Biotherapies of chronic diseases in the inter-war period: from Witte's peptone to Penicillium extract

In the inter-war period physicians elaborated numerous 'biotherapies' grounded in the complex interactions between physiology, bacteriology and immunology. The elaboration of these non-specific biological treatments was stimulated by the theory of generalized anaphylaxis that linked the violent reaction to a foreign protein to a broad array of chronic diseases, from asthma and urticaria to rheumatism or chronic colitis. Such diseases were perceived as the result of an 'abnormal reactivity' to a sensitisation of tissues and organs by bacteria and by foreign proteins, a view that provided an effective bridge between new concepts derived from bacteriology and immunology and the long-standing pathological tradition. Accordingly, physicians attempted to treat these conditions through specific desensitisation and non-specific biological therapies: peptone treatment, protein therapy, haemotherapy, 'antivirus' or 'opotherapy'. Therapies that attempted to neutralise the harmful effects of chronic infections through 'desensitisation' were not seen as marginal medical practices, but were promoted by leading advocates of the 'Pasteurian sciences', such as Richet, Widal, Vallery-Radot, Wright and Fleming. They also led to development of new products by the pharmaceutical industry.     

Immune Balance: The Development of the Idea and Its Applications

It has long been taken for granted that the immune system’s capacity to protect an individual from infection and disease depends on the power of the system to distinguish between self and nonself. However, accumulating data have undermined this fundamental concept. Evidence against the self/nonself discrimination model left researchers in need of a new overarching framework able to capture the immune system’s reactivity. Here, I highlight that along with the self/nonself model, another powerful representation of the immune system’s reactivity has been developed in the twentieth century immunology. According to this alternative view, the immune system is not a killer of nonself strangers but a peace-maker helping to establish harmony with the environment. The balance view of the system has never become part of the dominant paradigm. However, it is gaining more and more currency as new research develops. Advances in mucosal immunology confirm that instead of distinguishing between self and foreign the immune system reacts to microbial, chemical and self-induced alterations to produce responses that counterbalance effects of these changes.     

John Freeman,hay fever and the origins of clinical allergy in Britain, 1900–1950

In 1911, Drs John Freeman and Leonard Noon published an account of a novel treatment for hay fever. Their method of desensitisation consisted of injecting increasing doses of an extract of pollen subcutaneously until the hypersensitivity reaction was diminished or abolished. Over subsequent decades, desensitisation established itself as the cornerstone of clinical allergy in both England and the United States, at least until the advent of novel pharmaceutical agents in the 1950s and 1960s. Although British allergists such as Noon and Freeman were aware of conceptual developments within European immunology and pathology (such as the identification of anaphylaxis by Richet and Portier or von Pirquet’s coining of the term allergy), their approach to hay fever was driven by more immediate pragmatic, and indeed financial, considerations. Freeman’s immersion in the problems of hay fever and asthma and his pioneering use of allergen desensitisation or immunotherapy were shaped by his adherence to the convictions and bacteriological practices of his principal at St Mary’s Hospital, Almroth Wright, and by the drive to produce commercial vaccines which would help to subsidise the experimental and therapeutic work at St Mary’s. The aim of this paper is to explore early twentieth-century approaches to hay fever and other allergic diseases by tracing the intellectual and institutional origins of clinical allergy in Britain.     

Recent development in hormone research

A classical distinction between endocrine cells and neurons cannot be accepted without exception. This dichotomy was first challenged by the concept of neurosecretion. Recent observations indicate that hormone synthesis takes place in many extraendocrine tissues since the gene expression for prohormone synthesis seems to be common for all eukaryotes although the secretion of biological active hormone products is limited by posttranslational processing for differentiated cells. Increasing number of data support the view that regulation of pituitary hormone secretion is under multifactorial control in addition to specific signaling molecular effects of hormone-releasing hormones. Such modulators are co-secreted messengers from hypothalamic sources or co-functioning at the pituitary cell level. Multichannel regulation of pituitary tropic hormones appears to be important for understanding the interactions of pharmacological agents with pituitary hormone release, on the one hand, and the modulation of hormone release in pathological conditions, on the other hand. Perinatal transient hazards may induce permanent alterations in adaptive behavior when tested in adult age. Corticosteroid-induced deviation of avoidance behavioral reactions may be opposed by simultaneous administration of ACTH-like peptides. These observations revealed that a balance of the glucocorticoids and ACTH-like peptides in perinatal period basically determine the adaptative reaction of animals in adult age. Immune system may be called as a mobile brain since its tremendous information capacity and its responsiveness to alterations of chemical environmental signals. Recent data support the view that there is a bidirectional communication between the neuro-endocrine adaptational axis and the immune system. Stress hormones can alter the immune response and mononuclear cells produce factors that change the neuroendocrine regulation. In addition to these, prohormones are synthesized in mononuclear cells that may be involved in regulation of signalization between cells and in activation of endocrine system and brain functions.     

