Sustained remission of multicentric castleman disease in children treated with tocilizumab, an anti-interleukin-6 receptor antibody

Multicentric Castleman Disease (MCD) is an idiopathic lymphoproliferative disorder, reported exceptionally in children and generally believed to be an autoinflammatory disease resulting in an increase of interleukin-6 secretion. Previous studies in adult patients suggested a beneficial role of the anti-interleukin-6 receptor antibody tocilizumab on the clinical and biologic disease manifestations of MCD. Here, we describe the efficacy and safety of tocilizumab in two children with MCD, which was diagnosed on the basis of clinical and histologic findings. In both cases, tocilizumab was administered intravenously at a dose of 8 mg/kg every 2 weeks. The tocilizumab treatment alleviated fever and restored growth rate in both patients. The patients' hypergammaglobulinemia, high C-reactive protein, and high erythrocyte sedimentation rates normalized simultaneously. Nevertheless, splenomegaly persisted in the first patient, and a secondary hepatic node appeared in the second patient. The side effects, essentially sustained thrombocytopenia, were mild in both cases. For the first patient, following an initial 10-month period, the interval between infusions was increased. This patient benefited from sustained remission for a period of 3 years. Tocilizumab was effective and safe in these two children with MCD. Mol Cancer Ther; 11(8); 1623-6. ?2012 AACR.     

The application of gene therapy in autoimmune diseases

The application of gene therapy in autoimmune disease represents a novel use of this technology. The goal of gene therapy in the treatment of autoimmune disease is to restore 'immune homeostasis' by countering the pro-inflammatory effects of the CD4+ T cells in the lesions of autoimmunity. This can be accomplished by adoptive therapy with transduced T cells which can specifically home to the site of inflammation and secrete 'regulatory' protein(s) to ameliorate the inflammation or by direct targeting of the retroviral vector to activated T cells in the sites of inflammation. Transduction of autoantigen recognizing CD4+ T cells, to secrete anti-inflammatory products, may become the 'magic bullet' to combat the ravages of autoimmune inflammation and tissue destruction. Gene Therapy (2000) 7, 9-13.     

抗核抗体谱检测在自身免疫性疾病诊断中的价值

目的：分析自身免疫性疾病（autoimmune disease, AID）患者抗核抗体（antinuclear anti-body, ANA）谱检测结果,评价ANA谱在诊断AID中的应用价值。方法选择2012年5月-2013年5月于我院就诊的AID患者513例,非AID患者353例,并对其ANA谱的检测结果进行回顾性分析。结果系统性红斑狼疮组抗dsDNA抗体、抗组蛋白抗体、抗核小体抗体、抗SM抗体、抗SSA抗体、抗rRNP抗体阳性率均高于对照组,且差异均有统计学意义（P均〈0．05）;混合性结缔组织病组抗U1RNP抗体、抗SSA抗体阳性率均高于对照组,且差异均有统计学意义（P均〈0．05）;干燥综合征组抗SSA抗体、抗SSB抗体阳性率均高于对照组,且差异均有统计学意义（P均〈0．05）;进行性系统性硬化病组抗SCL-70抗体、抗CENP-B抗体阳性率均高于对照组,且差异均有统计学意义（P均〈0．05）;多发性肌炎/皮肌炎组抗JO-1抗体阳性率高于对照组,且差异有统计学意义（P〈0．05）。当抗组蛋白抗体、抗核小体抗体、抗rRNP抗体和抗dsDNA抗体同时阳性时,系统性红斑狼疮组阳性率显著高于混合性结缔组织病组,且差异有统计学意义（P〈0．05）。结论 ANA谱检测对AID的诊断及鉴别诊断有重要价值。     

Gene therapy for autoimmune diseases

Autoimmune diseases are threatening an increasing number of patients in developed countries, representing one of the major causes of disability and an enormous social cost. Current therapies mainly treat the symptoms of autoimmune diseases and are only partially able to interfere with disease evolution, and therefore decrease the degree of physical impairment. Thus, the development of new therapeutic strategies is imperative. This review focuses on gene therapy, as one possible alternative approach to the treatment of autoimmune disorders. The potential of gene therapy to specifically target tissues affected by autoimmune aggression, and its ability to interfere with the destructive pathogenic process while providing functional replacement and fostering reparative mechanisms will be emphasized. Gene therapy studies in experimental models of diabetes, rheumatoid arthritis and multiple sclerosis are reviewed.     

