Special feature for the Olympics: effects of exercise on the immune system: exercise effects on systemic immunity

Heavy exertion has acute and chronic influences on systemic immunity. In the resting state, the immune systems of athletes and non-athletes are more similar than disparate with the exception of NK cell activity, which tends to be elevated in athletes. Many components of the immune system exhibit adverse change after prolonged, heavy exertion. These immune changes occur in several compartments of the immune system and body (e.g. the skin, upper respiratory tract mucosal tissue, lung, blood and muscle). Although still open to interpretation, most exercise immunologists believe that during this 'open window' of impaired immunity (which may last between 3 and 72 h, depending on the immune measure) viruses and bacteria may gain a foothold, increasing the risk of subclinical and clinical infection. The infection risk may be amplified when other factors related to immune function are present, including exposure to novel pathogens during travel, lack of sleep, severe mental stress, malnutrition or weight loss.     

精神药理影像遗传学研究进展及其临床应用前景

精神疾病危害严重,其发病机制复杂难解,临床治疗效果不一,且存在明显的个体差异.近期精准医学研究发现精神药物作用于脑神经的生化过程受到遗传多态性的影响.本文从五羟色胺能、去甲肾上腺素能和多巴胺能三大系统入手,系统综述精神药理影像遗传学的相关研究进展,深入探讨精神药理的神经作用机制以及药物-基因-脑之间的交互作用.我们发现:SLC6A4、BDNF、FKBP5、COMT和多巴胺相关受体等基因多态性与多种精神疾病的发生发展及其治疗效果具有一定的相关性,可能成为相关精神疾病诊断的候选基因.杏仁核、海马、眶额叶、扣带回和前额叶等皮层与皮层下脑结构可能是不同神经递质相关的基因多态性影响精神药物生化作用过程的关键靶点脑区.在建立精神药物-基因-脑影像-行为的因果链中,仍然存在很多相互矛盾的结果和一定的局限性.因此,开展同质性强的临床试验、研究表观遗传作用等可以作为未来的研究发展趋势.     

STANDARDS OF THERAPY FOR TUBERCULOSIS, 1962

The progress and changes in management of tuberculosis are extensive and dramatic. Chemotherapy now leads the list of methods, and combinations of drugs containing isoniazid are the most effective. The use of such drugs in chemoprophylaxis has a new and expanding basis of value.The other methods of therapy are considered to be adjunctive. Among them, pulmonary resection is of greatest value, although needed less often. Rest may be less complete than once was prescribed, and of shorter duration; exercise may be prescribed sooner and be more vigorous.Rehabilitation is a part of treatment. It may be physical, mental, and social restoration or training. It may often be initiated in the early phases of treatment. The methods depend on the individual, the objective, and the pulmonary disease.     

Chemotherapy and the Immune Response in Protozoal Infections1

Available evidence indicates that many of the antiprotozoal drugs currently in use significantly modify the immune response of the host. The effect depends on both the drug and the host. Some drugs enhance the immune response, some are immuno-suppressants, and others enhance some types of immune mechanisms while suppressing others. Future efforts in the development of antiprotozoal drugs should consider their effects on both the parasite and the immune response of the host. Also in the chemotherapy of protozoal infections consideration should be given to the combined usage of immunoenhancing agents and antiprotozoal drugs.     

Recombinant therapeutic proteins: production platforms and challenges

Since the approval of insulin in 1982, more than 120 recombinant drug substances have been approved and become available as extremely valuable therapeutic options. Exact copying of the most common human form is no longer a value per se, as challenges, primarily related to the pharmacokinetics of artificial recombinant drugs, can be overcome by diverging from the original. However, relatively minor changes in manufacturing or packaging may impact safety of therapeutic proteins. A major achievement is the development of recombinant proteins capable of entering a cell. Such drugs open up completely new opportunities by targeting intracellular mechanisms or by substituting intracellularly operating enzymes. Concerns that protein variants would cause an intolerable immune response turned out to be exaggerated. Although most recombinant drugs provoke some immune response, they are still well tolerated. This knowledge might result in a change in attitude towards antibody formation, i.e., neutralizing antibody activity (in vitro) may be overcome by dosing consistently on the basis of antibody titers and not only on body weight. As with other drugs, efficacy and safety of therapeutic proteins have to be demonstrated in clinical studies, and superiority over available products has to be proven instead of just claimed.     

