Broad-spectrum Immunosuppression Research Articles

Kidney Manifestations of Rheumatological Diseases in Children

Opinion statementPaediatric rheumatological diseases are a group of multi-systemic inflammatory diseases affecting children and young people. The kidneys constitute a target organ during the acute presentation and life course of several multi-systemic inflammatory conditions including childhood systemic lupus erythematosus (cSLE), IgA vasculitis and ANCA-associated vasculitis. Unlike adults with rheumatic diseases, who may have prior concomitant kidney disease, children are more likely to have an acute, potentially reversible inflammatory process that typically requires prompt immunosuppressive treatment. Despite broad-spectrum immunosuppression, kidney outcomes remain suboptimal, with children progressing to irreversible chronic kidney disease and ultimately kidney failure, requiring kidney replacement therapy or transplantation. In cSLE, for example, the kidney failure rate is 1–14% depending on the length of follow-up, with the average age of requiring a kidney transplant reported to be 24 years, thus illustrating the importance of follow-up into adulthood. Advances in improving the outcomes for these patients remain slow, and the recruitment of children to drug trials can be challenging. The aim of this review article is to summarise the key paediatric rheumatic diseases that commonly involve the kidney to highlight the epidemiology and current kidney outcomes. Useful information is also provided on suggested screening to detect the presence of active kidney inflammation and improvements in this field for the future.

Novel Therapeutics for Management of Lupus Nephritis: What Is Next?

Lupus nephritis is a severe, organ-threatening manifestation of systemic lupus erythematosus. The current standard of care in the treatment of lupus nephritis is limited to broad-spectrum immunosuppressants, which have significant concerns of short- and long-term toxicity. With traditional approaches, kidney survival and patient outcomes have remained suboptimal. Robust research in the therapeutics of lupus nephritis has resulted in development of many novel drugs targeting specific inflammatory response pathways. Some newer agents have shown a definitive signal of benefit when added to standard of care. With the advent of precision medicine in nephrology, lupus nephritis treatment may undergo a shift toward incorporating approaches using these newer drugs and individualizing care of our patients. This review highlights major advances in management of lupus nephritis over the last 25 years and explores the ongoing trials of emerging therapies in lupus nephritis.

The positive effect of JAK inhibitor tofacitinib in the treatment of primary Sjögren’s syndrome: a clinical case

Primary Sjögren’s syndrome (pSS, Sjögren’s disease) is a systemic autoimmune disease which develops in previously healthy individuals and characterized by damage to exocrine glands, mainly lacrimal and salivary glands, with gradual formation of their secretory insufficiency and various systemic manifestations. According to EULAR recommendation (2019) therapeutic management of pSS bases on symptomatic treatment of sicca syndrome and broad-spectrum immunosuppression for systemic manifestations. The perspective group for the treatment of autoimmune disease is Janus kinase inhibitors, which can block the signals from biologically active molecules (interferons, erythropoietins and cytokines) and providing a response to these target cell signals. Therefore, the use of JAK inhibitors in patients with pSS requires clinical confirmation of effectiveness. The article described the clinical case of the positive effect of tofacitinib with methotrexate combination in the treatment of patient with pSS. A 55-year-old female with sicca syndrome (confirmed by Schirmer’s test), arthralgia, low-grade fever, weight loss and a positive test for the detection of specific antibodies (SS-A/Ro > 240 units/ml, SS-B/La 94 units/ml) was diagnosed with pSS. The total score of EULAR Sjögren’s syndrome disease activity index (ESSDAI) was 9 (activity grade II). The treatment included symptomatic methods of sicca syndrome correcting (replacement therapy with artificial tear preparations and chewing gums with xylitol) in combination with immunosuppressive therapy. The addition of tofacitinib 5 mg twice daily to methotrexate (10 mg weekly) has been shown to significantly reduce disease activity after 6 months of treatment (ESSDAI = 0).

Suppression of Autoimmune Rheumatoid Arthritis with Hybrid Nanoparticles That Induce B and T Cell Tolerance to Self-Antigen.

