Infektionen und Immuntherapie

Allogeneic stem cell transplantation (SCT) can expose patients to a transient but marked immunosuppression, during which viral and fungal infections are an important cause of morbidity and mortality. Control of these infections ultimately depends on restoring adequate T-cell immunity. Most viral infections after SCT are caused by the endogenous reactivation of persistent pathogens such as adenovirus (ADV), cytomegalovirus (CMV), and Epstein-Barr-virus (EBV), whereas invasive infections due to Aspergillus spp. are mostly exogenous. Cellular immunotherapy is an attractive approach to enable immune protection of the host. The isolation of pathogen-specific T cells from a healthy donor and their infusion into a recipient is done by a procedure known as adoptive T-cell transfer. The separation of pathogen-specific T cells is necessary to deplete alloreactive T cells and avoid graft-versus-host disease. Adoptive T-cell transfer has been performed after allogeneic SCT in many patients with CMV, EBV, and ADV infections using time- and labour-consuming protocols. Based on basic research, new immunotherapeutic protocols aim at a broader and faster availability of adoptive T-cell transfer. However, the manipulation of antigen-specific T-cell responses as a treatment approach remains an ongoing challenge.     

Human natural killer cells in health and disease

Natural killer (NK) cells are an essential component of the innate immune system and play a critical role in tumor immune surveillance. NK cells express their own repertoire of receptors (NKRs) that bind to major histocompatibility class I or class I-like molecules. The balance of signals from stimulation or inhibition of NKRs determines the ability of NK cells to lyse specific targets. In haploidentical stem cell transplantation with purified stem cells, NK cell alloreactivity (killer immunoglobulin-like receptor [KIR] mismatch) has been demonstrated to reduce the risk of relapse in acute myeloid leukemia. There is a need for adequately powered prospective randomized studies to determine the usefulness of NK cells as adoptive immunotherapy, optimal NK cell doses and timing of administration. Further studies are required to determine optimal selection of donors and recipients, both on NKR matching/mismatching, undergoing haploidentical and unrelated hematopoetic stem cell transplantation.     

肠道病毒71型调控宿主免疫反应机制的研究进展

病毒感染可以引起各种宿主免疫反应,防止病毒的扩散传播.固有免疫是宿主抵抗病毒感染的第一道防线,病毒进入机体后,一方面由巨噬细胞吞噬,加工处理病毒抗原,另一方面激活固有的抗病毒免疫应答.肠道病毒71型（EV71）感染诱导干扰素表达可能与细胞特异性应答有关.多数研究表明EV71可以通过多种途径抑制干扰素的表达,以达到免疫逃逸的目的.随后由抗原呈递细胞将抗原信息呈递给T/B细胞,特异性T/B细胞被抗原刺激后活化、增殖、分化为免疫效应细胞,分泌抗体、细胞因子或细胞毒性介质,最终发挥免疫效应.EV71感染过程中体液免疫和细胞免疫均被激活,并在介导保护效应方面起重要作用.细胞免疫应答在防止EV71感染后严重并发症的发展方面起重要作用,而体液免疫产生的中和抗体在EV71感染的保护性免疫方面起关键作用,但是抗体应答水平与疾病严重性并没有相关性.另外,病毒感染时也可以诱导细胞凋亡,阻止病毒增殖和子代病毒的扩散.     

Unleashing the immune response against childhood solid cancers

Tumor immunotherapy has come to the fore fuelled by impressive clinical responses to checkpoint inhibitor antibodies in a range of adult malignancies and by the success of chimeric antigen receptor T cells targeting adult and pediatric B‐cell malignancies. Clearly, if appropriately fine‐tuned, the immune system has the capability to seek out and destroy cancer. Studies in pediatric solid cancers so far have not shown the therapeutic potential checkpoint inhibitors described in adult cancers and this may reflect fewer tumor‐associated antigens or different immune evasion mechanisms. One potential approach to overcome these limitations will be to combine interventions to undermine immune evasion mechanisms with engineered T‐cell adoptive transfer.     