Liposomes in Host Defense Mechanism: A Key Role for Macrophages

Abstract

Liposomes can be used as carriers for antigens, immunomodulators and cytotoxic drugs. Such liposomes may serve as a tool to manipulate immune and non-immune host defense mechanisms. In most cases their effects are mediated by macrophages. Macrophages seem to be involved in humoral (antibody) responses and in cytotoxic T-lymphocyte responses. They are also important in non-immune defense mechanisms against foreign invaders and altered self. Which macrophages can be influenced by the liposome encapsulated molecules depends on the administration route of the liposomes. The macrophages ingest the liposomes. Once within the cell, lysosomal phospholipases disrupt the phospholipid bilayers. In this way, encapsulated molecules are released in the cell. Such liposome delivered molecules can be processed (antigens), activate the macrophage (immunomodulators) or disturb the metabolism of the cells (cytotoxic drugs). That the latter inhibition of macrophage functions may result in immunopotentiation is explained by the fact that certain macrophages are regulating immune functions by suppression.     

Methodologies for developmental immunotoxicity (DIT) testing

Developmental immunotoxicity has gained increasing recognition as a significant factor influencing the risk of later life disease. Based on the data collected thus far on different chemicals and drugs, the developing immune system can be significantly more sensitive than the adult immune system to xenobiotic-induced insult. There are distinct differences between the immune system surrounding birth and that in the mature adult as well as differences in the nature of immunotoxic changes based on age. Immunosuppresssion is not the only concern. Immunotoxic changes that increase the risk for allergic or autoimmune responses should also be considered. Therefore, one should not assume that immunotoxicity assays validated for adult exposure assessment are inherently the most predictive for developmental immunotoxicology (DIT) evaluation. Many of those adult-based protocols were developed solely to detect immunosuppression, whereas DIT concerns include shifts in immune balance. For this reason, it is useful to examine the various immune endpoints that have been employed in recent perinatal immunotoxicity studies, compare those against routine adult immunotoxicity evaluation protocols, and consider the options that are available for effective DIT testing. The results published on several chemicals and drugs in recent years suggest that functional tests are a front-line priority for perinatal immunotoxicity detection and that a combination of at least two functional tests (such as a multi-isotype T-dependent antibody response (TDARs), and a cell-mediated immune response assay such as the delayed-type hypersensitivity assay and/or T cell or NK cytotoxicity assays) should be paired with immune cell populations and histopathological analysis. Cytokine production measurements offer outstanding promise and may eventually be able to be substituted for other more laborious procedures. However, multi-cytokine analysis needs to be standardized in terms of optimum source for analysis and protocol.     

Coadaptation and malaria control

Malaria emerges from a disequilibrium of the system 'human-plasmodium-mosquito' (HPM). If the equilibrium is maintained, malaria does not ensue and the result is asymptomatic plasmodium infection. The relationships among the components of the system involve coadaptive linkages that lead to equilibrium. A vast body of evidence supports this assumption, including the strategies involved in the relationships between plasmodium and human and mosquito immune systems, and the emergence of resistance of plasmodia to antimalarial drugs and of mosquitoes to insecticides. Coadaptive strategies for malaria control are based on the following principles: (1) the system HPM is composed of three highly complex and dynamic components, whose interplay involves coadaptive linkages that tend to maintain the equilibrium of the system; (2) human and mosquito immune systems play a central role in the coadaptive interplay with plasmodium, and hence, in the maintenance of the system's equilibrium; the under- or overfunction of human immune system may result in malaria and influence its severity; (3) coadaptation depends on genetic and epigenetic phenomena occurring at the interfaces of the components of the system, and may involve exchange of infectrons (genes or gene fragments) between the partners; (4) plasmodia and mosquitoes have been submitted to selective pressures, leading to adaptation, for an extremely long while and are, therefore, endowed with the capacity to circumvent both natural (immunity) and artificial (drugs, insecticides, vaccines) measures aiming at destroying them; (5) since malaria represents disequilibrium of the system HPM, its control should aim at maintaining or restoring this equilibrium; (6) the disequilibrium of integrated systems involves the disequilibrium of their components, therefore the maintenance or restoration of the system's equilibrium depend on the adoption of integrated and coordinated measures acting on all components, that means, panadaptive strategies. Coadaptive strategies for malaria control should consider that: (1) host immune response has to be induced, since without it, no coadaptation is attained; (2) the immune response has to be sustained and efficient enough to avoid plasmodium overgrowth; (3) the immune response should not destroy all parasites; (4) the immune response has to be well controlled in order to not harm the host. These conditions are mostly influenced by antimalarial drugs, and should also be taken into account for the development of coadaptive malaria vaccines.     

