Immunotherapy in Hodgkin and non-Hodgkin lymphoma: Innate,adaptive and targeted immunological strategies

Since the clinical introduction of anti-CD20 monoclonal antibodies into lymphoma treatment, immunologic approaches in lymphoma have made substantial progress. Advances in our understanding of tumor immunology have led to the development of strategies to overcome immunologic barriers responsible for an ineffective immune response. Specifically, therapeutic agents have been developed and tested against molecules that are responsible for T-cell exhaustion. The use of monoclonal antibodies against immune checkpoints in the adaptive immune system, such as programmed cell death-1 and cytotoxic T-lymphocyte-associated protein 4, has changed the landscape of cancer therapy including the treatment of lymphoma. This achievement has recently been accompanied by the development of novel immune checkpoint inhibitors targeting the innate immune system, including the CD47-SIRPα signaling pathway, and this approach has yielded promising results. To overcome impaired antigen presentation, antibody-based cytotoxic strategies, namely antibody-drug conjugates (polatuzumab vedotin and brentuximab vedotin) and bispecific T-cell or NK-cell engagers (blinatumomab, REGN1979, RG6206, and AFM13), have rapidly evolved with promising clinical activity. As additional tools become available for lymphoma treatment, formulation of safe, rational combination strategies to combine them with standard therapy will be of paramount importance. A successful approach to the treatment of lymphoma may require both an optimized anti-tumor immune response as well as effective depletion of malignant lymphoid cells.     

中药对免疫介导性再生障碍性贫血T淋巴细胞的实验研究

实验用Balb／c小鼠经亚致死剂量的射线照射后，输入取自DBA／2小鼠的胸腺淋巴结细胞来制作免疫介导性再障的模型。用正气活血、温补脾肾、扶正解毒中药煎出液，分别浓缩成含生药量为0．79g／ml浓度的药液灌胃，每日1次，每次0．5ml。探讨这些方药对免疫介导型再障的治疗效果和作用机理。结果表明：这些方药在不同程度上都能提高再障小鼠的TH细胞，降低TS细胞，使TH／TS比值升高，减轻免疫异常对骨髓造血细胞的抑制和损伤，有利于再障骨髓造血的修复和重建。提示了辨证论治对指导用药的重要性。     

Myo-Spain: Registro de pacientes con miopatía inflamatoria idiopática de España. Metodología

ObjectivesTo describe the methods of the Spanish Registry of patients with idiopathic inflammatory myopathy (IIM) (Myo-Spain), as well as its strengths and limitations. The main objective of the project is to analyse the evolution and clinical management of a cohort of patients with IIM.MethodsObservational, longitudinal, ambispective and multicentre study of a cohort of patients with IIM seen in rheumatology units in Spain. All patients with a diagnosis of IMM will be included in the regular follow-up of the participating centres, regardless of age on initiation of the process. Incident cases will be all patients who at the beginning of the study have been diagnosed for less than 12 months and prevalent cases for more than 12 months. The registry will include data from the visit at baseline, one year and two years. Socio-demographic, clinical, analytical variables, complications, comorbidities, association with other rheumatic diseases, hospital admissions, mortality and treatments will be collected. In addition, indices, scales and questionnaires of activity, muscle involvement, damage, disability, and quality of life will be determined. The recruitment period will be 23 months. The purpose is to obtain a cohort of 400 patients with IMM.ConclusionsMyo-Spain registry provides the opportunity to develop a cohort of incident and prevalent patients with IMM in Spain. Myo-Spain will be able to assess in detail the clinical characteristics of the disease at different times. The comprehensive information collected during the visits is expected to provide a broad source of data for future analysis.     

Patterns of intermediate filaments, VLA integrins and HLA antigens in a new human biliary epithelial cell line sensitive to interferon-γ

Background/Aims: Intra-hepatic bile ducts are the primary site of damage in several immunologically mediated liver diseaes. However, immunological processes underlying biliary epithelial cell recognition by T lymphocytes are poorly understood. Therefore, a convenient in vitro model that could mimic these immunologic disorders would be of great interest.Methods: A human cell line (HuGB) was established from a metastasis of gallbladder adenocarcinoma in the liver. Intermediate filament expression was analysed by immunostaining, and gamma-glutamyl transpeptidase and albumin secretion were measured. VLA integrin expression pattern, expression of HLA class I and II antigens and ICAM-1 protein were analysed by flow cytometry and their modulation by interferon-γ was quantitated using a QIFIKIT commercial kit.Results: Histological analysis showed high similarity between the initial gallbladder adenocarcinoma and the established cell line. Cytokeratins 8 and 19 and vimentin showed strong positive staining in the established cell line. Gamma-glutamyl transpeptidase was secreted by these cells while albumin expression was negative. HuGB cells also expressed VLA-α2, VLA-α3, VLA-α6, VLA-β1, but not VLA-α1, VLA-α4 and NCAM, a pattern of adhesion molecule expression compatible with the biliary epithelium. Also, similar to the biliary epithelium found in normal liver, HuGB cells expressed abundant HLA class I but few HLA class II antigens. We found that the expression of HLA antigens and ICAM-1 protein were increased during interferon-γ treatment of HuGB cell line.Conclusions: Both phenotypic and morphological characteristics of HuGB cells suggested their biliary origin. Sensitivity of HuGB cells to interferon-γ suggests that this new cell line could represent a suitable model to investigate the up-regulation of membrane antigens occurring in immune diseases involving biliary epithelial cells.     