Autoimmune diseases affect over 4% of the world's population. Treatments are generally palliative or use broad spectrum immunosuppressants to reduce symptoms and disease progression. In some diseases, antibodies generated to a single autoantigen are the major cause of pathogenic inflammation, suggesting that treatments to induce tolerance to the autoantigen could be therapeutic. Here we report the development of hybrid nanoparticles (NPs) that induce tolerance in both T cells and B cells. The NPs comprise a lipid monolayer encapsulating a PLGA core loaded with rapamycin that promotes development of regulatory T cells (Tregs). The lipid monolayer displays the protein antigen and a ligand of the B cell inhibitory co-receptor CD22 (CD22L) that act together to suppress activation of B cells recognizing the antigen. We demonstrate that the hybrid NPs decorated with ovalbumin (OVA) elicit tolerance to OVA in naı̈ve mice, as judged by low OVA-specific antibody titers after the challenge. In the K/BxN mouse model of rheumatoid arthritis caused by B and T cell-dependent responses to the self-antigen glucose-6-phosphate-isomerase (GPI), we show that GPI hybrid NPs delay development of disease, with some treated mice remaining arthritis-free for 300 days. We provide evidence that the mechanism of rheumatoid arthritis suppression involves induction of B cell tolerance, as measured by low anti-GPI antibodies and decreased plasma cell populations, and T cell tolerance, as measured by increased Tregs. The results show the potential of this versatile NP platform for inducing immune tolerance to a self-antigen and suppressing autoimmune disease.

Drug repurposing in cardiovascular inflammation: Successes, failures, and future opportunities.

Drug repurposing is an attractive, pragmatic approach to drug discovery that has yielded success across medical fields over the years. The use of existing medicines for novel indications enables dramatically reduced development costs and timescales compared with de novo drug discovery and is therefore a promising strategy in cardiovascular disease, where new drug approvals lag significantly behind that of other fields. Extensive evidence from pre-clinical and clinical studies show that chronic inflammation is a driver of pathology in cardiovascular disease, and many efforts have been made to target cardiovascular inflammation therapeutically. This approach has been met with significant challenges however, namely off-target effects associated with broad-spectrum immunosuppression, particularly in long-term conditions such as cardiovascular disease. Nevertheless, multiple anti-inflammatory medicines have been assessed for efficacy in cardiovascular clinical trials, with most of these being repurposed from their original indications in autoimmune conditions like rheumatoid arthritis. In this review, we discuss the mixed successes of clinical trials investigating anti-inflammatory drugs in cardiovascular disease, with examples such as anti-cytokine monoclonal antibodies, colchicine, and methotrexate. Looking to the future, we highlight potential new directions for drug repurposing in cardiovascular inflammation, including the emerging concepts of drug re-engineering and chrono-pharmacology.

Autoimmune Pemphigus: Latest Advances and Emerging Therapies.

Pemphigus represents a group of rare and severe autoimmune intra-epidermal blistering diseases affecting the skin and mucous membranes. These painful and debilitating diseases are driven by the production of autoantibodies that are mainly directed against the desmosomal adhesion proteins, desmoglein 3 (Dsg3) and desmoglein 1 (Dsg1). The search to define underlying triggers for anti-Dsg-antibody production has revealed genetic, environmental, and possible vaccine-driven factors, but our knowledge of the processes underlying disease initiation and pathology remains incomplete. Recent studies point to an important role of T cells in supporting auto-antibody production; yet the involvement of the myeloid compartment remains unexplored. Clinical management of pemphigus is beginning to move away from broad-spectrum immunosuppression and towards B-cell-targeted therapies, which reduce many patients’ symptoms but can have significant side effects. Here, we review the latest developments in our understanding of the predisposing factors/conditions of pemphigus, the underlying pathogenic mechanisms, and new and emerging therapies to treat these devastating diseases.

Ustekinumab for Ulcerative Colitis

Ustekinumab for Ulcerative Colitis

Immunomodulatory effects of mesenchymal stem cells for the treatment of cardiac allograft rejection.

Heart transplantation continues to be the gold standard clinical intervention to treat patients with end-stage heart failure. However, there are major complications associated with this surgical procedure that reduce the survival prognosis of heart transplant patients, including allograft rejection, malignancies, infections, and other complications that arise from the use of broad-spectrum immunosuppression drugs. Recent studies have demonstrated the use of mesenchymal stem cells (MSCs) against allotransplantation rejection in both in vitro and in vivo settings due to their immunomodulatory properties. Therefore, utilization of MSCs provides new and exciting strategies to improve heart transplantation and potentially reduce the use of broad-spectrum immunosuppression drugs while alleviating allograft rejection. In this review, we will discuss the current research on the mechanisms of cardiac allograft rejection, the physiological and immunological characteristics of MSCs, the effects of MSCs on the immune system, and immunomodulation of heart transplantation by MSCs.

Interferon blockade in systemic lupus erythematosus: Light at the end of the tunnel for novel therapies for lupus?

Interferon blockade in systemic lupus erythematosus: Light at the end of the tunnel for novel therapies for lupus?

