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The Failure of Antibody Production in the Chick Embryo

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The Failure of Antibody Production in the Chick Embryo

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Immunology and Cell Biology focuses on the general functioning of the immune system in its broadest sense, with a particular emphasis on its cell biology. Areas that are covered include but are not limited to: Cellular immunology, Innate and adaptive immunity, Immune responses to pathogens,Tumour immunology,Immunopathology, Immunotherapy, Immunogenetics, Immunological studies in humans and model organisms (including mouse, rat, Drosophila etc)

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... In 1950, Burnet and his Australian colleagues tried to demonstrate his theory through an experiment using the chick embryo [55]. In designing their experiments, Burnet and his team thought that three kinds of extrinsic entities injected into a chick embryo-influenza virus A, bacterial virus C16, and human red blood cells-would not only be indefinitely tolerated but also make the chicken receive the same entity after its growth without generating antibody response. ...
... There were other research articles with related implication. As I have shown, Burnet himself along with his colleagues conducted an experiment on immunological tolerance using viruses and red blood cells, although he did not obtain a result that fit with his expectation [55]. A more interesting work was published in 1952 by Jack A. Cannon and William P. Longmire at the University of California, Los Angeles. ...
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The Nobel Prize in Physiology and Medicine in 1960 was awarded to two renowned scientists in Australia and Britain, Frank Macfarlane Burnet and Peter Brian Medawar. Many historical accounts have described Burnet's theoretical prediction of immunological "tolerance" and its experimental confirmation by Medawar as a momentous achievement in immunology. This new book examines their distinct research pathways, especially their different ways of approaching the immunological changes of the host organism during embryogenesis and fetal development.
... Like everything in biology these control mechanisms are neither infallible nor universal. A failure in the selection process against self--directed antigen--receptors is the best known example, which can lead to the development of autoimmunity [20] . Consequently, proteins that are expressed somewhere at a site of the body receive the capability to induce an immune response, and as adaptive immunity is launched, IM is affected with severe long--term consequences for the inflicted organs. ...
... Depending on which organs are exposed to the responsible substance, the manifestation of atopic allergy leads to regular excessive responses of the eyes (allergic conjunctivitis), the nose (allergic rhinitis), the skin (allergic dermatitis), or the lung (allergic asthma). When the first experimental anaphylaxis phenomena were induced during immunization procedures, it was not clear what caused the increasing hypersensitivity in vaccine--treated subjects [20] . This transition to permanent hypersensitivity is based on the concept of IM and resembles very much the process of immunization. ...
Thesis
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IMMUNOLOGICAL MEMORY (IM) is the ability of the immune system to respond faster, more effectively and with greater magnitude to a previously encountered antigen. This ability is mediated by memory lymphocytes generated during first antigen encounter. Generation of memory lymphocytes is beneficial in recurrent infections because they provide long-lasting protection from pathogens. On the other hand, memory lymphocytes can also have a pathological role. The immune system of atopic persons has a tendency to react against harmless environmental antigens (allergens), like dust and pollen. Exposure of atopic individuals to allergens can lead to development of allergen-specific CD4+ T helper 2 cells (Th2 cells). Allergen-specific Th2 cells elicit a pathological cascade resulting in elevated IgE antibody titers and an increased number of eosinophils, amongst other parameters. Reactions to allergens are manifested in diverse ways, depending on the affected organ and potentially the allergen itself. A patient with allergic asthma (AA) suffers from recurrent episodes of wheezing, breathlessness and coughing due to a severe chronic inflammation of the airways, hyper-secretion of mucus, bronchial hyper-responsiveness and reversible airway obstruction. The potential importance of memory Th2 cells in asthma is accentuated by the findings about T helper 1 (Th1) cells and cytotoxic T cells (CTLs) in mice that perpetuation of numerous chronic inflammatory disease states is possible through antigen-specific memory cell installation in peripheral tissue. Mouse models of AA are well defined. Sensitization and subsequent antigen aerosol challenge of mice induces an acute inflammatory response in lungs that resembles AA in humans. After recovery from this acute episode of AA, recovered mice retain cell-infiltrates in lungs and display elevated titers of IgG1 and IgE antibodies in sera, when compared to naïve mice. Interestingly, infiltrates in the lungs of recovered mice contain antigen-specific memory Th2 cells. Earlier work has shown that these memory Th2 cells remain in the lungs for the lifetime of recovered mice and appear to be essential for disease relapse after antigen re-exposure. OBJECTIVES This study aims to elucidate the role of chemokine receptors (CKRs) in the maintenance and migration of allergen-specific Th2 memory cells in the lungs of asthmatic mice. It will also focus on many genes that could serve to indicate the presence and activation of allergen-specific Th2 memory cells in the lungs, including Th2 cytokines and T cell activation markers. To examine the role of CKRs in maintenance of allergen-specific Th2 memory cells, gene expression was compared between naïve healthy controls and mice recovered from an acute asthma attack. To investigate the role of mentioned genes in the disease relapse, expression differences between recovered and mice that were re-challenged with allergen were compared. METHODS We examined differences in CKR and selected marker gene expression between healthy mice (naïve), asthmatic mice recovered from acute disease (recovered), and normal asthmatic mice that are re-exposed to allergen (re-challenged) in a comparative gene expression evaluation of the whole pulmonary transcriptome via real-time PCR. RESULTS TCR variable region α13 and the two monogamous receptors CCR6 and CCR9 were the only three genes that showed detectable