6, and increase in gene expression of connective tissue growth factor (CTGF), TGFß-1, matrix metalloproteinase-9 (MMP9), fibronectin, laminin, and collagen in FHKO mice with CSS (P < 0.05). Clodronate treatment led to relative protection from immune complex- (IC-) mediated disease pathology during CSS as assessed by the significantly reduced glomerular pathology (GN) and extracellular matrix. Our results suggest that complement activation is one of the mechanism that regulates the macrophage landscape and thereby fibrosis. The exact mechanism remains to be deciphered. In brief, our data shows that Mϕs play a critical role in FH-dependent ICGN and Mϕ depletion reduces disease progression.

Local complement factor H protects kidney endothelial cell structure and function.

Factor H (FH) is a critical regulator of the alternative complement pathway and its deficiency or mutation underlie kidney diseases such as dense deposit disease. Since vascular dysfunction is an important facet of kidney disease, maintaining optimal function of the lining endothelial cells is important for vascular health. To investigate the molecular mechanisms that are regulated by FH in endothelial cells, FH deficient and sufficient mouse kidney endothelial cell cultures were established. Endothelial FH deficiency resulted in cytoskeletal remodeling, increased angiogenic potential, loss of cellular layer integrity and increased cell proliferation. FH reconstitution prevented these FH-dependent proliferative changes. Respiratory flux analysis showed reduced basal mitochondrial respiration, ATP production and maximal respiratory capacity in FH deficient endothelial cells, while proton leak remained unaltered. Similar changes were observed in FH deficient human glomerular endothelial cells indicating the translational potential of these studies. Gene expression analysis revealed that the FH-dependent gene changes in mouse kidney endothelial cells include significant upregulation of genes involved in inflammation and the complement system. The transcription factor nuclear factor-kB, that regulates many biological processes, was translocated from the cytoplasm to the nucleus in the absence of FH. Thus, our studies show the functional relevance of intrinsic FH in kidney endothelial cells in man and mouse.

Exercise alleviates symptoms of CNS lupus.

Systemic lupus erythematosus (lupus) is a global health problem where 20-80% patients display cognitive problems and central nervous system (CNS) dysfunction. Early diagnosis and treatment of lupus remains a clinical challenge. Exercise improves experimental lupus nephritis. However, the effects of exercise in CNS lupus remains unknown. This study investigates the effects of controlled exercise (CE) that consisted of treadmill walking (5 m/min for 10 min everyday) on experimental CNS lupus using the well-established mouse model, MRL/lpr mice. The MRL/lpr mice were subjected to CE from 8 weeks (preclinical) to 16 weeks (disease). Multiplex gene expression analysis revealed significant upregulation of genes involved in neurite growth, proliferation and synaptic plasticity, and a decrease in inflammatory genes including complement proteins, NFkB, chemokines and cytokines in exercised mice compared to the unmanipulated, age-matched controls. The loss of blood-brain barrier integrity, astrogliosis and edema seen in MRL/lpr mice were reduced with exercise. Exercised mice performed better in behavioral assessments such as open field, nesting, and tail suspension test. For the first time our results show that a supervised, well-regulated and controlled exercise regimen alleviates CNS lupus and could potentially serve as an intervention strategy to improve the quality of life. Exercise could also serve as an adjunct therapy for lupus and other neuroinflammatory diseases, thereby reducing the need for the current therapies with toxic side effects. The validity of the findings and a safe exercise regimen needs to be established by additional studies in patients.

Differentiated timing of induction for women with intrahepatic cholestasis of pregnancy-A historical cohort study.