Anticytokine gene therapy of autoimmune diseases

Viral and nonviral gene therapy vectors have been successfully employed to deliver inflammatory cytokine inhibitors (anticytokines), or anti-inflammatory cytokines, such as transforming growth factor β-1 (TGF-β1), which protect against experimental autoimmune diseases. These vectors carry the relevant genes into a variety of tissues, for either localised or systemic release of the encoded protein. Administration of cDNA encoding soluble IFN-γ receptor (IFN-γR)/IgG-Fc fusion proteins, soluble TNF-α receptors, or IL-1 receptor antagonist (IL-1ra), protects against either lupus, various forms of arthritis, autoimmune diabetes, or other autoimmune diseases. These inhibitors, unlike many cytokines, have little or no toxic potential. Similarly, TGF-β1 gene therapy protects against numerous forms of autoimmunity, though its administration entails more risk than anticytokine therapy. We have relied on the injection of naked plasmid DNA into skeletal muscle, with or without enhancement of gene transfer by in vivo electroporation. Expression plasmids offer interesting advantages over viral vectors, since they are simple to produce, non-immunogenic and nonpathogenic. They can be repeatedly administered and after each treatment the encoded proteins are produced for relatively long periods, ranging from weeks to months. Moreover, soluble receptors which block cytokine action, encoded by gene therapy vectors, can be constructed from non-immunogenic self elements that are unlikely to be neutralised by the host immune response (unlike monoclonal antibodies [mAbs]), allowing long-term gene therapy of chronic inflammatory disorders.     

Biological therapy of autoimmune blistering diseases

Introduction: Autoimmune blistering skin diseases are a group of disorders subdivided according to the location of blister formation: intraepidermal blistering in the pemphigus group and subepidermal in the pemphigoid group. These conditions are clinically heterogeneous and are treated with systemic corticosteroids and/or other forms of immunosuppression on the basis of clinical subtype and disease severity. These approaches may not be effective for the induction and maintenance of clinical response or need to be stopped because of intolerable side effects.

Areas covered: Biological therapies can represent a valid alternative strategy in various autoimmune blistering disorders and this review article will address this issue with a special focus on pemphigus vulgaris and bullous pemphigoid. These biological approaches are designed to target B cells, autoantibodies, complement proteins, and several cytokines.

Expert opinion: Innovative strategies for the treatment of autoimmune blistering conditions primarily depend on the use of drugs with a high degree of specificity targeting crucial steps in the immunopathology of these disorders. Novel biological agents offer treatment alternatives to patients with autoimmune blistering conditions by targeting B cells, pathogenic autoantibodies, complement and cytokines.     

Gene therapy in autoimmune rheumatic diseases

Several investigators have reported the possibility of gene therapy for experimental autoimmune diseases such as type-1 insulin-dependent diabetes (IDDM), experimental allergic encephalomyelitis (EAE), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE). Although there are no reports about gene therapies for human autoimmune rheumatic diseases including RA and SLE, we reviewed these experimental therapies for model animals and discussed the possibility of gene therapy for human autoimmune rheumatic disorders as a new therapeutic strategy.     