difference in gene expression between naïve and recovered mice: while TCR α13 and CCR9 expression were increased, CCR6 expression was decreased in recovered mice compared to naïve mice. Expression levels of all Th2-specific cytokines, IL-4, IL-5 and IL-13, were immensely up-regulated after allergen re-challenge, while IFNγ showed a significant up-regulation between 4 and 6 h after allergen exposure of asthmatic mice. Several genes of secreted asthma promoting factors (TSLP, IL-33 and eotaxins-1 and -2) showed clear up-regulation, while specific genes of Th2 cells were either not affected (ST2) or down-regulated (CRTh2 and IL-25R). Evaluation of CKR expression after allergen re-challenge revealed different regulation patterns, while CCR1 and CXCR2 showed clear up-regulation from 2 h and CCR10 and CX3CR1 showed clear down-regulation from 4 h after contact with allergen. We observed that a group of CKR genes did not react to the re-challenge at all (CCR4, CCR7, CCR9, CXCR1 and CXCR6). CONCLUSIONS On the scale of the whole lung RNA vα13+ TCR sub-chain variant expression was a reliable marker for the presence of allergen-specific memory T cells in the lung tissue of asthmatic mice. Further, our results imply that CCR9 might be involved in the maintenance of these memory cells, which has to be further validated in subsequent experiments. Upon allergen re-challenge, pulmonary cytokine gene expression indicates elicitation of a strong Th2-mediated allergen-specific immune response within the first two hours after re-challenge. Gene expression pattern of diverse asthma and lymphocyte-related markers assisted in gaining insight in the early events after allergen re-challenge. Global pulmonary gene expression patterns of almost the whole panel of known CKRs was markedly changed after re-challenge. This change, however, was only permanent for CCR1, CxCR2, CCR5, CCR10 and Cx3CR1. Additionally, we observed that there might be a limited number of distinct regulation pattern that CKRs obey as the lungs are re-challenged. One group of CKRs did not react to allergen exposure and gene expression alterations of these genes (CCR4, CCR7, CCR9, CxCR1 and CxCR6) might therefore not be necessary for the initiation of an asthmatic response. Yielded information should serve the design of specific pharmaceuticals and/or treatments for the cure from recurrent asthmatic phenotype upon contact with aeroallergens.
... In the model system used each ORF encoding putative neo-antigen was generated after the invasive T. cruzi replicated in the embryonic tissues prior to the development of the chick immune system in the first week of growth. Therefore, a functional role for ORF's encoded neo-antigen in the pathogenesis of Chagas disease did not hold promise in the absence of humoral autoimmune factors in the actively tolerized kDNA-mutated chicken6263646566. ...
... The tolerance mechanism in kDNA-mutated chickens could not discriminate between self and non-self target tissues because the immune surveillance, fundamental to keep the self constituents free of the destructive reactions from the body self-defense apparatus, may be dampened due to the genotype modifications. The anti-self lymphocyte destruction of the heart happens when breakdown of self-tolerance or deregulation of the surveillance mechanism occurs6263646566. Thus, cardiomegaly with lymphocyte destruction Autoimmune Chagas Disease www.plosntds.orgof ...
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The administration of anti-trypanosome nitroderivatives curtails Trypanosoma cruzi infection in Chagas disease patients, but does not prevent destructive lesions in the heart. This observation suggests that an effective treatment for the disease requires understanding its pathogenesis. To understand the origin of clinical manifestations of the heart disease we used a chicken model system in which infection can be initiated in the egg, but parasite persistence is precluded. T. cruzi inoculation into the air chamber of embryonated chicken eggs generated chicks that retained only the parasite mitochondrial kinetoplast DNA minicircle in their genome after eight days of gestation. Crossbreeding showed that minicircles were transferred vertically via the germ line to chicken progeny. Minicircle integration in coding regions was shown by targeted-primer thermal asymmetric interlaced PCR, and detected by direct genomic analysis. The kDNA-mutated chickens died with arrhythmias, shortness of breath, cyanosis and heart failure. These chickens with cardiomyopathy had rupture of the dystrophin and other genes that regulate cell growth and differentiation. Tissue pathology revealed inflammatory dilated cardiomegaly whereby immune system mononuclear cells lyse parasite-free target heart fibers. The heart cell destruction implicated a thymus-dependent, autoimmune; self-tissue rejection carried out by CD45(+), CD8γδ(+), and CD8α lymphocytes. These results suggest that genetic alterations resulting from kDNA integration in the host genome lead to autoimmune-mediated destruction of heart tissue in the absence of T. cruzi parasites.
... In the model system used each ORF encoding putative neo-antigen was generated after the invasive T. cruzi replicated in the embryonic tissues prior to the development of the chick immune system in the first week of growth. Therefore, a functional role for ORF's encoded neo-antigen in the pathogenesis of Chagas disease did not hold promise in the absence of humoral autoimmune factors in the actively tolerized kDNA-mutated chicken [62][63][64][65][66]. ...
... The tolerance mechanism in kDNA-mutated chickens could not discriminate between self and non-self target tissues because the immune surveillance, fundamental to keep the self constituents free of the destructive reactions from the body self-defense apparatus, may be dampened due to the genotype modifications. The anti-self lymphocyte destruction of the heart happens when breakdown of self-tolerance or deregulation of the surveillance mechanism occurs [62][63][64][65][66]. Thus, cardiomegaly with lymphocyte destruction Figure 7. Clinical and pathological findings in Gallus gallus with Trypanosoma cruzi kDNA mutations. ...
... Subcutaneous grafts of kDNA+ reporter hearts into NC birds that had their BMCs destroyed by drugs and replaced by healthy marrow cells were not rejected either. These findings suggest that putative neo-antigens in the kDNA+ heart grafts either were not expressed or were not 'visible' to the immune system of the syngeneic chickens [119]. Taken together, the data suggest that the rejection of the hearts in kDNA+ chickens was an antigen-independent autoimmune phenomenon resulting from parasite-induced genotype modification and clonal proliferation of the effector T cells that attacked the heart. ...
