The mucosal immune system for vaccine development

Mucosal surfaces are continuously exposed to the external environment and therefore represent the largest lymphoid organ of the body. In the mucosal immune system, gut-associated lymphoid tissues (GALTs), including Peyer's patches and isolated lymphoid follicles, play an important role in the induction of antigen-specific immune responses in the gut. GALTs have unique organogenesis characteristics and interact with the network of dendritic cells and T cells for the simultaneous induction and regulation of IgA responses and oral tolerance. In these lymphoid tissues, antigens are up taken by M cells in the epithelial layer, and antigen-specific immune responses are subsequently initiated by GALT cells. Nasopharynx- and tear-duct-associated lymphoid tissues (NALTs and TALTs) are key organized lymphoid structures in the respiratory tract and ocular cavities, respectively, and have been shown to interact with each other. Mucosal surfaces are also characterized by host-microbe interactions that affect the genesis and maturation of mucosa-associated lymphoid tissues and the induction and regulation of innate and acquired mucosal immune responses. Because most harmful pathogens enter the body through mucosal surfaces by ingestion, inhalation, or sexual contact, the mucosa is a candidate site for vaccination. Mucosal vaccination has some physiological and practical advantages, such as decreased costs and reduced risk of needle-stick injuries and transmission of bloodborne diseases, and it is painless. Recently, the application of modern bioengineering and biochemical engineering technologies, including gene transformation and manipulation systems, resulted in the development of systems to express vaccine antigens in transgenic plants and nanogels, which will usher in a new era of delivery systems for mucosal vaccine antigens. In this review, based on some of our research group's thirty seven years of progress and effort, we highlight the unique features of mucosal immune systems and the application of mucosal immunity to the development of a new generation of vaccines.     

The mucosal immune system: from fundamental concepts to vaccine development.

Recent studies in experimental animals and humans have shown that the mucosal immune system, which is characterized by secretory IgA (S-IgA) antibodies as the major humoral defence factor, contains specialized lymphoid tissues where antigens are encountered from the environment, are taken up and induce B- and T-cell responses. This event is followed by an exodus of specific lymphocytes, which home to various effector sites such as the lamina propria regions and glands. These responses are regulated by T cells and cytokines and lead to plasma cell differentiation and subsequent production of S-IgA antibodies in external secretions. This knowledge has led to practical approaches for vaccine construction and delivery into mucosal inductive sites in an effort to elicit host protection at mucosal surfaces where the infection actually occurs.     

Regulation of mucosal immune responses in effector sites

In human disease and rodent models, immune responses in the intestinal mucosa can be damaging. Damage is characterised by villus atrophy, crypt hyperplasia and reduced ability to digest and absorb nutrients. In normal individuals active responses to harmless environmental antigens associated with food and commensal bacteria are controlled by the development of immunological tolerance. Similar pathological changes occur in piglets weaned early from their mothers. Active immune responses to food antigens are observed in these piglets, and we and others have hypothesised that the changes occur as a result of transient allergic immune responses to novel food or bacteria antigens. The normal mechanism for producing tolerance to food antigens may operate at induction (Peyer's patches and mesenteric lymph nodes) or at the effector stage (intestinal lamina propria). In our piglet studies immunological tolerance occurs despite the initial active response. Together with evidence from rodents, this observation suggests that active responses are likely to be controlled at the effector stage, within the intestinal lamina propria. Support for this mechanism comes from the observation that human and pig intestinal T-cells are susceptible to apoptosis, and that this process is accelerated by antigen. We suggest that the role of the normal mature intestinal lamina propria is a balance between immunological effector and regulatory function. In neonatal animals this balance develops slowly and is dependant on contact with antigen. Immunological insults such as weaning may tip the balance of the developing mucosal immune system into excessive effector or regulatory function resulting in transient or chronic allergy or disease susceptibility.     