INTRODUCTION: Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disease characterized by pruritus and abnormal liver function tests and it has been associated with intrauterine fetal distress and stillbirth. We compared two guidelines of the management of ICP: one mandating induction at 38 weeks of gestation (Rigshospitalet and Hvidovre Hospital before 2012) and another separating ICP into mild and severe forms, and only women with severe ICP were recommended for induction at 38 weeks (Hvidovre Hospital after 2012). MATERIAL AND METHODS: We performed a historical cohort study at two Copenhagen Hospitals from 2004 to 2015. We included 62 937 women with singleton deliveries at Rigshospitalet and 71 015 at Hvidovre Hospital, of whom 971 women (1.5%) and 998 women (1.4%) were diagnosed with ICP at Rigshospitalet and Hvidovre Hospital, respectively. Data were retrieved from a local medical database. For the analysis of induction and comparison of obstetrical outcomes we only included pregnancies with an ICP diagnosis and excluded women with other medical conditions that could mandate induction. Main outcome measures were induction and cesarean section rates, asphyxia and stillbirth. RESULTS: We found no changes in the rate of spontaneous labor, cesarean section and induction over the years at Rigshospitalet (P = .17) and Hvidovre Hospital (P = .38). For women with intended vaginal delivery we found no change in the final mode of delivery over the years at Rigshospitalet (P = .28) and Hvidovre Hospital (P = .57). CONCLUSIONS: The two approaches to the management of mild ICP regarding the timing of induction are comparable. Women with mild ICP and their clinicians should be encouraged to engage in shared decision-making when discussing timing of induction.

Absence of complement factor H reduces physical performance in C57BL6 mice.

Complement (C) system is a double edge sword acting as the first line of defense on the one hand and causing aggravation of disease on the other. C activation when unregulated affects different organs including muscle regeneration. However, the effect of factor H (FH), a critical regulator of the alternative C pathway in muscle remains to be studied. FH deficiency results in excessive C activation and generates proinflammatory fragments C5a and C3a as byproducts. C3a and C5a signal through their respective receptors, C5aR and C3aR. In this study, we investigated the role of FH and downstream C5a/C5aR signaling in muscle architecture and function. Using the FH knockout (fh-/-) and fh-/-/C5aR-/double knockout mice we explored the role of C, specifically the alternative C pathway in muscle dysfunction. Substantial C3 and C9 deposits occur along the walls of the fh-/- muscle fibers indicative of unrestricted C activation. Physical performance assessments of the fh-/- mice show reduced grip endurance (76 %), grip strength (14 %) and rotarod balance (36 %) compared to controls. Histological analysis revealed a shift in muscle fiber populations indicated by an increase in glycolytic MHC IIB fibers and reduction in oxidative MHC IIA fibers. Consistent with this finding, mitochondrial DNA (mtDNA) and citrate synthase (CS) expression were both reduced indicating possible reduction in mitochondrial biomass. In addition, our results showed a significant increase in TGFß expression and altered TGFß localization in this setting. The architecture of cytoskeletal proteins actin and vimentin in the fh-/- muscle was changed that could lead to contractile weakness and loss of skeletal muscle elasticity. The muscle pathology in fh-/- mice was reduced in fh-/-/C5aR-/- double knockout (DKO) mice, highlighting partial C5aR dependence. Our results for the first time demonstrate an important role of FH in physical performance and skeletal muscle health.

Automated Curation of CNMF-E-Extracted ROI Spatial Footprints and Calcium Traces Using Open-Source AutoML Tools.

In vivo 1-photon (1p) calcium imaging is an increasingly prevalent method in behavioral neuroscience. Numerous analysis pipelines have been developed to improve the reliability and scalability of pre-processing and ROI extraction for these large calcium imaging datasets. Despite these advancements in pre-processing methods, manual curation of the extracted spatial footprints and calcium traces of neurons remains important for quality control. Here, we propose an additional semi-automated curation step for sorting spatial footprints and calcium traces from putative neurons extracted using the popular constrained non-negative matrixfactorization for microendoscopic data (CNMF-E) algorithm. We used the automated machine learning (AutoML) tools TPOT and AutoSklearn to generate classifiers to curate the extracted ROIs trained on a subset of human-labeled data. AutoSklearn produced the best performing classifier, achieving an F1 score >92% on the ground truth test dataset. This automated approach is a useful strategy for filtering ROIs with relatively few labeled data points and can be easily added to pre-existing pipelines currently using CNMF-E for ROI extraction.

Why Have Two When One Will Do? Comparing Task Representations across Amygdala and Prefrontal Cortex in Single Neurons and Neuronal Populations.

Many brain areas represent aspects of learned behavior. How do representations differ between regions? In this issue of Neuron, Kyriazi et al. (2020) show how the amygdala and prefrontal cortex use distinct strategies to code features of a complex task.

The role of neuronal excitability, allocation to an engram and memory linking in the behavioral generation of a false memory in mice.