... Collectively, the data indicated that the immune effector lymphocytes primarily destroyed the target heart cells. Furthermore, a role for humoral immunity was not detected due to the absence of auto-antibodies in the chickens, which acquired complete immune tolerance early in embryonic development [119]. ...
Article
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Infection with the protozoan Trypanosoma cruzi manifests in mammals as Chagas heart disease. The treatment available for chagasic cardiomyopathy is unsatisfactory. To study the disease pathology and its inhibition, we employed a syngeneic chicken model refractory to T. cruzi in which chickens hatched from T. cruzi inoculated eggs retained parasite kDNA (1.4 kb) minicircles. Southern blotting with EcoRI genomic DNA digests revealed main 18 and 20 kb bands by hybridization with a radiolabeled minicircle sequence. Breeding these chickens generated kDNA-mutated F1, F2, and F3 progeny. A targeted-primer TAIL-PCR (tpTAIL-PCR) technique was employed to detect the kDNA integrations. Histocompatible reporter heart grafts were used to detect ongoing inflammatory cardiomyopathy in kDNA-mutated chickens. Fluorochromes were used to label bone marrow CD3+, CD28+, and CD45+ precursors of the thymus-dependent CD8α+ and CD8β+ effector cells that expressed TCRγδ, vβ1 and vβ2 receptors, which infiltrated the adult hearts and the reporter heart grafts. Genome modifications in kDNA-mutated chickens can be associated with disruption of immune tolerance to compatible heart grafts and with rejection of the adult host's heart and reporter graft, as well as tissue destruction by effector lymphocytes. Autoimmune heart rejection was largely observed in chickens with kDNA mutations in retrotransposons and in coding genes with roles in cell structure, metabolism, growth, and differentiation. Moreover, killing the sick kDNA-mutated bone marrow cells with cytostatic and anti-folate drugs and transplanting healthy marrow cells inhibited heart rejection. We report here for the first time that healthy bone marrow cells inhibited heart pathology in kDNA+ chickens and thus prevented the genetically driven clinical manifestations of the disease.
... Brent McFarlane introduced the concept of immune surveillance in 1950, which is the physiological function of immune system, and means to identify and to destroy transformed cells prior to becoming tumor cells. It is now clear that innate and adaptive immunity systems act against many tumors and destroy them 32 . Tumor cells express some antigens which can be identified by the host immune system. ...
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Cancer is one of the main causes of mortality in worldwide. When the normal cell division and growth is distorted or on the other hand, the normal cell cycle control processes, which normally occur, are destroyed, the cells will be cancerous. In the event that these cells migrate to other places are known as malignant cancer. Scientists use different methods to treat cancer, such as surgery, chemotherapy, laser therapy. These methods may also cause damage to healthy cells. For this reason, a method is optimal for this purpose as it can involve the least side effects. Immunotherapy is a method in which abnormal cells are Identified and destroyed. Since the immune system is used as the major part in immunotherapy, it is an appropriate method for the purpose. The cancer cells can be detected by immune system and appropriate responses can be taken to them since they induce modifications on the surface, or display their specific antigens. Accordingly, the vaccines can be constructed by which the body will be resistance against cancer. Antigens, especially cancer-specific epitopes are important in vaccine developing. Nowadays scientists have developed several vaccines on this basis, including vaccines against prostate and breast cancers. In this study, we studied various methods of cancer treatment, and then studied the immunotherapy as optimal method in cancer treatment. Ultimately various methods of tumor escape from the immune system will be discussed.
... 27 After writing this book, Burnet"s team conducted an experiment on immunological tolerance using viruses and red blood cells, although they did not obtain a result that fit with his theoretical expectation. 28 Another interesting work was published in 1952 by Jack Cannon and William Longmire at the University of California. 29 They arrived at a more successful result using chickens" skin homograft rather than employing viruses and red blood cells as Burnet did. ...
Article
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Using tissue transplantation, the British scientist Peter Brian Medawar showed how extrinsic cells could be permanently integrated into an animal's body without provoking immune responses. With his study of this phenomenon--which he called 'actively acquired tolerance'--Medawar was awarded the Nobel Prize in Medicine and Physiology in 1960 along with the Australian scientist Frank Macfarlane Burnet, who theoretically predicted the possibility. The monumental work of Medawar stems from his long and deep interest in the nature of living organisms' changes over time, such as growth, aging, and evolution. In particular, his concern for the phenomenon of decline played a critical role in his research design regarding tolerance and its interpretation.
... These early investigators sought a specific human example of what had been called "Burnet's 'marker' concept" of the generation of tolerance in chick embryos using human RBC as antigen 16 and extended work from the late 1940s. Ray Owen's observation of mutual tolerance to erythrocyte antigens in dizygotic calf twins in 1945 17 was a seminal contribution to the emerging study of immunologic tolerance and to the allograft experiments that were ultimately awarded the Nobel Prize in 1960. ...
Article
Transfusion therapy is complicated by the production of alloantibodies to antigens present in the donor and lacking in the recipient through the poorly-understood but likely multi-factorial process of alloimmunization. The low prevalence of alloimmunization in transfused patients (6.1%)11. Klein HGA, D.J. Mollison's Blood Transfusion in Clinical Medicine. Wiley-Blackwell, 2005. View all references suggests that processes central to immunologic tolerance may be operating in the vast majority of transfused patients who do not produce alloantibodies. Using RhD as a prototype, evidence is reviewed that the ability to make antibodies to red blood cell (RBC) antigens may result in part from immunologic tolerance acquired in utero. These ideas are extended to other examples of maternal microchimerism (MMc) of other non-inherited maternal antigens (NIMA). An evolutionary argument is offered that multi-generational immunity supports the hypothesis that MMc may partly explain the “non-responder” phenotype in RBC alloimmunization.