Breast milk immunoprotection and the common mucosal immune system: a review

It is universally known that breastfeeding provides a broad spectrum of nutritional and non-nutritional advantages to the developing infant. Nonnutritive protecting potentials of breast milk towards different infections and non-infectious diseases are still attracting the attention of researchers in different specialties. The neonate, who is suddenly exposed to a wide variety of organisms, is in dire need of protection, enhancement and education of his immature immune system to encounter these organisms. The lactating mammary gland is an integral part of the common mucosal immune system which stands as a sentinel in combating pathogens that enter the body via the mucosal route. The common mucosal immune system also competently controls tolerance mechanisms to innocent proteins and is involved in surveillance of carcinogensis. The diverse roles of general mucosal immunity are nearly well established but the specialised functions of breast tissue and breast milk in boosting the immune responses need more emphasis and highlighting. The detailed understanding and evaluation of breast milk as an immunological tool is reviewed within the domain of the diverse activities of the common mucosal immune system.     

New approach on the development of a mucosal vaccine against strangles: Systemic and mucosal immune responses in a mouse model

Streptococcus equi subspecies equi affects animals of Equidae family and is the causative agent of strangles, an acute, extremely contagious and deadly disease. Prolonged periods of protection associated to absence of serious adverse reactions were not yet achieved. Thus, this experimental work is focused on the study of mucosal, humoral and cellular immune responses developed in a mouse model, after the intranasal administration of S. equi antigens associated by adsorption or encapsulation to poly(lactic acid) nanospheres, modified by mucoadhesive polymers and absorption enhancers. Particles fitted the nanometer range and proteins integrity and antigenicity were not affected. PLA nanospheres induced a mixed Th1 and Th2 response, being therefore potential carriers for the delivery of S. equi antigens.     

Altered Fos immunoreactivity in the hypothalamus after glucose administration in pre- and post-weaning malnourished rats

Abstract

The present study explored the effects of malnutrition and nutritional rehabilitation on the response to glucose in hypothalamic nuclei involved in metabolic homeostasis. Male Wistar rats were malnourished during gestation–lactation (MGL) or at weaning to 55 days (MPW). Two groups of rats were rehabilitated with a balanced diet until 90 days (MGL-R and MPW-R, respectively). After a glucose tolerance test (GTT), brains were processed for Fos immunoreactivity (Fos-IR). Both malnourished groups displayed hyperglycemia after GTT. MGL exhibited an increased number of Fos-IR neurons in the ventromedial hypothalamic nucleus (VMH), while MPW showed increased Fos-IR in the arcuate nucleus (ARC) and VMH and a decrease in the paraventricular nucleus (PVN), as compared with their controls. Nutritional rehabilitation normalized values of glucose after GTT in both groups, while low number of Fos-IR neurons remained in the ARC, PVN and VMH of MPW-R rats, indicating a deleterious, long-lasting effect after post-weaning malnutrition.     

The effect of cGMP on the function of immune system cells

Cyclic GMP is a key messenger molecule in several cellular processes. It is also an important modulator of immune response. In this paper we summarize current data concerning regulatory and modulatory function of cGMP in the cells of immune system. Metabolism of the nucleotide as well as its role in processes such as cell proliferation, differentiation, chemotaxis and release of mediators are described. The fields of future research are indicated as well.     