Memory is a constructive, not reproductive, process that is prone to errors. Errors in memory, though, may originate from normally adaptive memory processes. At the extreme of memory distortion is falsely "remembering" an event that did not occur. False memories are well-studied in cognitive psychology, but have received relatively less attention in neuroscience. Here, we took advantage of mechanistic insights into how neurons are allocated or recruited into an engram (memory trace) to generate a false memory in mice using only behavioral manipulations. At the time of an event, neurons compete for allocation to an engram supporting the memory for this event; neurons with higher excitability win this competition (Han et al., 2007). Even after the event, these allocated "engram neurons" remain temporarily (~6 h) more excitable than neighboring neurons. Should a similar event occur in this 6 h period of heightened engram neuron excitability, an overlapping population of neurons will be co-allocated to this second engram, which serves to functionally link the two memories (Rashid et al., 2016). Here, we applied this principle of co-allocation and found that mice develop a false fear memory to a neutral stimulus if exposed to this stimulus shortly (3 h), but not a longer time (24 h), after cued fear conditioning. Similar to co-allocation, the generation of this false memory depended on the post-training excitability of engram neurons such that these neurons remained more excitable during exposure to the neutral stimulus at 3 h but not 24 h. Optogenetically silencing engram neurons 3 h after cued fear conditioning impaired formation of a false fear memory to the neutral stimulus, while optogenetically activating engram neurons 24 h after cued fear conditioning created a false fear memory. These results suggest that some false memories may originate from normally adaptive mnemonic processes such as neuronal excitability-dependent allocation and memory linking.

Double negative T cells, a potential biomarker for systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease that is a challenge to diagnose and treat. There is an urgent need for biomarkers to help define organ involvement, and more effective therapies. A unique population of T cells, the CD3+CD4-CD8- (DNeg) cells, is significantly increased in lupus patients. Twenty-seven cases (53%) of pediatric SLE patients had elevated DNeg cells in their peripheral blood, which correlated with kidney function (R2  = 0.54). Significant infiltration of DNeg cells was observed in both adult and pediatric lupus kidneys by immunofluorescence. For the first time, this study provides direct evidence that DNeg cells facilitate kidney injury in preclinical 8-week-old MRL/lpr lupus mice. In lupus mice, the increase in DNeg cells tracked with worsening disease and correlated with kidney function (R2  = 0.85). Our results show that DNeg cells per se can cause kidney dysfunction, increase in number with increase in disease pathology, and could serve as a potential biomarker.

Efficacy and safety of low-dose IL-2 in the treatment of systemic lupus erythematosus: a randomised, double-blind, placebo-controlled trial.

OBJECTIVES: Open-labelled clinical trials suggested that low-dose IL-2 might be effective in treatment of systemic lupus erythematosus (SLE). A double-blind and placebo-controlled trial is required to formally evaluate the safety and efficacy of low-dose IL-2 therapy. METHODS: A randomised, double-blind and placebo-controlled clinical trial was designed to treat 60 patients with active SLE. These patients received either IL-2 (n=30) or placebo (n=30) with standard treatment for 12 weeks, and were followed up for additional 12 weeks. IL-2 at a dose of 1 million IU or placebo was administered subcutaneously every other day for 2 weeks and followed by a 2-week break as one treatment cycle. The primary endpoint was the SLE Responder Index-4 (SRI-4) at week 12. The secondary endpoints were other clinical responses, safety and dynamics of immune cell subsets. RESULTS: At week 12, the SRI-4 response rates were 55.17% and 30.00% for IL-2 and placebo, respectively (p=0.052). At week 24, the SRI-4 response rate of IL-2 group was 65.52%, compared with 36.67% of the placebo group (p=0.027). The primary endpoint was not met at week 12. Low-dose IL-2 treatment resulted in 53.85% (7/13) complete remission in patients with lupus nephritis, compared with 16.67% (2/12) in the placebo group (p=0.036). No serious infection was observed in the IL-2 group, but two in placebo group. Besides expansion of regulatory T cells, low-dose IL-2 may also sustain cellular immunity with enhanced natural killer cells. CONCLUSIONS: Low-dose IL-2 might be effective and tolerated in treatment of SLE. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registries (NCT02465580 and NCT02932137).