Вульвовагинальный кандидоз: актуальные аспекты этиопатогенеза, диагностики и лечения

During the reproductive age, 75% of women experience at least one episode of vulvovaginal candidiasis (VVC) and 40–50% of women experience two or more episodes. Recurrent VVC is referred to as at least four episodes of the disease within a 12-month period. The aim of this paper is to review the etiology, pathogenesis, clinical signs, diagnosis, and treatment for VVC. Both domestic and foreign published data are analyzed. It is now recognized that urogenital disorders and systemic comorbidities are the key predisposing factors to recurrent VVC. Other risk factors include the use of broad-spectrum antibiotics, immunosuppressants, and hormone replacement therapy, endocrine disorders, and intestinal Candida persistence. Intravaginal medications are the preferred treatment for VVC. A 6-month maintenance therapy reduces the rate of VVC recurrences by 90%. Further studies on the etiopathogenesis of recurrent VVC will improve treatment efficacy. KEYWORDS: vulvovaginal candidiasis, recurrent vulvovaginal candidiasis, vulvovaginal candidiasis, Candida albicans, non-albicans Candida, Candida spp., Lactobacilli, vaginal colonization resistance. FOR CITATION: Murakov S.V., Vladimirova E.V., Kovalyk V.P. et al. State-of-the-art of vulvovaginal candidiasis: etiopathogenesis, diagnosis, and treatment. Russian Medical Inquiry. 2020;4(10):625–631. DOI: 10.32364/2587-6821-2020-4-10-625-631.

Fatal encephalopathy with wild‐type JC virus and ruxolitinib therapy

JC virus (JCV) infection is a lytic infection of oligodendrocytes in progressive multifocal leukoencephalopathy; less common forms of central nervous system manifestations associated with JCV infection include granule cell neuronopathy, encephalopathy, and meningitis. Presented is the first case of fatal JCV encephalopathy after immunosuppressive therapy that included ruxolitinib. Postmortem analysis included next generation sequencing, Sanger sequencing, tissue immunohistochemistry, and formalin-fixed hemisphere 7T magnetic resonance imaging. JCV DNA isolated from postmortem tissue samples identified a novel 12bp insertion that altered the transcription site binding pattern in an otherwise "wild-type virus," which has long been thought to be the nonpathogenic form of JCV. Anti-VP1 staining demonstrated infection in cortical neurons, hippocampal neurons, and glial and endothelial cells. This expands the spectrum of identified JCV diseases associated with broad-spectrum immunosuppression, including JAK-STAT inhibitors, and sheds light on an additional neurotropic virus strain of the archetype variety. ANN NEUROL 2019;86:878-884.

Local miscommunications between glomerular cells as potential therapeutic targets for crescentic glomerulonephritides

Necrotizing and crescentic rapidly progressive glomerulonephritis or crescentic glomerulonephritis is one of the severest forms of acquired glomerular diseases with significant mortality. Risk of end-stage renal failure at 5 years is near 30%, with a number of patients developing chronic kidney disease. Currently, autoimmune crescentic glomerulonephritides are treated with broad-spectrum immunosuppression inducing remission of the injury in the majority of patients. However, treatment is associated with significant side effects and by the time remission is achieved the majority of patients have developed renal tissue damage and significant impairment of their kidney function with a steep slope of deterioration within the first weeks following initiation of immunosuppression. It is therefore important to develop complementary strategies that would be immediately active on the common process of destructive epithelial processes. We have worked to identify the major cellular pathways contributing to glomerular destruction in this context by a systematic comparison of patient tissues and experimental models. Our studies demonstrate the pivotal role of local intra- and intercellular communications in orchestrating the global glomerular tolerance to a severe rapidly progressive glomerulonephritis model with excellent anatomoclinical correlative expressions in kidney biopsies of individuals diagnosed with crescentic glomerulonephritis, irrespectively of the causal immune disorder. We hope that such approaches deciphering mechanisms of cellular adaptation that underlie kidney damage control in response to vasculitides, integrating both stress and damage responses, will delineate novel complementary therapies.

New perspectives on the regulation of type II inflammation in asthma.