Single-cell RNA Sequencing Deciphers Immune Landscape of Human Recurrent Miscarriage

正Introduction Pregnancy is a mysterious biological process that presents great challenges to the maternal immune system.In the early1950s,the "etal allograft" concept was described for the first time by Peter Medawar,and the unique immunology of the maternal-fetal interface was recognized [1].Correct and precise interaction between mother and fetus plays an important role during pregnancy process,such as the apposition,adhesion,     

Comparative Immunology

Comparative Immunology includes an evolutionary approach toimmunity revealing the immune system as widespread and necessaryfor survival. Although many immunology textbooks and coursesare often oriented solely toward medicine orallied professions,comparative immunology is a unique beginning for advanced undergraduatestudents of biology, zoology, and immunology. A more biologicapproach to immune competence causes mammalian immunologiststo view comparative immunology as an introduction to numerousectothermic vertebrates and invertebrates. Such exotic animalsare sources of meaningful facts important for anyone viewingsignificant breakthroughs in immunology in phylogenetic perspective.Animals preserve their unique individuality by distinguishingbetween self and non-self to protect against infection and possibleextinction. The earliest beginnings of immune reactions arebest exemplified among the invertebrates by recognition, phagocytosis,graft rejection accompanied by specificity and weak memory,and the induction of agglutinins and lectins. Although vertebratesshare these same responses, the main differences include moreextensive evidence of specificity and memory and the uniquecapacity to synthesize immunoglobulins. Acknowledging the problemof recognition as the common basis for the immune response,certain members of the Ig superfamily, notably Thy-1 and ß₂-microglobulin,will help our attempts to define evolutionary pressures thatcaused the development of immunity.     

A systems biology approach to nutritional immunology - focus on innate immunity

Innate immunity and nutrient metabolism are complex biological systems that must work in concert to sustain and preserve life. The effector cells of the innate immune system rely on essential nutrients to generate energy, produce metabolic precursors for macromolecule biosynthesis and tune their responses to infectious agents. Thus disruptions to nutritional status have a substantial impact on immune competence and can result in increased susceptibility to infection in the case of nutrient deficiency, or chronic inflammation in the case of over-nutrition. The traditional, reductionist methods used in the study of nutritional immunology are incapable of exploring the extremely complex interactions between nutrient metabolism and innate immunity. Here, we review a relatively new analytical approach, systems biology, and highlight how it can be applied to nutritional immunology to provide a comprehensive view of the mechanisms behind nutritional regulation of the innate immune system.     

Bacterial antigens elicit T cell responses via adaptive and transitional immune recognition

T cells are a critical component of host immune responses against bacterial pathogens. T cell activation relies on recognition of antigen(s) derived from the bacteria, and this activation triggers potent biological effector mechanisms. Therefore, the characterization of antigens that are stimulatory for T cells provides insight into host-pathogen interactions and advances rational vaccine design. The adaptive immune response is defined by its ability to detect variable or unique single-gene products, whereas a 'transitional' immune system recognizes more conserved structures or products of multigene pathways. This transitional system functionally overlaps the canonical innate and adaptive immune responses. Antigen identification has relied upon biochemistry, genetics and expression cloning strategies. The development of computational approaches, fuelled by advances in immunology and genomic information, will facilitate the discovery of antigens and expand our understanding of both beneficial and pathological immune responses.     

On the adaptive significance of stress-induced immunosuppression.

We approach the field of stress immunology from an ecological point of view and ask: why should a heavy physical workload, for example as a result of a high reproductive effort, compromise immune function? We argue that immunosuppression by neuroendocrine mechanisms, such as stress hormones, during heavy physical workload is adaptive, and consider two different ultimate explanations of such immunosuppression. First, several authors have suggested that the immune system is suppressed to reallocate resources to other metabolic demands. In our view, this hypothesis assumes that considerable amounts of energy or nutrients can be saved by suppressing the immune system; however, this assumption requires further investigation. Second, we suggest an alternative explanation based on the idea that the immune system is tightly regulated by neuroendocrine mechanisms to avoid hyperactivation and ensuing autoimmune responses. We hypothesize that the risk of autoimmune responses increases during heavy physical workload and that the immune system is suppressed to counteract this.     

Immunity to fungal infections

Fungal diseases represent an important paradigm in immunology, as they can result from either a lack of recognition by the immune system or overactivation of the inflammatory response. Research in this field is entering an exciting period of transition from studying the molecular and cellular bases of fungal virulence to determining the cellular and molecular mechanisms that maintain immune homeostasis with fungi. The fine line between these two research areas is central to our understanding of tissue homeostasis and its possible breakdown in fungal infections and diseases. Recent insights into immune responses to fungi suggest that functionally distinct mechanisms have evolved to achieve optimal host-fungus interactions in mammals.     