A humanized anti-IL-6 receptor antibody(MRA) in RA therapy

Hyperproduction of Interleukin-6(IL-6) is observed in the rheumatoid arthritis(RA) patients and serum level of IL-6 is closely related to disease activity. IL-6 is a pleiotropic cytokine and its hyperfunctions explain most of the clinical symptoms in RA. Since MRA is humanized antibody from a mouse anti-human IL-6 receptor antibody, MRA can be administered repeatedly because of its low antigenesity to human. MRA inhibits IL-6 function by the blocking IL-6 binding to IL-6 receptor, resulting the prevention of development on collagen inducing arthritis(CIA) in cynomolgus monkeys whose IL-6R is cross-reacted with MRA. These evidence suggest that MRA has anti-arthritic effects. Clinical trials of MRA for RA patients have already started, and MRA therapy is effective as well as anti-TNF alpha and anti-IL-1 therapies.     

Extracorporeal photopheresis as a therapy for autoimmune diseases

Systemic autoimmune diseases (AID) have multiorgan, heterogeneous clinical presentations and are characterized by dysregulation of the immune system, immunodeficiency, irreversible organ damage and increased morbidity and mortality. Preventing or decreasing flares of AID correlate with durable disease control, significant reduction of inflammation and prevention of disability or therapy‐related toxicity. There is an urgent need for better treatment of severe, therapy‐refractory AID. Extracorporeal photopheresis (ECP) is a cell‐based immunomodulatory treatment which has been extensively used in variety of autoimmune disorders for the last two decades. ECP treatment is FDA approved for the treatment of cutaneous T‐cell lymphoma (CTCL) with particularly promising results seen in graft‐versus‐host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HCT). Prolonged therapy is safe, well tolerated and allows reduction of systemic immunosuppression in therapy‐refractory patients. Both clinical and experimental evidence suggest that ECP mechanism of action is characterized by apoptosis and phagocytosis of activated cells by antigen‐presenting cells (APC), secretion of anti‐inflammatory cytokines and stimulation of regulatory T cells (Tregs). The focus of this paper is to review the current evidence of ECP use in the treatment of AID. Here, we summarize the experience of nine major AID from 65 published reports. The key findings demonstrate substantial evidence of ECP feasibility, safety and in some AID also promising efficacy. However, the role of ECP in AID therapy is not established as most published studies are retrospective with limited number of patients and the trials are small or poorly standardized. The available data support future investigations of ECP as a therapeutic modality for the treatment of AID in well‐designed prospective clinical studies. J. Clin. Apheresis 30:224–237, 2015. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.     

自身免疫性疾病中抗核抗体与抗ENA抗体的相关性分析

目的探讨抗核抗体(ANA)荧光核型与抗可提取性核抗原抗体(ENA)之间的相关性。方法 ANA采用间接免疫荧光法检测,抗ENA抗体采用德国欧蒙公司免疫斑点法检测,检测结果采用双盲对照法分析。结果 132例抗ENA抗体阳性病例ANA的阳性率为93.9%,荧光核型主要以颗粒型为主。另外检测的103例ANA阳性病例中,抗ENA抗体常规6项阳性率为78.6%。结论抗ENA抗体类型与ANA荧光核型之间没有绝对的规律,临床检测自身抗体时需将两者结合分析。     

Epratuzumab (humanised anti-CD22 antibody) in autoimmune diseases

B cells play an important role in the pathogenesis of many autoimmune diseases. Different approaches targeting the B cell compartment are under investigation. Selective modulation of B cells has been recently achieved using a humanised monoclonal antibody against the B cell surface marker CD22. This antibody (epratuzumab) was originally developed for the treatment of non-Hodgkin’s lymphoma and was found to be effective, with a very good safety profile. Recent studies have demonstrated the efficacy and safety of epratuzumab in several autoimmune diseases, including systemic lupus erythematosus and primary Sjögren’s syndrome.     