Nonverbal treatment of neurosis; techniques for general practice

"Psychosomatic medicine" does not demand that the general practitioner function as a psychiatrist; rather, it is a psychiatric orientation that can increase the effectiveness of purely medical treatment for such conditions as neuroses. The general practitioner to whom the patient turns may achieve permanent results with nonverbal techniques where formal psychotherapy would be impracticable or unacceptable. The first aim is to relieve pressure so that the patient can regain his mental balance and thereby his self-confidence. Arts, hobbies, sports, and the like can be prescribed rather specifically according to the patient's personality and needs. Nutrition can be improved simply at first by prescribing needed additions to diet rather than imposing restrictions. Vitamin deficiency may by itself be the cause of neurosis or more serious mental disease, whereas psychic stress by itself may create a need for additional vitamin intake. Hormone therapy may be extremely helpful but must be based on clear indication and limited to specific purposes. Since lack of sleep and rest quickly impairs mental function, it is important for neurotic persons to learn relaxation as a necessity for sleep. Sedatives may be used in a crisis but should be abandoned as soon as possible. With all drugs there are problems of excess and habituation. The least, the mildest, the shortest dosage is the ideal. THE INITIAL STEPS OF PSYCHOTHERAPY ARE AVAILABLE TO ANY PHYSICIAN: Establishing rapport, noting how complaints are stated, encouraging ventilation, winning confidence rather than immediate results.     

Addictive drugs and their relationship with infectious diseases

The use of drugs of abuse, both recreationally and medicinally, may be related to serious public health concerns. There is a relationship between addictive drugs of abuse such as alcohol and nicotine in cigarette smoke, as well as illegal drugs such as opiates, cocaine and marijuana, and increased susceptibility to infections. The nature and mechanisms of immunomodulation induced by such drugs of abuse are described in this review. The effects of opiates and marijuana, using animal models as well as in vitro studies with immune cells from experimental animals and humans, have shown that immunomodulation induced by these drugs is mainly receptor-mediated, either directly by interaction with specific receptors on immune cells or indirectly by reaction with similar receptors on cells of the nervous system. Similar studies also show that cocaine and nicotine have marked immunomodulatory effects, which are mainly receptor-mediated. Both cocaine, an illegal drug, and nicotine, a widely used legal addictive component of cigarettes, are markedly immunomodulatory and increase susceptibility to infection. The nature and mechanism of immunomodulation induced by alcohol, the most widely used addictive substance of abuse, are similar but immunomodulatory effects, although not receptor-mediated. The many research studies on the effects of these drugs on immunity and increased susceptibility to infectious diseases, including AIDS, are providing a better understanding of the complex interactions between immunity, infections and substance abuse.     

Lipid rafts as viral entry routes and immune platforms: A double-edged sword in SARS-CoV-2 infection?

Lipid rafts are nanoscopic compartments of cell membranes that serve a variety of biological functions. They play a crucial role in viral infections, as enveloped viruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can exploit rafts to enter or quit target cells. On the other hand, lipid rafts contribute to the formation of immune synapses and their proper functioning is a prerequisite for adequate immune response and viral clearance. In this narrative review we dissect the panorama focusing on this singular aspect of cell biology in the context of SARS-CoV-2 infection and therapy. A lipid raft-mediated mechanism can be hypothesized for many drugs recommended or considered for the treatment of SARS-CoV-2 infection, such as glucocorticoids, antimalarials, immunosuppressants and antiviral agents. Furthermore, the additional use of lipid-lowering agents, like statins, may affect the lipid composition of membrane rafts and thus influence the processes occurring in these compartments. The combination of drugs acting on lipid rafts may be successful in the treatment of more severe forms of the disease and should be reserved for further investigation.     