Asthma is a chronic inflammatory disease of the lungs which has been thought to arise as a result of inappropriately directed T helper type-2 (Th2) immune responses of the lungs to otherwise innocuous inhaled antigens. Current asthma therapeutics are directed towards the amelioration of downstream consequences of type-2 immune responses (i.e. β-agonists) or broad-spectrum immunosuppression (i.e. corticosteroids). However, few approaches to date have been focused on the primary prevention of immune deviation. Advances in molecular phenotyping reveal heterogeneity within the asthmatic population with multiple endotypes whose varying expression depends on the interplay between numerous environmental factors and the inheritance of a broad range of susceptibility genes. The most common endotype is one described as “type-2-high” (i.e. high levels of interleukin [IL]-13, eosinophilia, and periostin). The identification of multiple endotypes has provided a potential explanation for the observations that therapies directed at typical Th2 cytokines (IL-4, IL-5, and IL-13) and their receptors have often fallen short when they were tested in a diverse group of asthmatic patients without first stratifying based on disease endotype or severity. However, despite the incorporation of endotype-dependent stratification schemes into clinical trial designs, variation in drug responses are still apparent, suggesting that additional genetic/environmental factors may be contributing to the diversity in drug efficacy. Herein, we will review recent advances in our understanding of the complex pathways involved in the initiation and regulation of type-2-mediated immune responses and their modulation by host factors (genetics, metabolic status, and the microbiome). Particular consideration will be given to how this knowledge could pave the way for further refinement of disease endotypes and/or the development of novel therapeutic strategies for the treatment of asthma .

A Review of Clinical Trials of Belimumab in the Management of Systemic Lupus Erythematosus.

There have been few changes over the last 50 years in the treatment of Systemic lupus erythematosus (SLE), using non-specific anti-inflammatory agents such as: nonsteroidal anti-inflammatory drugs along with the immune cell modulating agent hydroxychloroquine for mild disease, and broad spectrum immunosuppressants plus antiinflammatories such as corticosteroids, azathioprine, cyclophosphamide, or mycophenolate during flares or severe disease with organ involvement. In some patients, the response is inadequate and side effects appear from mild unpleasant up to severe toxicity. Drug metabolism and clearance may be severely compromised. Therefore, it is a priority to develop better treatments with fewer adverse events that can be used at different stages of disease activity. In recent years, a member of the tumor necrosis factor (TNF) family, soluble human B Lymphocyte Stimulator protein (BLyS), also referred to as B-cell activating factor (BAFF) and TNFSF13B has been studied extensively. This protein is synthesized by myeloid cell lines, specifically interacts with B lymphocytes and increases their life-span. BlyS plays a key role in the selection, maturation and survival of B cells and it has a significant role in the pathogenesis of SLE. In this review, we analyzed the role of BLyS as a diagnostic/prognostic marker and/or therapeutic target for lupus patients, and the different clinical studies published using belimumab.

Preferential uptake of antioxidant carbon nanoparticles by T lymphocytes for immunomodulation.

Autoimmune diseases mediated by a type of white blood cell—T lymphocytes—are currently treated using mainly broad-spectrum immunosuppressants that can lead to adverse side effects. Antioxidants represent an alternative approach for therapy of autoimmune disorders; however, dietary antioxidants are insufficient to play this role. Antioxidant carbon nanoparticles scavenge reactive oxygen species (ROS) with higher efficacy than dietary and endogenous antioxidants. Furthermore, the affinity of carbon nanoparticles for specific cell types represents an emerging tactic for cell-targeted therapy. Here, we report that nontoxic poly(ethylene glycol)-functionalized hydrophilic carbon clusters (PEG-HCCs), known scavengers of the ROS superoxide (O2•−) and hydroxyl radical, are preferentially internalized by T lymphocytes over other splenic immune cells. We use this selectivity to inhibit T cell activation without affecting major functions of macrophages, antigen-presenting cells that are crucial for T cell activation. We also demonstrate the in vivo effectiveness of PEG-HCCs in reducing T lymphocyte-mediated inflammation in delayed-type hypersensitivity and in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. Our results suggest the preferential targeting of PEG-HCCs to T lymphocytes as a novel approach for T lymphocyte immunomodulation in autoimmune diseases without affecting other immune cells.