Impfungen bei prim?ren Immundefekten

Vaccination strategies help to prevent the development of infectious diseases in the population. Vaccines should be designed to bring a maximum advantage accompanied by a minimal risk. Since the immunological memory is mediated by antigen-specific T and B lymphocytes, the precondition for a vaccine to be successful is the presence of a competent immune system. In immunodeficient patients, this precondition is lacking to a variable extent depending on the specific molecular defect. Primary immunodeficiencies (PID) are genetically transmitted in an x-linked or autosomal recessive form. Moreover, PID can either affect the specific (combined T/B cell immunity, humoral B cell immunity, cellular T cell immunity) or the nonspecific (phagocyte system, innate immunity, complement system) immune system. The experiences from HIV and stem cell transplantation can help to decide how vaccines may be beneficial or harmful in patients with PID. The following publication reviews current vaccination strategies in immunodeficient patients with special consideration given to inactivated and live vaccines as well as risks and benefit. The question of whether or not a patient is under immunoglobulin replacement therapy needs to be considered.     

Understanding asthma pathogenesis: linking innate and adaptive immunity

PURPOSE OF REVIEW: Treatment and even prevention of allergic asthma will require a detailed understanding of disease pathogenesis and in particular identification of factors that govern T-helper type 2 (Th2) immunity. This review defines the priming and differentiation steps necessary to develop antiallergen Th2 immunity and highlights recently identified stimuli that satisfy these requirements. RECENT FINDINGS: Striking discoveries in innate immunity have advanced our understanding of how adaptive immune responses are initiated, yet only recently have these principles been applied to allergic disease. Signaling through certain innate immune receptors, the toll-like receptors (TLR) have been shown to modulate Th2-mediated disease in animal models. The dendritic cell has emerged as the central player in the intricate interplay between the adaptive and innate systems of immunity. Recent studies have also uncovered alternative pathways of initiating allergen sensitization that depend entirely on adaptive, rather than innate immune, triggers. SUMMARY: The adaptive immune system cannot initiate a response without the "permission" of the innate immune system, and this holds true for Th2 responses to aeroallergens, although induction of Th2 immunity in response to TLR signaling varies with the type and dose of TLR ligand. However, under conditions of ongoing Th2 inflammation, the adaptive immune system can act as its own adjuvant and provide the necessary activating signals to initiate an immune response to foreign protein antigens. This may be the mechanism underlying the clinically observed phenomenon of polysensitization in atopic patients and provides another therapeutic target in asthma.     

Checkpoint inhibition in pediatric hematologic malignancies

Immune surveillance comprising of adaptive and innate immune systems is naturally designed to eliminate cancer development; overexpression of inhibitory receptors and their ligands prevent this check and lead to evasion and hence cancer progression and metastasis. The use of tumor-specific monoclonal antibodies (MAbs) targeting these checkpoint regulators is promising and has led to this novel field of cancer immunotherapy. The first antibody directed against cytotoxic T-lymphocyte associated protein 4 (CTLA-4), ipilimumab, showed promising results in clinical trials and was approved by the US Food and Drug Administration (FDA) for the treatment of metastatic melanoma in 2011. Since then, various other immune checkpoint inhibitors are being studied in preclinical and clinical trial phases, targeting programmed-death-1 (PD-1) and its ligand programmed death ligand 1 (PD-L1), T cell lymphocyte activation gene-3 (LAG-3), and others. Results from clinical trials are promising, and currently this approach has proven effective and safe in patients with solid tumors and some hematological malignancies in adults. In general, CTLA-4 and PD-1 inhibitors are well tolerated; however, the augmented immune response enabled by this class of agents is associated with a unique group of side effects called immune-related adverse events (irAEs). Experience in pediatrics using immune checkpoint inhibitors for hematological malignancies is limited to Hodgkin's disease and non-Hodgkin's lymphoma as in the ongoing Children's Oncology Group (COG) protocol ADVL1412. Therapeutic advances in childhood leukemia and lymphoma (TACL) consortium will initiate an early phase clinical trial with PD-1 inhibitor nivolumab in relapsed/refractory acute myeloid leukemia (AML) in the next few months.     