Immune signaling in sex-specific neural and behavioral development: Adolescent opportunity

Sex differences in neural and behavioral development are integral to understanding neurodevelopmental, mental health, and neurodegenerative disorders. Much of the literature has focused on late prenatal and early postnatal life as a critical juncture for establishing sex-specific developmental trajectories, and data are now clear that immune signaling plays a central role in establishing sex differences early in life. Adolescence is another developmental period during which sex differences arise. However, we know far less about how immune signaling plays a role in establishing sex differences during adolescence. Herein, we review well-defined examples of sex differences during adolescence and then survey the literature to speculate how immune signaling might be playing a role in defining sex-specific adolescent outcomes. We discuss open questions in the literature and propose experimental design tenets that may assist in better understanding adolescent neurodevelopment.     

Initiation of antiretroviral therapy during chronic SIV infection leads to rapid reduction in viral loads and the level of T-cell immune response

In the present era of increasing resistance of human immunodeficiency virus (HIV) to antiviral drugs, exploration of adjunct therapies directed at immune responses in combination with antiretroviral drugs may be of value for the treatment of acquired immunodeficiency syndrome. In this study, we designed a model for immune therapy using SIVmac251 infection in rhesus macaques. We explored the outcomes of primary infection on viral loads and the resulting T-cell immune responses in primates. The SIV-infected rhesus macaque model exhibited features similar to those observed in HIV-1 infection of humans. Major histocompatibility complex (MHC) segregation with viral loads were found to associate with viral containment and hence the duration of the disease-free latency period. Thus a better understanding of the relative roles of MHC class I allele in control of viral replication may provide important information for prophylactic or therapeutic vaccine designs. Mamu-A01 is significantly associated with higher immune response and control of viral replication. This allele is frequent in rhesus macaques of Indian origin (22%). Interestingly, Mamu-B01 (26% animals) was associated with lower immune responses and higher viral loads. Another allele, A08 was also predominantly present in 37% of the animals in this study. We observed higher viral replication in individual SIV-infected rhesus monkeys that did not demonstrate strong cellular immune responses. The results are important for understanding SIV disease progression in different MHC Mamu alleles and also for improving the interpretation and quality of pre-clinical studies in rhesus monkeys.     

Immune responses and the emergence of drug-resistant virus strains in vivo

The treatment of viral infections using antiviral drugs has had a significant public health benefit in the setting of human immunodeficiency virus (HIV) infection, and newly developed drugs offer potential benefits in the management of other viral infections, including acute self-limiting infections such as influenza and picornaviruses (including the rhinoviruses that are responsible for a large proportion of 'common colds'). A serious concern with such treatments is that they may lead to the selection of drug-resistant strains. This has been a significant problem in the case of HIV infection. Existing mathematical-modelling studies of drug resistance have focused on the interactions between virus, target cells and infected cells, ignoring the impact of immune responses. Here, we present a model that explores the role of immune responses in the rise of drug-resistant mutants in vivo. We find that drug resistance is unlikely to be a problem if immune responses are maintained above a threshold level during therapy. Alternatively, if immune responses decline at a fast rate and fall below a threshold level during treatment (indicating impaired immunity), the rise of drug-resistant mutants is more likely. This indicates an important difference between HIV, which impairs immunity and for which immune responses have been observed to vanish during treatment, and viral infections such as influenza and rhinoviruses, for which such immune impairment is not present. Drug resistance is much more likely to be a problem in HIV than in acute and self-limiting infections.     

The endocannabinoid system: a revolving plate in neuro-immune interaction in health and disease

Studies of the last 40 years have brought to light an important physiological network, the endocannabinoid system. Endogenous and exogenous cannabinoids mediate their effects through activation of specific cannabinoid receptors. This modulatory homoeostatic system operates in the regulation of brain function and also in the periphery. The cannabinoid system has been shown to be involved in regulating the immune system. Studies examining the effect of cannabinoid-based drugs on immunity have shown that many cellular and cytokine mechanisms are modulated by these agents, thus raising the hypothesis that these compounds may be of value in the management of chronic inflammatory diseases. The special properties of endocannabinoids as neurotransmitters, their pleiotropic effects and the impact on immune function show that the endocannabinoid system represents a revolving plate of neural and immune interactions. In this paper, we outline current information on immune effects of cannabinoids in health and disease.     