风湿免疫科门诊长期口服糖皮质激素患者服药依从性现状研究及其药学干预

目的：评估风湿免疫科长期口服糖皮质激素（GC）患者服药依从性现状,分析影响患者服药依从性的因素;探讨门诊药师的药学干预能否提高其服药依从性,促进其合理用药。方法：收集2018年1月-3月在我院风湿免疫科门诊就诊并需长期口服GC的患者共242名,通过人口学资料和问卷调查分析患者服药依从性的现状及其影响因素。将患者随机分为干预组和非干预组,为干预组患者提供持续药学服务并每月随访一次,至患者停用或连续随访6个月,最后对两组患者进行调查评估和结果分析。结果：242例风湿免疫科长期口服GC患者服药依从性得分的平均值为（5.28±1.79）,其中115例患者（47.52%）依从性较好（6.92±0.76）,127例患者（52.48%）依从性较差（3.80±0.98）。影响患者服药依从性的因素主要为病程、患者服药信念,自我效能和药物与疾病知识知晓水平（P<0.05）。非干预组纳入患者116例,干预组126例。干预组患者的服药依从性、服药信念、自我效能、对疾病和药物的知晓水平较非干预组得到明显的改善（P<0.01）,疾病控制情况也较非干预组高（P<0.05）。两组患者总的不良反应发生率无显著性差异（P>0.05）,其中皮质醇增多（P<0.01）和骨密度下降情况（P<0.05）有所改善,代谢型改变情况无显著性差异（P>0.05）。结论：针对影响患者服药依从性的可控制因素进行药学干预能提高患者对疾病和药物的认识,增强其服药信念,改善患者的服药依从性。     

误诊为精神障碍的抗N-甲基-D-天冬氨酸受体脑炎43例分析

目的:探讨误诊为精神障碍的抗N-甲基-D-天冬氨酸受体（N-methyl-D-aspartate-receptor;NMDAR）脑炎患者的临床特征,提高早期诊断率,减少误诊。方法:收集2012年至2018年在郑州大学第一附属医院确诊的抗NMDA受体脑炎患者的临床资料,筛选出误诊为精神障碍疾病的患者,回顾性分析其精神症状特征、病程特点、影像学及实验室检查结果,治疗及预后情况。结果:共收集121例确诊为抗NMDA受体脑炎患者,筛选出误诊为精神障碍的43例。43例患者中,16例（37.2％）存在前驱症状,所有患者均有精神行为异常（100％）,其中癫痫发作32例（74.4％）、意识水平下降13例（30.2％）、不自主运动21例（48.8％）、记忆力下降15例（34.9％）、言语功能障碍8例（18.6％）、其他神经系统症状（中枢性低通气、自主神经功能障碍）8例（18.6％）,各种不同症状可能在同一患者身上同时或相继出现,症状完全缓解或只留下轻微肢体障碍者38例,遗留精神异常和癫痫发作反复入院者5例,复发率占11.6%（5/43）。结论:抗NMDA受体脑炎临床表现复杂多样,多数以精神行为异常为首发症状,极易误诊为精神障碍,延迟治疗会导致病程延长,预后不良。     

髓源抑制细胞对HBV转基因小鼠肝脏炎症损伤抑制作用的研究

目的：建立HBV抗原特异性细胞毒性T细胞（CTLs）介导的小鼠肝炎模型,探讨肿瘤诱导的髓源抑制性细胞（MDSCs）在免疫介导的HBV转基因小鼠肝损伤中的有效性。方法制备新鲜的HBV转基因小鼠肝脏匀浆,予普通小鼠腹腔注射,1次/周,连续4周,以诱导致敏小鼠（Sensitized-mice）产生HBV抗原特异性CTLs（HBV-specific CTLs,HBV-CTLs）。分离致敏小鼠脾脏来源HBV-CTLs,静脉回输给高复制型HBV转基因小鼠,分别在注射前,注射后1 d、3 d、6 d和9 d经眶后取血测血清ALT/AST水平。分离荷瘤小鼠骨髓来源的MDSCs,静脉注射给HBV-CTLs诱导的肝炎小鼠,并在注射后24 h,经眶后取血测血清ALT/AST水平,肝脏组织经固定、石蜡包埋、HE染色进行组织形态学检测。结果致敏小鼠脾脏来源的HBV-CTLs可诱导HBV转基因小鼠肝组织损伤,血清ALT、AST水平呈升高趋势;且与CTLs注射组小鼠相比,CTLs联合MDSCs注射组小鼠肝脏组织损伤程度减轻,小鼠血清转氨酶水平显著降低[ALT：（254.5±25.50）vs （80.67±11.57）,P ＜0.05;AST：（301.5±40.50）vs（249.0±79.00）,P ＞0.05）]。结论静脉回输肿瘤诱导的MDSCs可有效减轻HBV-CTLs诱导的肝炎小鼠中肝组织损伤。     