Session 1: Feeding and infant development breast-feeding and immune function

The newborn receives, via the placenta, maternal IgG antibodies against the microbes present in its surroundings, but such antibodies have a pro-inflammatory action, initiating the complement system and phagocytes. Although the host defence mechanisms of the neonate that involve inflammatory reactivity are somewhat inefficient, this defence system can still have catabolic effects. Breast-feeding compensates for this relative inefficiency of host defence in the neonate by providing considerable amounts of secretory IgA antibodies directed particularly against the microbial flora of the mother and her environment. These antibodies bind the microbes that are appearing on the infant's mucosal membranes, preventing activation of the pro-inflammatory defence. The major milk protein lactoferrin can destroy microbes and reduce inflammatory responses. The non-absorbed milk oligosaccharides block attachment of microbes to the infant's mucosae, preventing infections. The milk may contain anti-secretory factor, which is anti-inflammatory, preventing mastitis in mothers and diarrhoea in infants. Numerous additional factors in the milk are of unknown function, although IL-7 is linked to the larger size of the thymus and the enhanced development of intestinal Tgammadelta lymphocytes in breast-fed compared with non-breast-fed infants. Several additional components in the milk may help to explain why breast-feeding can reduce infant mortality, protecting against neonatal septicaemia and meningitis. It is therefore important to start breast-feeding immediately. Protection is also apparent against diarrhoea, respiratory infections and otitis media. There may be protection against urinary tract infections and necrotizing enterocolitis, and possibly also against allergy and certain other immunological diseases, and tumours. In conclusion, breast-feeding provides a very broad multifactorial anti-inflammatory defence for the infant.     

Odor from industrial hog farming operations and mucosal immune function in neighbors

The authors evaluated whether exposure to malodor from industrial hog farming operations has a psychophysiologically mediated immunosuppressive effect on secretory immunoglobulin A (sIgA) in neighbors. Fifteen adults living within 2.4 km (1.5 mi) of at least one hog farming operation rated odor intensity on a 9-point scale and provided saliva samples twice daily for two weeks. The authors used hierarchical regression to model the association between reported odor and sIgA; study participants were their own controls. The natural log of slgA concentration and secretion rate declined, on average, 0.058 (0.032) and 0.116 (0.103), respectively, for each incremental 1-unit increase in reported odor from 4 to 9, adjusted for time of day, suggesting reduced levels of sIgA in response to moderate or high odor. Findings support the hypothesized immunosuppressive effect of malodor on mucosal immunity and provide preliminary data useful in understanding health effects related to malodor from industrial hog farming operations.     

Symposium on 'dietary influences on mucosal immunity'. How dietary antigens access the mucosal immune system

The intestinal epithelium is a selective barrier where incompletely-digested food antigens are transmitted to the immune system. Food antigens are often the starting point of intestinal diseases such as food allergy or coeliac disease. The intestinal epithelial cells (IEC) take up and process food antigens mainly by fluid-phase transcytosis involving two functional pathways, one minor direct pathway without degradation and another major lysosomal degradative pathway. Among the peptidic metabolites generated during transepithelial transport of luminal antigens, some have a molecular mass compatible with a binding to restriction (major histocompatibility complex; MHC) molecules; the latter can be up regulated on enterocytes, especially in inflammatory conditions. Indeed, interferon-gamma not only increases the paracellular absorption of antigens, but also their transcytosis across epithelial cells. It has been reported that enterocytes may even directly present peptidic epitopes to underlying T-cells. As a new potential way of transmitting peptidic information to the local or systemic immune system, the secretion by IEC of antigen-presenting vesicles called exosomes and bearing MHC-peptide complexes has recently been proposed. Many other factors such as nutritional or environmental factors can also influence the properties of the epithelial barrier and the outcome of the immune response to lumen antigens.     

Nomenclature for secreted regulatory proteins of the immune system (interleukins): update

The officially adopted designations for interleukins now include IL-11, IL-12 and IL-13, in addition to the previously recommended IL-1 to IL-10, including IL-1α and IL-1β.     