Dissecting tumor responsiveness to immunotherapy: the experience of peptide-based melanoma vaccines

Recent years have witnessed important breakthroughs in our understanding of tumor immunology. A variety of immunotherapeutic strategies has shown that immune manipulation can induce the regression of established cancer in humans. The identification of the genes encoding tumor-associated antigens (TAA) and the development of means for immunizing against these antigens have opened new avenues for the development of an effective anticancer immunotherapy. However, an efficient immune response against tumor requires an intricate cross-talk between cancer and immune system cells, which is still poorly understood. Only when the molecular basis underlying tumor susceptibility to an immune response is deciphered could new therapeutic strategies be designed to fit biologically defined mechanisms of cancer immune rejection. In this article, we address some of the critical issues that have been identified in cancer immunotherapy, in part from our own studies on immune therapies in melanoma patients treated with peptide-based vaccination regimens. This is not meant to be a comprehensive overview of the immunological phenomena accompanying cancer patient vaccination but rather emphasizes some emergent findings, puzzling controversies and unanswered questions that characterize this complex field of oncology. In addition to reviewing the main immunological concepts underlying peptide-based vaccination, we also review the available data regarding naturally occurring and therapeutically induced anticancer immune response, both at the peripheral and intratumoral level. The hypothesized role of innate immunity in predetermining tumor responsiveness to immunotherapeutic manipulation is also discussed.     

The role of cytokines in immunological tolerance: potential for therapy

Current immunosuppression protocols, although often effective, are nonspecific and therefore hazardous. Consequently, immunological tolerance that is antigen specific and does not globally depress the patient's immune system has become one of the Holy Grails of immunology. Since the discovery that cytokines have immunomodulatory effects, extensive research has investigated the potential of these molecules to induce and maintain specific immunological tolerance in the context of transplantation, allergy and autoimmunity. In this article, we review the possible mechanisms by which cytokines can modulate the immune response and the animal models that frequently confound the theory that a single cytokine, or group of cytokines, can induce tolerance in a predictable manner. Finally, we discuss the role of cytokines at a paracrine level, particularly in the context of inducing and maintaining antigen-specific, regulatory T cells with the clinical potential to suppress specific immune responses.     

The Self Model and the Conception of Biological Identity in Immunology

The self/non-self model, first proposed by F.M. Burnet, has dominated immunology for 60 years now. According to this model, any foreign element will trigger an immune reaction in an organism, whereas endogenous elements will not, in normal circumstances, induce an immune reaction. In this paper we show that the self/non-self model is no longer an appropriate explanation of experimental data in immunology, and that this inadequacy may be rooted in an excessively strong metaphysical conception of biological identity. We suggest that another hypothesis, one based on the notion of continuity, gives a better account of immune phenomena. Finally, we underscore the mapping between this metaphysical deflation from self to continuity in immunology and the philosophical debate between substantialism and empiricism about identity.     

Concepts of Neuroendocrine Cardiology and Neuroendocrine Immunology,Chemistry and Biology of Signal Molecules

Discovery of neurosecretion of cardioactive neurohormones produced by hypothalamic nuclei (NSO and NPV), as well as the biosynthesis of several immunomodulators (signal molecules of the neuroendocrine immune system of brain), deciphering of their chemical structure and study of their biological properties led to the foundation of two important trends of neurobiology: neuroendocrine immunology and cardiology. Hormone formation by atrium ganglionary nerve cells and auriculum establishment of neurohumoral interactions between hypothalamic and atrium neurosecretion indicated the existence of the system neuroendocrine hypothalamus—endocrine heart. Study of their biological properties promoted creation of powerful neurohormonal preparations for the treatment of immune, cardio-vascular, neurodegenerative, infectious and tumor diseases. Concepts suggested by us on neuroendocrine cardiology and immunology, create large perspectives for development of the theory and its implementation in medicine.     

Interleukin 18: Friend or foe in cancer

In the last few years, the field of tumor immunology has significantly expanded and its boundaries, never particularly clear, have become less distinct. Although the immune system plays an important role in controlling tumor growth, it has also become clear that tumor growth can be promoted by inflammatory immune responses. A good example that exemplifies the ambiguous role of the immune system in cancer progression is represented by interleukin 18 (IL-18) that was first identified as an interferon-γ-inducing factor (IGIF) involved in T helper type-1 (Th1) immune response. The expression and secretion of IL-18 have been observed in various cell types from immune cells to circulating cancer cells. In this review we highlighted the multiple roles played by IL-18 in immune regulation, cancer progression and angiogenesis and the clinical potential that may result from such understanding.     