... The experiment failed, with experimental verification of the theory eventually being provided by Sir Peter Medawar. Burnet 15 suggested that his experiments did not yield the predicted result because continual, rather than transient, presence of an antigen during embryonic life was required to induce acquired immunological tolerance. ...
Article
Immunology and Cell Biology focuses on the general functioning of the immune system in its broadest sense, with a particular emphasis on its cell biology. Areas that are covered include but are not limited to: Cellular immunology, Innate and adaptive immunity, Immune responses to pathogens,Tumour immunology,Immunopathology, Immunotherapy, Immunogenetics, Immunological studies in humans and model organisms (including mouse, rat, Drosophila etc)
... Parenchymal and nonparenchymal antigen-presenting cells (APCs) in the liver induce peripheral tolerance towards such antigens to avoid chronic activation of the immune system [3]. (2) Neonatal tolerance [4,5] can additionally explain the inability of perinatally infected chronic HBV carriers to sufficiently respond to HBsAg, HBeAg and HBV core protein. The idea of therapeutic vaccination is to overcome HBV-specific peripheral tolerance in chronic carriers and activate a potent and timely restricted cytotoxic T lymphocyte (CTL) response that eliminates HBV with minimized hepatocyte damage. ...
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A mouse model for persistent HBV infection is essential for the development of a therapeutic vaccine against HBV. Because HBV cannot infect mouse hepatocytes, even if the HBV receptor is introduced, surrogate models are used. A suitable model needs to establish persistent HBV replication and must allow the establishment of HBV-specific adaptive cellular and humoral immune responses. Therefore, an immunocompetent mouse model is needed in which one can break HBV-specific tolerance and ideally eliminate the HBV transcription template. The most widely used model for chronic HBV infection is the HBV transgenic mouse. Although HBV replicates from an integrated transgene, HBV-specific immune tolerance can be broken upon adequate immune stimulation because antigen expression only starts shortly before birth. Alternative mouse models of chronic HBV infection are generated by introducing HBV genomes either using viral vectors or using hydrodynamic injection. In these alternative models, the HBV transcription template is introduced into a proportion of hepatocytes and stays extra-chromosomal. It thus mimics the natural HBV transcription template, the HBV cccDNA in humans. Unlike an HBV transgene, however, it can be cleared upon appropriate treatment or immune stimulation. Human hepatocyte chimeric mice in which murine hepatocytes are widely replaced by human hepatocytes represent another important mouse model for persistent HBV infection. These mice are susceptible for HBV infection, but need to be severely immune deficient to accept human hepatocytes. In conclusion, a variety of mouse models for persistent HBV infection are available suitable for preclinical efficacy evaluations of therapeutic vaccination strategies against HBV.
... Early failures to induce antibody formation in the chick embryo (e.g. Burnet, Stone and Edney, 1950) could have been partly due to inhibition by maternal antibody. However, these failures played their part in fashioning the concept of immunological tolerance (Burnet and Fenner, 1949) although this concept, itself, obscured the embryo's ability to initially react immunologically to foreign antigens. ...
... A TTEMPTS to immunize chick embryos -have generally proven unsuccessful (Grasset, 1929;Burnet, 1941;and Burnet et al., 1950). However, if immunized immediately after hatching they show the presence of circulating antibody by the eleventh day of age (Wolfe and Dilks, 1948;Buxton, 1954;and Wolfe et al., 1957). ...
Article
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INTRODUCTION ATTEMPTS to immunize chick embryos have generally proven unsuccessful (Grasset, 1929; Burnet, 1941; and Burnet et al., 1950). However, if immunized immediately after hatching they show the presence of circulating antibody by the eleventh day of age (Wolfe and Dilks, 1948; Buxton, 1954; and Wolfe et al., 1957). Although humoral antibody cannot be detected during embryonic development, cellular bound antibody may be present (Engelhart and Lendle, 1955; Tyler, 1955; and Ebert, 1960). One report has described the occurrence of systemic anaphylaxis in chicks at three days post-hatch, if previously immunized at fourteen to fifteen days of incubation (Van Alten and Schechtman, 1963). The immunobiology of the chicken has been reviewed by Jaffe (1966). Attempts by this investigator to induce systemic anaphylaxis in three day post-hatch chicks have been unsuccessful. It was therefore decided to undertake this investigation to determine the age at which an immunized chicken will normally respond . . .
Article
We present data of extended studies on the possibility of maternally derived allotype Ig inducing a state of natural immunological tolerance to a non-inherited allotype in the offspring. Rabbits homozygous at the a locus, encoding allotypes in the variable region of immunoglobulin heavy chains, and rabbits homozygous at the unliked b locus, encoding allotypes of the constant region of x1 light chains, were immunized at the age of 2 months against the non-inherited allotype of their heterozygous mothers to which they had been exposed in utero and in early life. As control, we immunized rabbits of the same Ig phenotype but born to homozygous mothers, and therefore not exposed to that allotype. Immunization was done in a3/a3 offspring of either a1/a3 or a3/a3 mothers, by injecting al IgG, and in b6/b6 offspring of b4/b6 or b6/b6 mothers, by injecting b4 IgG. The IgG was injected either in a soluble form or emulsified in adjuvant. Injection of soluble IgG elicited only a low response, if any, revealing no differences between the various groups. All rabbits responded upon immunization with IgG in adjuvant.
1.1. Fetal serum immunoglobulin levels in seven viviparous and one ovoviviparous species of shark ranged from less than 0·3 to 4·8 per cent of the maternal levels.2.2. Apparently little or no maternofetal transfer of immunoglobulins occurs in sharks either via the placenta as it does in some mammals or via the yolk as it does in birds.3.3. Immunoglobulins can be synthesized by fetal shark spleen and in the adult shark by spleen, liver, stomach and the anal organ.4.4. The low serum levels of immunoglobulin in the spiny dogfish fetus may be due in part to a relative unresponsiveness to antigens before birth.