Pathogenic Inflammation and Its Therapeutic Targeting in Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE, lupus) is a highly complex and heterogeneous autoimmune disease that most often afflicts women in their child-bearing years. It is characterized by circulating self-reactive antibodies that deposit in tissues, including skin, kidneys, and brain, and the ensuing inflammatory response can lead to irreparable tissue damage. Over many years, clinical trials in SLE have focused on agents that control B- and T-lymphocyte activation, and, with the single exception of an agent known as belimumab which targets the B-cell survival factor BAFF, they have been disappointing. At present, standard therapy for SLE with mild disease is the agent hydroxychloroquine. During disease flares, steroids are often used, while the more severe manifestations with major organ involvement warrant potent, broad-spectrum immunosuppression with cyclophosphamide or mycophenolate. Current treatments have severe and dose-limiting toxicities and thus a more specific therapy targeting a causative factor or signaling pathway would be greatly beneficial in SLE treatment. Moreover, the ability to control inflammation alongside B-cell activation may be a superior approach for disease control. There has been a recent focus on the innate immune system and associated inflammation, which has uncovered key players in driving the pathogenesis of SLE. Delineating some of these intricate inflammatory mechanisms has been possible with studies using spontaneous mouse mutants and genetically engineered mice. These strains, to varying degrees, exhibit hallmarks of the human disease and therefore have been utilized to model human SLE and to test new drugs. Developing a better understanding of the initiation and perpetuation of disease in SLE may uncover suitable novel targets for therapeutic intervention. Here, we discuss the involvement of inflammation in SLE disease pathogenesis, with a focus on several key proinflammatory cytokines and myeloid growth factors, and review the known outcomes or the potential for targeting these factors in SLE.

Vedolizumab for the treatment of inflammatory bowel diseases

Although multiple therapies for IBD currently exist, a substantial proportion of patients do not respond to conventional agents and important safety concerns have emerged regarding the use of broad-spectrum immunosuppression. Given these limitations, development of more specific, gut-targeted therapy is an attractive approach. Vedolizumab specifically blocks trafficking to the gut of a small proportion of circulating T-lymphocytes to prevent the chronic inflammatory response observed in IBD. Several large-scale clinical trials support the efficacy of vedolizumab for the treatment of IBD, and have led to regulatory approval of this agent. However, multiple questions remain regarding the use of vedolizumab in clinical practice. This article will explore several of these issues.

A mechanistic understanding of the selective clearance of encephalitogenic T cells (THER3P.882)

Abstract Most therapeutic approaches to control multiple sclerosis (MS) target autoimmune effector cells via broad spectrum immunosuppression. In contrast to this approach we have recently described a therapeutic intervention for the MS model experimental autoimmune encephalomyelitis (EAE) that selectively eliminates encephalitogenic T cells, while sparing protective naive and memory T cell responses. Here we report the mechanistic pathway by which our selective therapy acts. The specificity of action that targets encephalitogenic T cell is through the action of the drug, etoposide, which acts by targeting the double stranded break repair mechanism associated with highly activated T cells. In combination with differential expression of Bcl-2 family member leads to the preferential deletion of effector T cells over memory and naive T cells clearance. Based on our understanding of etoposide-mediated clearance of encephalitogenic T cells we expanded our findings to include other genotoxic and non-genotoxic agents that synergize to afford more specific and less toxic means of controlling autoimmunity. This study further defines the mechanism for the selective clearance of self-reactive T cells by establishing a mechanistic understanding and rational approach to the use of agents that target autoreactive T cells in vivo and result in novel and enhanced therapy for autoimmune diseases.

Proteasome inhibitors for malignancy‐related lambert‐eaton myasthenic syndrome

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder characterized by autoantibodies against presynaptic voltage-gated calcium channels that impair neuromuscular transmission. Malignancies, especially small cell lung cancer (SCLC), have been associated with LEMS and account for approximately 60% of cases, making malignancy management a central step in LEMS therapy. In addition, immunosuppressive therapy is also recommended for symptomatic control. Interestingly, both pathological and epidemiological data suggest that the autoimmune response can inhibit progression of tumors in malignancy-associated LEMS. Thus, conventional broad-spectrum immunosuppressants may not be effective agents for treatment of LEMS, especially in those with malignancy-associated LEMS. Recent preclinical and clinical studies have indicated that proteasome inhibitors can eliminate antibody-producing cells efficiently, block dendritic cell maturation, and have anti-tumor activity. We hypothesize that proteasome inhibitors may be promising agents for treatment of malignancy-related LEMS.

Targeting plasma cells with proteasome inhibitors: possible roles in treating myasthenia gravis?

Myasthenia gravis (MG) is treated primarily with broad-spectrum immuno-suppressants such as prednisone or azathioprine, which normally require several months to reduce autoantibody titers significantly. This delay may be caused by the resistance of the main antibody-producing cells, the plasma cells, to these drugs. In particular, long-lived plasma cells are resistant to immunosuppressive treatments and can produce (auto-) antibodies for months. Bortezomib is a proteasome inhibitor approved for treating patients with multiple myeloma, a plasma cell malignancy. Recent preclinical studies in cell cultures and animal models, and clinical studies in organ-transplant recipients, have demonstrated that bortezomib can kill non-neoplastic plasma cells within hours. This suggests that proteasome inhibitors could also be used for rapidly reducing autoantibody production in autoimmune diseases. We have begun to assess their potential in MG.