Epratuzumab (humanised anti-CD22 antibody) in autoimmune diseases

B cells play an important role in the pathogenesis of many autoimmune diseases. Different approaches targeting the B cell compartment are under investigation. Selective modulation of B cells has been recently achieved using a humanised monoclonal antibody against the B cell surface marker CD22. This antibody (epratuzumab) was originally developed for the treatment of non-Hodgkin's lymphoma and was found to be effective, with a very good safety profile. Recent studies have demonstrated the efficacy and safety of epratuzumab in several autoimmune diseases, including systemic lupus erythematosus and primary Sj?gren's syndrome.     

抗核抗体谱的检测在自身免疫性疾病中的应用价值

目的探讨用间接免疫荧光法(IIF)抗核抗体(ANA)与免疫印迹法(LIA)特异性抗核抗体谱(ANAs)的联合检测在自身免疫性疾病(AID)中的应用价值。方法 436例患者,其中自身免疫病患者271例,非自身免疫病患者165例,所有患者同时检测血清ANA和ANAs,两种检测方法产生4种检出模式:IIF(+)/LIA(+)、IIF(-)/LIA(-)、IIF(+)/LIA(-)和IIF(-)/LIA(+)。结果 436份标本中IIF(+)/LIA(+)占40.15%,IIF(-)/LIA(-)占25.52%,IIF(+)/LIA(-)占15.27%,IIF(-)/LIA(+)占9.81%,IIF与LIA检测ANA的结果总体符合率为65.67%,ANA和ANAs在自身免疫病患者中的阳性率分别是65.3%和57.9%,显著高于非自身免疫病患者的17.6%和20.0%;ANA和ANAs在自身免疫病组和非自身免疫病组间阳性率比较,差异有统计学意义(P<0.01)。两检测结果仅在MCTD和SLE患者中存在相关性(P<0.01),在其他观察组中不存在相关性(P>0.05)。结论 IIF检测ANA容易导致AID患者部分具有临床意义的ANA特异性抗体漏检,而ANAs检测因其测定的抗体数量有限也容易导致AID患者的ANA漏检。IIF-ANA和LIA-ANAs检测不能相互代替,对需要通过检测ANA来排除AID的患者标本应同时进行IIF-ANA和LIF-ANAs的检测,以避免仅采用一种方法进行检测时导致AID患者漏诊。ANA的IIF法易导致以抗-SSA、抗-SSB和抗-Ro52为主要抗体的患者ANA假阴性,而LIA法特异性ANAs的检测因检测的抗体不全面也无法取代ANA的IIF法检测。在临床实际工作中两种ANA的检测方法不能相互取代,应联合应用。     

Targeting interleukin-6 in inflammatory autoimmune diseases and cancers

Interleukin-6 (IL-6) is a pleiotropic cytokine with significant functions in the regulation of the immune system. As a potent pro-inflammatory cytokine, IL-6 plays a pivotal role in host defense against pathogens and acute stress. However, increased or deregulated expression of IL-6 significantly contributes to the pathogenesis of various human diseases. Numerous preclinical and clinical studies have revealed the pathological roles of the IL-6 pathway in inflammation, autoimmunity, and cancer. Based on the rich body of studies on biological activities of IL-6 and its pathological roles, therapeutic strategies targeting the IL-6 pathway are in development for cancers, inflammatory and autoimmune diseases. Several anti-IL-6/IL-6 receptor monoclonal antibodies developed for targeted therapy have demonstrated promising results in both preclinical studies and clinical trials. Tocilizumab, an anti-IL-6 receptor antibody, is effective in the treatment of various autoimmune and inflammatory conditions notably rheumatoid arthritis. It is the only IL-6 pathway targeting agent approved by the regulatory agencies for clinical use. Siltuximab, an anti-IL-6 antibody, has been shown to have potential benefits treating various human cancers either as a single agent or in combination with other chemotherapy drugs. Several other anti-IL-6-based therapies are also under clinical development for various diseases. IL-6 antagonism has been shown to be a potential therapy for these disorders refractory to conventional drugs. New strategies, such as combination of IL-6 blockade with inhibition of other signaling pathways, may further improve IL-6-targeted immunotherapy of human diseases.     