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The chapter discusses humoral self-tolerance as the cumulative action of a series of separate checkpoints placed along the B cell lineage. The strategy of employing multiple and distinct checkpoints presumably minimizes the risk that one or two inherited or somatically acquired mutations leads to uncontrolled autoantibody production, analogous to the role of checkpoints in the cell cycle that minimize neoplasia. Each checkpoint may depend on distinct sets of genes and molecules. From a genetic perspective, the use of broad terms such as “deletion” or “anergy” can be used to describe several distinct checkpoint mechanisms that likely involve discrete molecular pathways. The chapter discusses self-tolerance checkpoints acting (1) during formation of the pre-immune B cell repertoire and (2) during subsequent formation of an immune repertoire. A series of cellular phenomena potentially censor and remove autoantibody-bearing B cells from the pathway to antibody secretion. Each of these checkpoints has triggering thresholds that depend on the local auto-antigen concentration, auto-antigen valency, and the B cell's binding affinity for elimination of auto-reactive B cells in the bone marrow. These thresholds impose limits on the extent of tolerance.
Article
The inability of hepatitis B virus (HBV) transgenic mice, which express abundant hepatitis B surface antigen (HBsAg) in sera from the neonatal period onwards, to produce antibody to HBsAg (anti-HBs) is considered to be due to defective function of lymphocytes. The defective function is thought to result from neonatal tolerance because antigenic challenge during the neonatal period is considered to be a tolerogenic event rather than an immunogenic one. However, a series of mixed culture experiments in vitro showed that lymphocytes taken from transgenic mice that had been injected with HBsAg in complete Freund's adjuvant (CFA) constitutively produced anti-HBs when cultured with dendritic cells from age-, sex- and major histocompatibility complex (MHC)-matched normal mice, but not when cultured with dendritic cells from transgenic mice. The expression of major histocompatibility complex (MHC) class II and B 7.2 (CD86) antigens on dendritic cells was significantly lower in transgenic mice compared with the same from the normal mice (P < 0.05). Treatment of transgenic mice with interferon-gamma (IFN-gamma) resulted in up-regulation of MHC class II on dendritic cells, and lymphocytes from HBsAg-injected transgenic mice produced anti-HBs in vitro when cultured with dendritic cells from IFN-gamma-treated transgenic mice, but not when cultured with the dendritic cells from untreated transgenic mice. These experiments have shown that defective function of antigen-presenting cells (APC), not immunogenic tolerance, is responsible for the inability of murine HBV-carriers to produce anti-HBs. Production of anti-HBs by lymphocytes from HBsAg-injected transgenic mice in the presence of dendritic cells that express higher levels of MHC class II and CD86 antigens has inspired optimism that a more effective vaccine therapy can be developed for chronic HBV-carriers, injecting vaccine containing HBsAg with modulator(s) of APC function of dendritic cells.
Article
HSA injected into chickens after hatching induces suppression of anti-HSA antibody formation. Unresponsive chickens react by producing the anti-HSA antibodies earlier and more intensively after BSA challenge than after challenge with HSA. This effect cannot be ascribed to T cells, because they were found to play no substantial role in the unresponsiveness to HSA. Neither was active suppression, which could account for the depressed antibody production, detected. B cell inactivation seems to be the major mechanism involved in this unresponsiveness. However, some additional mechanism must prevent B cells of unresponsive chickens from producing anti-HSA antibodies after HSA challenge, although they are able to form them after immunization with BSA. We suggest that cellular interactions, either between B cells of different specificities or between B cells and macrophages, are responsible for this differential reactivity.
Article
The chapter focuses on the developmental aspects of immunity. The ontogenetic development of immune responses in the immature animal and the developmental cellular stages of the immune response in the adult animal are discussed in this chapter. The cellular mechanisms underlying the several immune responses have not received the full attention either to the evolutionary principles underlying the development of all biological systems or to the broad biological rules that govern the proliferative and differentiate activities of cells in any biologically functioning system. The chapter reviews the immunological status of fetal and neonatal mammals as well as several aspects of the ontogeny of the immune response when examined by the most sensitive technique presently available. Developmental stages of immune reactions and their mutual relationships such as relationship of phagocytosis to specific cellular reactions, relationship of delayed hypersensitivity to antibody formation, and dynamics of antibody formation are also presented in this chapter. The increase of immunological capacity with age and the appearance of natural antibodies result solely from specific antigenic stimulation; the chapter discusses the Unitarian concept of cell differentiation and proliferation underlying any form of immunological response. Several methods for studying developmental aspects of immunity and immunological development are also discussed in this chapter.
Article
Artificially induced immunological tolerance is often envisaged as experimental mimicry of events which occur naturally during the acquisition of self tolerance. Thus, it has been inferred that similar circumstances will facilitate the induction of both types of unresponsiveness. Since tolerance to most self determinants appears to have been established by the time of birth and allograft tolerance can be experimentally induced more readily, if not exclusively, in very young animals, it is commonly assumed that susceptibility to induction of tolerance to foreign antigens will continue to increase as progressively younger animals are tested. The experiments reported in this study extend the range of circumstances under which younger animals may be found to be less susceptible, or even completely resistant, to tolerance induction.
Article
ALTHOUGH several hundred species of the protozoan parasite Eimeria occur in mammals and birds, only two are known to complete their life cycle in sites other than the intestinal tract. These species, E. truncata and E. stiedae, occur in the kidney of the goose and liver of the rabbit respectively and have not been found elsewhere.