Treatment of high-risk neuroblastoma

Although high-dose chemotherapy and autologous stem cell transplantation (HDCT/autoSCT) have improved the prognosis for patients with high-risk neuroblastoma (NB), event-free survival rates remain in the range of 30 to 40%, which is unsatisfactory. To further improve outcomes, several clinical trials, including tandem HDCT/autoSCT, high-dose (131)I-metaiodobenzylguanidine treatment, and immunotherapy with NB specific antibody, have been undertaken and pilot studies have reported encouraging results. Nonetheless, about half of high-risk NB patients still experience treatment failure and have no realistic chance for cure with conventional treatment options alone after relapse. Therefore, a new modality of treatment is warranted for these patients. In recent years, several groups of investigators have examined the feasibility and effectiveness of reduced-intensity allogeneic stem cell transplantation (RI alloSCT) for the treatment of relapsed/progressed NB. Although a graft-versus-tumor effect has not yet been convincingly demonstrated in the setting of relapsed NB, the strategy of employing RI alloSCT has provided hope that treatment-related mortality will be reduced and a therapeutic benefit will emerge. However, alloSCT for NB is still investigational and there remain many issues to be elucidated in many areas. At present, alloSCT is reserved for specific clinical trials testing the immunomodulatory effect against NB.     

Epstein-Barr病毒相关移植后淋巴组织增生性疾病免疫治疗的最新进展

Epstein-Barr病毒相关的移植后淋巴组织增生性疾病(EBV-PTLD)是造血干细胞移植或实体器官移植后病死率极高的并发症。在过去的十年中,对于存在高危因素的患者,免疫治疗干预措施包括减少免疫抑制剂,CD20单克隆抗体(利妥昔单抗)单药治疗或与化疗相结合,输注EBV-特异性T细胞的过继免疫治疗,使得EBV-PTLD患者的存活率有了显著的提高。本文旨在对造血干细胞移植或实体器官移植后EBV-PTLD的高危因素、 临床表现及免疫治疗的最新进展进行总结。     

Successful treatment of post‐transplant CMV meningoencephalitis with third‐party CMV virus‐specific T cells: Lessons learned

Cytomegalovirus encephalitis is a challenging life‐threatening complication following hematopoietic stem cell transplantation for which medical treatment is usually ineffective or toxic. However, in recent years, adoptive T‐cell therapy has been reported to provide a significant chance of cure for patients with viral infections. Herein, two cases of pediatric patients successfully treated with third‐party donor‐derived virus‐specific T cells for CMV meningoencephalitis are reported.     

Current status of methyl acetimidate as an extracorporeal antisickling agent

Methyl acetimidate has been shown to be an effective in vitro antisickling agent with few detrimental effects on the red cell. 51Cr-survival of red cells that had been incubated in vitro with methyl acetimidate was prolonged to near normal levels in sickle cell anemia patients. However, some patients developed an immune response following multiple reinfusions of the acetamidinated cells. Pre-equilibration of erythrocytes with the membrane-impermeable aldehyde, pyridoxal 5'-phosphate, prior to the addition of methyl acetimidate to the reaction mixture, has been shown to prevent agglutination of acetamidinated cells which were resuspended in immune serum. However, the protection was not extensive enough to prevent an immune response in a sickle cell anemia patient who had already been sensitized against acetamidinated cells. It is apparent that further consideration of imidoesters as extracorporeal antisickling agents will require complete protection of membrane amino groups against reaction with the imidoester.     

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??Intestinal microbiota is a general term of microbial communities that reside in the human intestine?? which can affect the systemic immune system by expansion of extra-intestinal T cell populations?? production of short-chain fatty acids??development of oral tolerance?? and control of inflammation.
Intestinal intestinal dysbiosis may be involved in a variety of disease processes. Animal experiments have found that normal intestinal flora is beneficial to increase lung immunity against bacterial pneumonia. This interaction between intestinal and lung is known as "Gut-Lung axis". Although the specific mechanism of the "Gut-Lung axis" is still poorly undertood??the proposal of which provides new insights into the use of
microecologic products or fecal bacteria transplantation to
regulate or restore the intestinal flora and then to treat lung
diseases.     

Viral and immunological bases of beta cell failure in insulin-dependent diabetes.