Electrophysiological findings in immune checkpoint inhibitor-related peripheral neuropathy

ObjectiveTo report the electrodiagnostic features of immune checkpoint inhibitor (ICI)-related neuropathy.MethodsWe retrospectively reviewed clinical presentations and electrodiagnostic features of 23 patients studied after receiving immune checkpoint inhibitors (ICIs). The presentations for electrodiagnostic evaluation included an acute neuropathy or neuromuscular junction disorder. We applied established electrodiagnostic criteria for polyneuropathy and acute demyelinating neuropathy.ResultsWe identified acute demyelinating neuropathy (13 cases), axonal sensory motor neuropathy (5), pure sensory neuropathy (4) and mononeuropathy (1). 13 patients had acute demyelinating neuropathy confirmed by demonstrating demyelination in 2 or more nerves; 3 additional patients had demyelination in only one nerve. Analysis of motor nerve conduction parameters revealed demyelination involving median and ulnar nerve distal motor latencies as well as median, ulnar and peroneal nerve conduction velocities. Conduction block was found in median, ulnar and peroneal nerves. The remaining one-third patients without demyelination had acute painful axonal neuropathy. Coexisting myopathic changes (6) and neuromuscular junction dysfunction (4) were also identified.ConclusionsOur findings suggest that, while immune-mediated motor nerve demyelination is the primary underlying mechanism of ICI-related neuropathy, axonal painful neuropathy can also be an important presentation. Early recognition and effective intervention may reduce morbidity and permanent disability.SignificanceElectrophysiological studies might be useful in the evaluation of ICI-related neuropathy.     

Lymphocyte subsets in immune-mediated otitis media with effusion

Summary To examine the role of T-cell subsets in immune-mediated otitis media with effusion induced by keyhole limpet hemocyanin (KLH), we used immuno-histochemical methods to investigate the kinetics of immunocytes of the middle ear (ME) and eustachian tube (ET) in healthy BALB/c mice. Antibodies against murine macrophages and granulocytes (anti-Mac-1), helper T cells (anti-Lyt-1), suppressor T cells (anti-Lyt-2), immunoglobulins (anti-IgG, -IgM, -IgA), secretory component (SC) and KLH were used. The ME exhibited a substantial immune response, whereas the response of the ET was minor and was associated with a secondary ME immune response. After KLH challenge, an effusion with an extensive infiltration of inflammatory cells (Mac-1, IgG⁺ and IgM⁺ cells) was observed at days 1 and 3 in the ME cavity and rapidly disappeared by day 7. Within the ME mucosa, a large number of cells was observed at days 1 and 3, peaking on day 7 when a submucosal lymphoid infiltration was detected. In the immune response of the ME mucosa, Mac-1 cells were the predominant cell type followed by helper T cells, IgG⁺ cells, IgA⁺ cells and then IgM⁺ cells. Suppressor T cells were rarely detected after KLH challenge. SC was present within ME epithelial cells from days 1 to 14. From these findings, we conclude (1) that the majority of infiltrating cells in the ME cavity originate from circulating blood; (2) that the ME mucosa has an excellent capacity to mount a strong immune response, including mucosal immunity, through the accumulation of immunocytes for antigen processing and antibody production; (3) that elimination of antigen appears to be the most important factor for returning the immune response to a quiescent state.     

Pulmonary hemorrhage in children with glomerulonephritis

Pulmonary hemorrhage may occur in patients with immune-mediated glomerulonephritis. This association can be seen in a variety of disorders including systemic lupus erythematosus, vasculitis, Wegener's granulomatosis, anaphylactoid purpura and Goodpasture's syndrome. Immune mechanisms, such as immune complexes and/or autoantibodies, play a role in the pathogenesis of pulmonary and glomerular injury. Acute pulmonary hemorrhage can lead to respiratory failure and has a high mortality. Therapy with immunosuppressive agents such as pulse methylprednisolone and cyclophosphamide will control the hemorrhage and improve pulmonary function in most cases.