Article
Newborn and 15-day-old rabbits were immunized with different doses of heat-inactivated suspension of Escherichia coli and Salmonella paralyphi B. The secondary immunization was performed after 4 weeks and the dynamics, magnitude and site of the secondary response studied. The magnitude of the secondary response was found to depend on the magnitude and rate of the primary response, this latter reflecting the dose used. A direct relationship was found in the range of the minimal and optimal dose: the higher the primary dose the higher the secondary response. After a rapid and pronounced primary response evoked by a high dose of 1010 microorganisms in 15-day-old rabbits, a partial inhibition of the secondary response was observed. The inhibition was pronounced primarily in the spleen; the lymphatic nodes reacted by a higher number of antibody producing cells as compared with the control nonprimed young rabbits. © 1969 Academia, nakladatelství Československé akademie věd.
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Youngner, Julius S. (University of Pittsburgh, Pittsburgh, Pa.), and Marion E. Kelly. Inhibition by exogenous interferon of replication of poliovirus ribonucleic acid in chick brain. J. Bacteriol. 90:443–445. 1965.—The replication of poliovirus was studied after the intracerebral inoculation of infectious ribonucleic acid (RNA) into the brains of 2-day-old chicks; these animals are not susceptible to intact virus. Single-cycle replication of virus, which reached a peak in about 12 hr, was completely inhibited by prior intraperitoneal injection of interferon prepared from the allantoic fluid of chick embryos infected with influenza virus. A single dose of as little as 500 units of interferon, measured by a plaque-reduction method, completely suppressed viral replication when injected 24 hr prior to infectious RNA. This system provides a model for the study of the protection of target organs by passively transferred interferon injected at a distance.
Article
Turkey poults inoculated with Mycoplasma meleagridis during embryonic life did not become immunologically tolerant. Antibody of the IgM type was detected by the serum plate agglutination test as early as 5 days of age, and remained at a low level until after 3 weeks of age, when it was detected by the tube agglutination test. Production of IgG antibody against M. meleagridis was not detected until 6 weeks of age, as shown by hemagglutination-inhibition and mercaptoethanol-resistant agglutination titers.
Article
Offspring of mother mice treated immediately after delivery with deaggregated human γ-globulins (dHGG) are unable to produce HGG-specific antibodies when challenged with immunogenic forms of HGG (HGG/CFA) in adulthood. Despite a defective antibody response, animals rendered tolerant to HGG as neonates retain tolerogen-specific T cells able to proliferate and secrete lymphokines. The pattern of IL-2 and IL-4 secretion by T cells isolated from tolerant animals could not be distinguished from the corresponding cells in control mice, suggesting that neonatal exposure to dHGG did not affect T cell reactivity or Th1/Th2 in vivo balance. Moreover, immunization of tolerant animals with haptenated HGG confirmed the presence of tolerogen-specific helper T cells in vivo. Functional T cell depletion by anti-CD3 mAbs during lactation failed to modify induction of B cell tolerance, suggesting that T cells are neither affected nor required to induce the selective tolerance status observed in this model. Based on the finding that antigen-presenting cell functions in secondary organs (spleen, peritoneal cavity) are a late acquisition during ontogeny and reach adult-like levels at weaning, we propose that most soluble proteins elude T cell recognition during lactation due to defective antigen presentation.
Article
Die schon mitgeteilten histologischen Befunde an Auto-, Homo- und Heterotransplantaten von Milz der Ratte bzw Maus werden fr die beiden ersten Wochen nach der Verpflanzung ergnzt. Besonders eingehend werden die Gefvernderungen beschrieben, die schon am 2. Tage eingetreten sind und nach unserer Auffassung das weitere Schicksal der Transplantate bestimmen. Die greren Arterien obliterieren fibroblastisch. Follikelarterien und andere Arteriolen degenerieren, die Media wird vacuolisiert und nekrotisch, die Elastica zersplittert, zerbrckelt und geht schlielich ganz zugrunde. Die verschlossenen oder degenerierten arteriellen Gefe verdmmern. Die Sinus der Pulpa verden zum grten Teil. Nur wenige Sinus werden in Capillaren umgewandelt und unmittelbar mit Gefen des Transplantatbettes vereinigt. — Es wird errtert, da viele Untersucher immunbiologische Vorgnge zwischen Transplantat und Wirt als entscheidend fr die Unvertrglichkeit krperfremder Transplantate ansehen. Aus diesem Grunde wird untersucht, ob unsere histologischen Befunde mit dieser Auffassung in Einklang zu bringen sind. Das ist aus nher errterten Grnden nicht mglich. Schlielich wird darauf hingewiesen, da vermutlich in vielen erfolglosen Transplantations-experimenten unbewut Adjuvantien in Form von Bakterien unter anderem eingefhrt worden sind, wodurch mglicherweise aus den an sich nur schwach antigenen homologen Geweben krftigere Antigene werden.
Chapter
The use of embryonic, induced pluripotent, or adult stem cells is upheld as a potentially valuable therapeutic approach for replacement or repair of diseased and damaged tissues, partly because these immature cells are considered to be non-immunogenic. It is becoming increasingly clear, however, that tissues differentiated from such stem cell sources have the potential to express immunogenic molecules and will be susceptible to a patient’s immune response. This chapter draws on experience of organ and tissue transplantation and the study of transplant immunology to identify cellular and molecular mechanisms that are likely to be relevant to the rejection of stem cell-derived tissues. Pathways of cellular recognition and immune activation are described, together with effector mechanisms that may be responsible, not only for destruction of stem cell transplants, but also for regulating immune responses, thereby improving their chance of survival.