Early nutrition and the development of immune function in the neonate

The present review will concentrate on the development of the gut-associated lymphoid tissue and the role of early nutrition in promoting immune function. The intestine is the largest immune organ in the body, and as such is the location for the majority of lymphocytes and other immune effector cells. The intestine is exposed to vast quantities of dietary and microbial antigens, and is the most common portal of entry for pathogens, some of which are potentially lethal. The development of normal immune function of the intestine is therefore vital for survival, and is dependent on appropriate antigen exposure and processing, and also an intact intestinal barrier. In early life innate mechanisms of defence are probably more important than active or adaptive mechanisms in responding to an infectious challenge, since the healthy neonate is immunologically na?ve (has not seen antigen) and has not acquired immunological memory. During this period maternal colostrum and milk can significantly augment resistance to enteric infections. The mechanisms of enhancing disease resistance are thought to be passive, involving a direct supply of anti-microbial factors, and active, by promoting the development of specific immune function. A tolerance response to dietary and non-invasive antigens is generally induced in the gut. However, it must also be able to mount an adequate immune response to ensure clearance of foreign antigens. It is now recognized that regulation of tolerance and active immune responses is critical to health, and failure to regulate these responses can lead to recurrent infections, inflammatory diseases and allergies. The education of the immune system in early life is thought to be critical in minimizing the occurrence of these immune-based disorders. During this phase of development maternal milk provides signals to the immune system that generate appropriate response and memory. One factor that has been proposed to contribute to the increase in the incidence of immune-based disorders, e.g. atopic diseases in Western countries, is thought to be the increased prevalence of formula-feeding.     

鼻功能既肺功能诊断系统的研究

本文介绍了一种既能检测肺功能，又能检测鼻功能的诊断系统，阐述了系统的工作原理及软件设计思想。该诊断系统由微差压传感器、应用电路板、计算机、显示器和打印机组成，实现了鼻肺功能检测的自动化、数字化。     

The mucosal immune system in health and disease, with an emphasis on parasitic infection

This article briefly describes the network of immunity involving selected humoral and cellular elements shared between mucosal surfaces that are both exposed to and remote from antigen challenge. The mechanisms promoting the production, concentration, and secretion of specific antibody isotypes, as well as the migration and localization of various lymphoid cell populations, have been discussed with regard to host mucosal protection against pathogenic agents and other potentially harmful macromolecules.     

The function of the immune system after the treatment of pediatric malignant diseases

INTRODUCTION: Currently, malignancies in childhood can be cured in 70 percent of the cases. However, the intensive cytostatic therapy may lead to late side effects influencing quality of life. AIM OF THE STUDY: Analysis of the reconvalescence of the immune functions after completion of therapy for malignancies in children. PATIENTS: 88 long-term survivors (51 boys, 37 girls) were investigated (43 acute lymphoid leukemia, 15 lymphoma, 20 bone tumors, 10 other solid tumors). Mean age at the time of diagnosis was 7.8 years (1 mo-17.7 years). METHODS: The following parameters were investigated: serum immunoglobulin levels after completion of the chemotherapy and in the next 4 years thereafter, lymphocyte subpopulations in the peripheral blood by flow-cytometry and cellular immunity by in vitro tests (natural killer activity, antibody-dependent cellular cytotoxicity, mitogen-induced T- and B-cell blastic transformations). RESULTS: Lower serum immunoglobulin (IgG) levels could be detected in patients with leukemia after completion of the chemotherapy (8.8 +/- 3.2 g/l). One year thereafter serum IgG levels increased significantly (10.1 +/- 2.9 g/l) (p<0.05). In patients with solid tumors the serum IgG levels were in the normal range at the end of the chemotherapy (12.1 +/- 4.3 g/l). At a mean of 1.3 years after the end of chemotherapy NK activity decreased in 7/43 (16.3%) leukemia patients, and in 3/45 (6.7%) solid tumor patients, ADCC decreased in 8/43 (18.6%) and 3/45 (6.7%), respectively (p<0.05 leukemia vs. solid tumor). At a mean of 15 months after the end of the therapy B-cell blastic transformation was decreased in 3/43 (7%) leukemia patients and in 4/45 (8.9%) solid tumor patients. At the same time point T-cell blastic transformation was altered in 5/43 (11.6%) and in 4/45 (8.9%) cases, respectively. CONCLUSION: Cytotoxic therapies lead to severe, long-term depression of the immune system. At the end of the chemotherapy this effect is more pronounced in leukemia patients. Years (1.5-3) after completion of the therapy in a significant proportion of the patients some in vitro parameters of the immune system are yet altered, so careful monitoring of this patient population is mandatory.     