Pathologists have confirmed the specific nature of the insulitis lesion in diabetes requiring insulin. Data from genetic studies implicate both genetic and environmental influences as important in the appearance of overt disease. Certain HLA histocompatibility antigens are associated with insulin-dependent diabetes and have been interpreted as markers for closely linked immune response genes, a situation that may lead to beta cell susceptibility to viral injury or to uncontrolled beta cell autoaggression following beta cell damage. There is much circumstantial evidence that viruses may precipitate the disease (coxsackie) or may precede the disease onset by a long interval (mumps, rubella). However, susceptibility to virus, if it exists in human insulin-requiring diabetes, would appear on clinical grounds to be localized to the pancreas. Autoimmune phenomena are common in insulin-requiring diabetes, and there is both human and animal evidence that suggest that cell-mediated immunity may have a central pathogenic role. The recent explosion of new findings should lead to a clearer understanding of the nature of the disease, and this knowledge will hopefully lend itself to the prevention or arrest of the disease through immunological intervention, vaccination programs, or other means yet to be discovered.     

Human papillomavirus infections in children

PURPOSE OF REVIEW: The human papillomavirus is a ubiquitous 55-nm DNA virus that causes a variety of clinical disease states in children, commonly referred to as warts. The natural history of warts is spontaneous regression through the development of a complex blend of cell-mediated and humoral immunity. Although spontaneous immunity can develop, as many as one third of children will have persistent human papillomavirus infection beyond 2 years. Therapeutic modalities are manifold, primarily because no therapy is universally effective. The purpose of this review is to update the reader with the latest information on the human papillomavirus and its therapeutics in children. RECENT FINDINGS: Recently, encouraging research has been conducted in human papillomavirus, including destructive and immunologic therapies. Vaccines tailored to genital human papillomavirus strains are just coming into clinical use. SUMMARY: Manipulation of the immune system through medications or vaccination will likely help contain human papillomavirus in the future and prevent secondary human papillomavirus oncogenesis of the skin and cervix.     

Humoral immune responses and CD27+ B cells in children with DiGeorge syndrome (22q11.2 deletion syndrome)

The spectrum of T-cell abnormalities in 22q11.2 syndrome is quite broad, ranging from profound and life threatening to non-existent defects. Humoral abnormalities have been described in some of these patients, although no data are currently available on their phenotypical and functional B cell subsets. The purpose of this study was to investigate humoral immune function in a cohort of 13 children with DiGeorge syndrome by immunophenotyping B and by analysing their functionality in vivo. Humoral immunity was assessed by serum immunoglobulin evaluation, IgG subclasses determination, and testing of specific antibody titers to recall antigens. B cells were analyzed by flow cytometry and the relevant percentage of membrane surface expression of CD27, IgM, IgD was evaluated. In our cohort, one of 13 children (7.7%) had a complete IgA deficiency, four of 13 (30.7%) had minor immunoglobulin abnormalities, and five (38%) had an impaired production of specific antibodies. Five of 13 children (38%) had recurrent infections. Interestingly, peripheral CD27+ B cells were reduced in our patients as compared with age-matched healthy controls, and this decrement was statistically significant for IgM+ IgD+ CD27+ B cells. Immunoglobulin abnormalities were associated with the occurrence of recurrent infections. We conclude that a significant proportion of patients with DiGeorge syndrome have defective humoral immunity, which may represent an additional pathogenic mechanism underlying the increased susceptibility to infections. Whether the decreased CD27+ B-cell subset might be one of the defects that contribute to impaired humoral immunity, and to susceptibility to infection remains to be elucidated.     

Immune monitoring of pediatric heart transplant recipients through serial donor specific antibody testing — An initial experience and review of the literature

Heart transplantation is the best therapy for patient with end stage heart failure from cardiomyopathy or congenital heart disease that is not amenable to further surgical palliation. However, the development of rejection, cardiac allograft vasculopathy, and graft failure limit long term survival. Standard tools to assess for these complications include Echo, ECG, endomyocardial biopsy, and coronary angiography. However, the measurement of anti-HLA antibodies before and after transplantation is emerging in the clinical management of pediatric heart transplant recipients. It has been demonstrated that the presence of anti-HLA antibodies prior to transplantation and the development of de novo donor specific antibodies are both associated with poor outcomes. Detection of donor specific antibodies may be useful to monitor highly sensitized patients post transplant and to diagnose and guide clinical decision making in the treatment of antibody mediated rejection. Immunologic monitoring for the presence of these antibodies can be integral to ongoing surveillance. This paper will review the role of the immune system in heart transplantation, discuss concepts of pretransplant allosensitization and post transplant donor specific antibodies, and, finally will review clinical scenarios in which immunologic monitoring through donor specific antibody testing can be helpful.     