Chapter
Im allgemeinen wird eine Antigen-Injektion von einem Organismus mit einer Antikörperproduktion beantwortet, oder eine schon im Gang befindliche Antikörperbildung wird durch einen erneuten Antigenreiz stimuliert. Unter bestimmten Bedingungen kann eine Antigen-Injektion aber auch gerade das Gegenteil bewirken und das Individuum in der Art verändern, daß auf einen erneuten Antigenreiz keine oder nur vermindert Antigenkörper gebildet werden. Dieses Phänomen wird heute allgemein als spezifische immunologische Toleranz, oder einfacher als Immuntoleranz, bezeichnet. Das Phänomen ist streng spezifisch. Die immunologische Lähmung kann nur durch das korrespondierende Antigen ausgelöst werden. Der Begriff der Immuntoleranz oder der erworbenen immunologischen Toleranz oder auch der Antigentoleranz (Oehme 1963) ist bis heute nicht klar umgrenzt. Manchmal wird dieser Begriff in sehr weitem Sinn für jedes Unvermögen, Antikörper zu produzieren, benützt. Chase (1959) z. B. versteht unter immunologischer Toleranz jegliche nachweisbare Verminderung einer Immunreaktion. Dem steht gegenüber die recht enge Fassung von Billingham, Brent und Medawar (1953), die den Begriff ursprünglich auf das Toleranzphänomen beschränken wollten, das man beobachtet, wenn man in der Embryonalzeit oder in der frühen Neugeborenenperiode genügend hohe Antigendosen verabfolgt.
Chapter
This chapter presents an introduction to immunological tolerance in molecular era. Immunological tolerance revisited in the molecular era looks like replaying the saga of immunoglobulin gene structure and organization. Repertoire purging, of both T- and B-cell subsets, is clearly the most important mechanism, although it may not always be deletional, as functional inactivation without cell death also occurs. The capacity to induce anergy or even deletion peripherally by contact between lymphocyte and antigen in the absence of a co-stimulatory signal remains an important mechanism for inducing tolerance toward antigens expressed only in particular tissues and not within the primary lymphoid organs. The notion that CD8 + T cells can inhibit other T cells without actually killing them is gaining favor. Clonal methods for enumerating T-cell-mediated inhibitory effects require renewed emphasis.
Chapter
This chapter presents the history of viral immunology. The use of viral components for vaccination has been the subject of experimental clinical trials with adenoviruses and influenza subunit vaccines are in current use. The effect of the production of antibodies against viral components during the course of infection is in vivo complement fixation, demonstrable in practice by the developing anti-complementary activity of serum. Other antibody reactions, which may or may not result in neutralization of infectivity, may play an important role in the production of lesions, especially in certain persistent viral infections. Immune complexes in which viral antigens rather than virions are involved may also play an important role in the pathogenesis of some acute infections, such as hemorrhagic dengue and in the glomerulonephritis found in several chronic viral infections. Indeed, antigenemia and the early formation of immune complexes, rather than viremia as such, may provide the pathogenetic basis for the fever and symptoms that mark the end of the incubation period in many generalized viral infections and the prodromal rash may have a similar explanation.
Chapter
Unter Immuntoleranz versteht man das Phänomen der spezifischen Areaktivität oder der Unterdrückung der Antikörperbildung, das durch Verabreichung von Antigen hervorgerufen wird. Für die Induktion der immunologischen Toleranz ist ein bestimmtes quantitatives Verhältnis zwischen dem Antigen und der Antikörperbildungskapazität des Rezipienten entscheidend. Die optimalen Bedingungen für die Induktion der immunologischen Toleranz bestehen bei dem immunologisch unreifen Organismus, wo die Antikörperbildungskapazität des Rezipienten gleich null, oder sehr niedrig ist. Prinzipiell kann man jedoch auch bei einem immunologisch reifen Organismus einen, der Toleranz beim Embryo völlig äquivalenten Zustand hervorrufen.
Article
This chapter discusses the acquisition of biological specificity. Most tissues of the body do not long survive their transplantation between randomly chosen individuals of the same avian or mammalian species. The state of resistance called into being by the transplantation of living tissue between individuals is called transplantation immunity. If a graft carries one or more genes, for which the host has different alleles, it evokes an antagonistic response. The survival end point of a skin homograft can be determined with accuracy only when the graft loses its cuticle and hair, exposing the epithelial surface to direct observation. In the mouse, this requires about 10 days. Actively acquired immunity is the state of heightened resistance to an antigen as a result of a previous exposure to the antigenic stimulus. Passive immunity is the resistance produced by the transfer of ready-made antibody from an actively immunized donor to a normal subject. In adoptively acquired immunity, the subject becomes immune as a result of the transfer of immunologically activated tissue.
Chapter
This chapter focuses on immunological tolerance of nonliving antigens, describes various individual experimental models depending on the mode of induction, including tolerance induced by exposure in prenatal period of life and tolerance induction in mature animals, analyzes the various experimental models, and presents the common features of each model. It is demonstrated that certain features of the various models are consistent for different antigens within the species, for the same antigen in most species studied, and to a lesser extent, for the tolerant state in general. General consistencies justifying an assumption of similar mechanisms are examined. Comparison of the features of the models in which the response to simple antigens has been most extensively investigated shows the evidence of many similarities of the tolerant state once induced. Therefore, it appears that the features of each can, with merit, be examined for tentative generalizations about the tolerant state. The chapter concludes that the data derived primarily from more completely characterized experimental models of tolerance of nonliving antigens appear to provide grounds for some tentative statements regarding the nature of the tolerant state, particularly the role of antigen in its induction and maintenance and the conditions permitting induction of tolerance rather than of an immune response.