The pathophysiology of autoimmune blistering diseases

Knowledge of the pathophysiology of immunobullous diseases has been advanced by the demonstration that passive transfer of antibodies against skin autoantigens can induce blisters in experimental animals with clinical, histologic, and immunopathologic features similar to those seen in human patients. In this issue of the JCI, Liu et al. extend their earlier observations regarding an experimental murine model of bullous pemphigoid by showing that the plasminogen/plasmin signaling cascade synergizes with MMP-9 during the early phase of antibody-induced blister formation in vivo. In a separate study, Sitaru et al. show for the first time to my knowledge that passive transfer of experimental antibodies against type VII collagen create subepidermal blisters in mice that mimic those seen in patients with epidermolysis bullosa acquisita (see the related article beginning on page 870). While the articles by Liu, Sitaru, and their colleagues identify pathways of inflammation and tissue injury that, if interrupted, may abrogate blister formation, in a third study, Payne et al. utilized phage display technologies to isolate human anti-desmoglein monoclonal antibodies from a patient with pemphigus vulgaris and show that such antibodies have restricted patterns of heavy and light chain gene usage - findings suggesting that autoantibodies may represent an additional target for therapeutic interventions in patients with immunobullous diseases (see the related article beginning on page 888).     

自身免疫性疾病噬菌体抗体库的构建和初步鉴定

目的构建系统性红斑狼疮（SLE）、类风湿性关节炎（RA）、强直性脊柱炎、干燥综合症（SS）、原发性胆汁性肝硬化（PBC）等自身免疫性疾病的噬菌体抗体库。方法从多例确诊的高滴度自身免疫病患者外周血淋巴细胞中抽提总RNA,用RT—PCR方法分别扩增免疫球蛋白分子轻链κ、λ基因及重链Fd基因。经SacI和XbaI限制性双酶切后,在T4连接酶的作用下,将轻链基因片段克隆入同样双酶切的pComb3Hss载体中以构建轻链文库,随后将重链Fd段PCR产物经XhoI和SpeI双酶切后载入同样处理的κ/λpComb3Hss载体,然后将重组质粒κ/λ—Fd-pComb3Hss转化大肠杆菌XL1-Blue。用辅助噬菌体M13K07感染XL1-Blue,则可在噬菌体表面表达出随机的重组抗体库。结果提取的淋巴细胞总RNA及合成的cDNA质量好,PCR扩增了长度为660bp的轻链κ、λ基因及重链Fd基因,成功构建了库容为4&#215;10^4的轻链抗体库和库容为6&#215;10^4的Fab片段噬菌体抗体库,酶切及PCR鉴定均正确无误。结论成功构建了自身免疫性疾病的噬菌体抗体库,为进-步筛选出高亲和力抗体打下了基础。     

Autologous blood stem cell transplantation as therapy for autoimmune diseases

Autologous stem cell transplantation (ASCT) is starting to be investigated as a potential therapy for severe refractory autoimmune disease including rheumatological, neurological and haematological diagnoses. Increasing numbers of cases are now reported in the literature. Data from all transplanted patients are being collated in a centralized register by the European Group for Blood and Marrow Transplantation (EBMT) and the European League against Rheumatism (EULAR) to enable effective evaluation of the safety and efficacy of this promising technique. Thus far, results have been encouraging; however, more treatment-related deaths were reported in multiorgan diseases such as scleroderma and less in diseases such as rheumatoid arthritis, which confirms the importance of careful patient selection. Optimization of mobilization, conditioning regimen and graft manipulation is required to maximize efficacy without increasing mortality and morbidity. The use of maintenance therapy after ASCT in order to prevent relapse needs to be explored. Following individual case reports and small cohort studies, the next step is likely to involve multicentre randomized controlled trials.