Development of hemolytic paroxysmal nocturnal hemoglobinuria without graft loss following hematopoietic stem cell transplantation for acquired aplastic anemia

PNH is the most common clonal hematopoietic disorder arising in patients with aAA. PNH is caused by mutations in PIGA, a gene that encodes the catalytic subunit of an enzyme involved in the biosynthesis of GPI anchors, transmembrane glycolipids required for cell surface expression of many proteins. PNH clones likely arise as immune escape mechanisms in aAA by preventing CD1D‐restricted T‐cell recognition of GPI anchors and GPI‐linked autoantigens. Though many patients with aAA treated with IST will develop subclinical PNH clones, only a subset will develop PNH disease, characterized by increased thrombosis, intravascular hemolysis, and potential for severe organ dysfunction. In contrast to IST, allogeneic HSCT for patients with aAA is thought to cure bone marrow aplasia and prevent hematopoietic clonal evolution to PNH. Herein, we present a phenomenon of host‐derived PNH disease arising in a patient with aAA many years following MSD‐BMT, highlighting the importance of monitoring for this clonal disease in aAA patients with stable mixed donor/recipient chimerism after HSCT. We also provide a literature review for similar occurrences of PNH arising after HSCT.     

儿科抗真菌药物的合理使用

近20年来,随着广谱抗菌药物、免疫抑制剂、激素、抗肿瘤药物和靶向生物制剂的广泛应用以及真菌检测方法的不断改进,儿童侵袭性真菌病的发病率呈逐年上升趋势,侵袭性真菌病成为免疫低下儿童的主要死亡原因之一。除了原发性免疫缺陷、肿瘤、造血干细胞移植、实体器官移植及获得性免疫缺陷综合征病毒(HIV)感染等,婴幼儿本身也是真菌感染的高危因素。因此早期诊断、及时应用有效抗真菌药是挽救患儿生命的重要措施。儿童作为特殊人群,抗真菌药物的选择和剂量与成人不同,该文主要探讨如何选择合适的抗真菌药物来预防和治疗儿童真菌病。     

特异性免疫治疗新进展

特异性免疫治疗(SIT)作为目前唯一可能根治变应性疾病的治疗方法,不仅可以减轻过敏症状,减少用药,还可阻止自然病程的进展,预防新变应原的产生.近年来舌下SIT因其良好的安全性、有效性和易操作性已在欧洲各国广泛开展.标准化的变应原制剂在国内外逐步应用,已取代非标准化制剂.然而无论是皮下注射还是舌下含服方法,其具体有效剂量、治疗方案、治疗疗程尚待规范统一.随着对其作用机制的不断深入研究,以及以重组变应原为主的新制剂的研发,SIT的应用范围将会进一步扩大,更好地用于变应性疾病的治疗.     

Role of colostrum in gastrointestinal infections

Colostrum is breast milk produced after the birth of the newborn and lasts for 2–4 days. Colostrum is very important part of breast milk and lays down the immune system and confers growth factors and other protective factors for the young ones in mammals. This is the source of passive immunity transferred to the baby from the mother. The biological value of bovine colostrum in present day medical practice is documented in clinical trials and large databases containing case reports and anecdotal findings. The main actions include an antibacterial effect and modulation of immune response with the ability to neutralize lipopolysaccharides arising from gram negative bacterial pathogens. It has been found to be effective in infantile hemorrhagic diarrheas, other diarrheas and reduces the likelihood of disease progressing to hemolytic uremic syndrome. It has also been tested in H pylori infection and diarrhea in immunodeficiency. Side effects of clinical relevance are limited to possible intolerance due to lactose and sensitivity to milk proteins.