PC机胃功能检测系统的研制

本文介绍了一种由ＰＣ微机外加传感器，胃电放大卡和Ａ／Ｄ卡组成的系统，只要一片１．２Ｍ３寸软盘即可通过人机对话实现人体胃电信号的实时采集，处理，存贮和显示，最后打印输出可供医生参考的辅助分析和诊断结果。在计算机越来越普及的今天。不乏是一种辅助检查胃功能疾病的简便而又无创伤、无痛苦的方法。     

统筹城乡医疗保障的实质及发展趋势

依据“统筹兼顾”作为贯彻落实科学发展观必须坚持运用的根本方法,论述了开展统筹城乡医疗保障研究的背景、意义和实质;阐述了首先必须使政府举办的法定基本医保体现一致性与统一性,而补充医保则体现多样性与差别性。提出应准确理解和把握统筹的涵义与核心实质;整合医保管理资源,克服多头管理的弊端,建立统一规范的经办机构,是今后管理体制发展的的必然趋势。整合归并统一后的医保制度,最终归属哪个部门管理,需要经过实践的检验、周密的论证与审慎的政治决策。     

肠内免疫营养和生态营养对创伤后大鼠免疫功能的影响

目的:探讨肠内免疫营养和生态营养对创伤后大鼠肠免疫功能的影响。方法:将40只大鼠随机分为对照组、普通营养组、免疫营养组和生态营养组。通过胃造口术建立动物创伤模型,给予不同成分的肠内营养7 d,观察各组大鼠小肠黏膜形态,检测小肠黏膜中IgA、CD3+、CD4+、CD8+细胞的数量。结果:免疫营养组和生态营养组大鼠术后恢复良好。生态营养组大鼠腹泻累计次数低于普通营养组和免疫营养组(P<0.05)。三个营养组大鼠的小肠上皮细胞绒毛高度、肠腺隐窝深度、黏膜厚度、绒毛表面积等检测值均优于对照组(P<0.05);对照组和普通营养组大鼠小肠黏膜IgA、CD3+、CD4+、CD8+细胞数量明显少于免疫营养组和生态营养组(P<0.05)。结论:应用肠内营养,特别是肠内免疫营养和生态营养,能较好地改善大鼠的小肠免疫屏障功能,增强肠道免疫功能,促进创伤后的恢复。     

冬虫夏草对大鼠肠黏膜屏障免疫功能影响的研究

目的:探讨冬虫夏草对T淋巴细胞亚群及小肠黏膜屏障免疫功能的影响. 方法:将大鼠分为对照组和实验组.实验组大鼠给予冬虫夏草5g/(kg·d)灌胃;对照组给予等量的等渗盐水灌胃,两组均自由进食、饮水.于灌胃第4、7和10天分别抽取8只大鼠的血,用流式细胞仪检测外周血液中CD+、CD4+、CD8+的百分率,计算CD4+/CD8+比例.同时取大鼠小肠黏膜,行常规病理计数上皮内淋巴细胞(IEL)的比例,用免疫组化染色检测CD4+、CD8+,计算CD4+/CD8+的比例. 结果:实验组大鼠第4天外周血中CD4+淋巴细胞即有明显提高,CD4+/CD8+的比例明显升高,至第7和第10天变化更为明显.肠黏膜上皮内淋巴细胞的数量和CD4+/CD8+比例的变化也较明显,差异有显著性意义(P<0.05). 结论:冬虫夏草可使正常大鼠外周血T淋巴细胞含量增加,同时可增强小肠黏膜的免疫屏障功能.