Cancer immunotherapy: the past,the present and the future

One of the most controversial issues in immunology for over a century has been whether an effective immune response can be elicited against malignant tumours. Whether the immunology community has believed cancer immunotherapy is feasible or impossible has been largely determined by the prevailing immunological paradigms at that time. In fact, during the last 110 years it is possible to trace at least five dramatic fluctuations in attitude towards cancer immunotherapy. It now appears, however, that overwhelming evidence is available to support the view that both the innate and adaptive immune responses can recognize and eliminate tumours. On the other hand, it remains to be seen if these immune responses can be harnessed to control cancer as, at the time of diagnosis, many tumours have already been immunoselected to be highly resistant to immune elimination. Based on these observations it is argued that immunotherapy approaches, other than the generation of tumour-specific cytotoxic T lymphocytes, must be explored. Alternative strategies include recruiting tumouricidal myeloid cells into tumours, generating antiangiogenic immune responses and directing innate immunity to hypoxia-induced ligands on tumour cells.     

Clone-specific immune reactions in a trematode-crustacean system

Variability of immune responses is an essential aspect of ecological immunology, yet how much of this variability is due to differences among parasite genotypes remains unknown. Here, variation in immune response of the crab, Macrophthalmus hirtipes, is examined as a function of experimental exposure to 10 clonal cercarial lineages of the trematode Maritrema novaezealandensis. Our goals were (1) to assess the variability of the host immune reaction elicited by 10 parasite clones, (2) to test if the heterozygosity-fitness correlation, whereby organisms with higher heterozygosities achieve a higher fitness than those with lower heterozygosities, applies to heterozygous parasites eliciting weak immune responses, and (3) to see how concomitant infections by other macroparasites influence the crab's immune response to cercariae. Parasite clones were distinguished and heterozygosities calculated using 20 microsatellite markers. We found that exposure to cercariae resulted in increased haemocyte counts, and that although interclonal differences in immune response elicited were detected, parasite heterozygosity did not correlate with host immune response. Additionally, the presence of other pre-existing parasites in hosts did not influence their immune response following experimental exposure to cercariae. Overall, the existence of variability in immune response elicited by different parasite clones is promising for future ecological immunology studies using this system.     

Modulation of the immune response by emotional stress

The influence of mild, emotional stress was investigated for its effect on the immune system by subjecting rats to the one-trial-learning passive avoidance test. The reactivity of the immune system was tested by determining the proliferative response after mitogenic stimulation in vitro as well as the capacity to generate a primary antibody response in vivo after immunization with sheep red blood cells. Our results demonstrate that exposure of rats to a single electric footshock (learning trial) or habituation to the passive avoidance apparatus, induces an increase of the immune response in vitro and in vivo. Thus, emotional stimuli seem to facilitate immunological responsiveness. However, when the animal is confronted with a conflict situation, as tested by the retention of the avoidance response after a single learning trial, the initially enhanced reactivity of the immune system decreases. It is concluded that the immune system is capable of reacting specifically and immediately to distinct psychological stimuli.     

Regulators and signalling in insect antimicrobial innate immunity: Functional molecules and cellular pathways

Insects possess an immune system that protects them from attacks by various pathogenic microorganisms that would otherwise threaten their survival. Immune mechanisms may deal directly with the pathogens by eliminating them from the host organism or disarm them by suppressing the synthesis of toxins and virulence factors that promote the invasion and destructive action of the intruder within the host. Insects have been established as outstanding models for studying immune system regulation because innate immunity can be explored as an integrated system at the level of the whole organism. Innate immunity in insects consists of basal immunity that controls the constitutive synthesis of effector molecules such as antimicrobial peptides, and inducible immunity that is activated after detection of a microbe or its product(s). Activation and coordination of innate immune defenses in insects involve evolutionary conserved immune factors. Previous research in insects has led to the identification and characterization of distinct immune signalling pathways that modulate the response to microbial infections. This work has not only advanced the field of insect immunology, but it has also rekindled interest in the innate immune system of mammals. Here we review the current knowledge on key molecular components of insect immunity and discuss the opportunities they present for confronting infectious diseases in humans.     

Decidual natural killer cells and the immune microenvironment at the maternal-fetal interface

During early pregnancy,an orchestrated evolutionary maternal adaption toward tolerance of the semiallogeneic fetus is required to ensure decidualization and early embryo development.Remodeling of the immune system involves natural killer cells(NKs),macrophages,T cells and dendritic cells(DCs) altering the microenvironment in the deciduas.In particular,a unique population of NK cells with a CD56~(bright)CD16~- phenotype in the decidua has been proposed to play a key role in the maternal adaptation to pregnancy.However,there is a tendency for pregnancy immunology to reflect transplantation immunology regarding the assumption that the maternal immune system should be suppressed.This tendency is misleading.We discuss how the immune system is formed in early deciduas and the interactions between maternal NK cells and fetal growth.We propose that the maternal immune response must not be fully suppressed and is even necessary for the local response of uterine NK cells.