全球免疫细胞治疗药物开发现状与趋势

目的:从产品开发角度分析免疫细胞治疗类药物的发展现状和未来趋势。方法:检索科睿唯安(Clarivate Analytics)的Cortellis数据库的数据,利用定量分析法和对比分析法对检索结果进行分析。结果:目前已有2种免疫细胞治疗类药物上市,1种免疫细胞治疗类药物处于预注册阶段,4种药物处于临床Ⅲ期,同时大量处于临床Ⅱ/Ⅰ期药物显示未来市场上将有更多免疫细胞治疗类药物。产品交易方面,目前在免疫细胞治疗类药物的商业交易也趋向频繁。通过列举分析目前已发生的交易金额前十的交易,发现其中药物开发及商业化许可是最主要的交易模式。结论:目前免疫细胞治疗类药物市场尚处于起步阶段,但随着未来技术的不断发展改进,相信未来有更多的药物进入商用市场,为癌症及其他疾病的治疗提供新的契机。     

Hepatitis C and treatment with pegylated interferon and ribavirin

Hepatitis C is a hepatotropic RNA virus with a propensity to cause chronic infection, causing a worldwide burden of chronic hepatitis, cirrhosis and hepatocellular carcinoma. Both viral elimination and hepatocellular damage are thought to be immune mediated with T-helper and cytotoxic T-lymphocytes central to these events. A delay in the onset of adaptive immunity following infection indicates that a defect in the innate immune response may lead to viral persistence with a combination of other mechanisms subsequently contributing. Antiviral therapy based on interferon-alpha leads to resolution of disease in approximately 50% of patients. Specific anti-hepatitis C anti-viral drugs are being developed.     

Frank A. Beach Award: Programming of neuroendocrine function by early-life experience: A critical role for the immune system

Many neuropsychiatric disorders are associated with a strong dysregulation of the immune system, and several have a striking etiology in development as well. Our recent evidence using a rodent model of neonatal Escherichia coli infection has revealed novel insight into the mechanisms underlying cognitive deficits in adulthood, and suggests that the early-life immune history of an individual may be critical to understanding the relative risk of developing later-life mental health disorders in humans. A single neonatal infection programs the function of immune cells within the brain, called microglia, for the life of the rodent such that an adult immune challenge results in exaggerated cytokine production within the brain and associated cognitive deficits. I describe the important role of the immune system, notably microglia, during brain development, and discuss some of the many ways in which immune activation during early brain development can affect the later-life outcomes of neural function, immune function, and cognition.     

Role of non-immune mechanisms of muscle damage in idiopathic inflammatory myopathies

Idiopathic inflammatory myopathies (IIMs) comprise a group of autoimmune diseases that are characterized by symmetrical skeletal muscle weakness and muscle inflammation with no known cause. Like other autoimmune diseases, IIMs are treated with either glucocorticoids or immunosuppressive drugs. However, many patients with an IIM are frequently resistant to immunosuppressive treatments, and there is compelling evidence to indicate that not only adaptive immune but also several non-immune mechanisms play a role in the pathogenesis of these disorders. Here, we focus on some of the evidence related to pathologic mechanisms, such as the innate immune response, endoplasmic reticulum stress, non-immune consequences of MHC class I overexpression, metabolic disturbances, and hypoxia. These mechanisms may explain how IIM-related pathologic processes can continue even in the face of immunosuppressive therapies. These data indicate that therapeutic strategies in IIMs should be directed at both immune and non-immune mechanisms of muscle damage.     

Viral chemokine-modulatory proteins: tools and targets

The chemokine network is an extensive system that regulates many immune functions such as leukocyte locomotion, T cell differentiation, angiogenesis and mast cell degranulation. Tight control of chemokines is vital for proper immune function. Not surprisingly, viruses have found ways to subvert or exploit the immune system in order to persist in co-existence with their hosts. Several viral immune evasion genes encode proteins that modulate the chemokine network. We attempt to identify which aspects of the chemokine control mechanisms are susceptible to modulation. Chemokine-glycosaminoglycan interaction, extracellular processing of chemokines and chemokine scavenging will be discussed in the light of poxvirus and herpesvirus immune evasion. Viral chemokine-modulatory proteins may either be targets for anti-viral therapy or lead the way to new anti-inflammatory chemokine-modulating drugs.