Chapter
This chapter discusses transplantation immunity and immunological tolerance, which are, under certain conditions, alternative reactions of the same organism to the same antigenic stimulus––namely, transplantation of tissues or cells from an antigenically different individual. Which of the two alternatives will take place is decided by the circumstances of the first experience by the reacting individual of the given antigens, especially important is the stage of development at which the first experience occurs. The chapter describes the methods of inducting tolerance in the prenatal and postnatal periods. It determines five techniques for induction of tolerance in the prenatal period comprising—namely, natural embryonic parabiosis, experimental embryonic parabiosis, the relation of mother and fetus, intraembryonic injections of cells, and transplantation of solid tissue in embryos. It discusses various tests for immunological tests, including tissue transplants, formation of serum antibodies, skin tests, susceptibility to infective agents, and autoimmunity to tissue antigens. It also examines the occurrence of immunological tolerance and the duration of the adaptive period in different species and presents the basic facts of immunological tolerance, along with some possible mechanisms of immunological tolerance.
Chapter
For embryologists working in the first half of the twentieth century, the most challenging problem was to differentiate between the embryo and its component parts. It was understood that the transplantation of tissues to genetically different adults was a failure, and because it was thought important for the tissue to mature in a developmentally similar environment. The hosts were either amphibian larvae or chick embryos atthe same level of development as the graft. Although, the importance of the immune system in graft rejection was not appreciated at that time, with hindsight these studies clearly demonstrated the immunologic immaturity of both amphibian embryos and larvae and avian embryos suggested that a small proportion of such grafts could survive into adulthood. Evidence from the transplantation of embryonic chick tissues to chick embryos is equally challenging; it was a widely used method for studying limb and feather differentiation, the migration of pigment cells from the neural crest, and the formation of feather color patterns. Others were bold enough to transplant xenogeneic tissues to chick embryoswith remarkable success.
Article
We have evaluated the impact of transgenic immunoglobulin (TGIg) expression on endogenous antibody repertoires. The transgenic system was chosen as to allow for normal recombination of endogenous Ig genes, secretion of TGIg from early development on, and distinguishing the TGIg from endogenous Ig by several serological markers on the C and V regions of the molecules. The transgenic construct encodes a complete anti-(4-hydroxy-3-iodo-5-nitrophenyl)acetyl (NP) antibody molecule carrying a well-defined idiotype, bearing a λ1 light chain and a chimeric heavy chain encoded by a human α2 C region devoid of its membrane exon, and the murine B1.8 VDJ-region. Endogenous antibody repertoires were analyzed in mitogen-driven limiting dilution cultures, in single-cell assays for naturally activated Ig-secreting cells, and in hybridomas derived by direct fusion of spleen cells from unmanipulated animals. The results show that a very high frequency of splenic resting B cells and plasma cells in transgenic animals produce IgM with B1.8-cross-reactive idiotypes. This was confirmed by hybridoma analysis which also established that the levels of transgene expression and of idiotype-positive IgM production by the same cell are not correlated. The affinities of idiotype-positive endogenous Ig varied, but were generally several orders of magnitude lower than the transgene-encoded idiotype. V regions from idiotype-cross-reactive IgM heavy chains showed marked diversity in sequences that were all different from the transgenic B1.8. These results are compatible with idiotypic mimicry resulting from intercellular selection based on degenerate, whole V region reactivities.
Article
The chapter discusses the ontogeny and phylogeny of adaptive immunity, including the acquisition of passive and active immunity by the developing fetus in relation to the phylogenetic development of active immunologic responses and relates immunologic capacity to the function of the thymus and of the bursa of Fabricus. The development of the lymphoid system plays a key role in development of the potential for adaptive immune response. Absence of the thymus during the period of development of the peripheral lymphoid tissues results in both abnormal lymphoid development and immunologic deficiency. In phylogeny, the data suggest that the transition to adaptive immunity occurs in the lower vertebrates and that it is paralleled by the development of a lymphoid thymus, other organized lymphoid tissues, and the lymphoid system of cells. The ontogenesis of immunity is discussed in terms of the following relationships and processes : interrelationship of fetus and mother, particularly serum immunoglobulin and antibody transfer; the beginning production of immunoglobulins during fetal and neonatal life; the origins of antibody-producing capacity and ability to initiate and express delayed allergic responses; the development of capacity for homograft rejection and the decrease of susceptibility to production of tolerance in the fetal and neonatal period; and the key role of the thymus and other central lymphoid tissue in the ontogeny of the lymphoid system and adaptive immunity. The studies of the lower fishes havenot been sufficiently comprehensive particularly with the more sophisticated methods of protein chemistry that are yielding such important information concerning the nature and interrelationships of the immunoglobulins.
Article
Zusammenfassung Die Frage nach den Wirkungen, die die Injektion embryonaler Zellen an einen höheren Organismus nach sich ziehen kann, wird diskutiert. Eine Versuchsanordnung wird gewählt, die es erlaubt, unter Ausschluß eigener Reaktionen des Wirtsorganismus den Nachweis wachstumssteigernder Stoffe aus Embryonalzellen zu erbringen. Eine verbesserte Methode zur Transplantation von Gewebe auf die Gefäßmembranen von Hühnerembryonen wird beschrieben. Mit dieser Methode wird der Einfluß transplantierter embryonaler Leberstückchen auf die Organe, insbesondere die Lebern der Wirtstiere, untersucht. In keinem Fall konnte eine Beeinflussung des Wachstums und der Zusammensetzung der Organe (DNS, RNS und Protein) beobachtet werden.
Article
Summary Immunological tolerance denominates a specific unresponsiveness of the lymphoid system on a cellular level. The phenomenon is preceded by specific recognition of the tolerogen. — Induction of tolerance is possible in the immunologically incompetent as well as the competent organism. — The achievement of immunological tolerance depends on the complexity of the antigen used. In the case of biological antigens increasing the genetic disparity between donor and recipient always increases the antigen complexity. In adults, the induction of immunological tolerance toward cells of another subject is possible only when both of them are highly compatible. In immunological immature subjects the number of potential tolerogens is larger. It can be assumed therefore that immunological tolerance develops under quantitatively and/or qualitatively different conditions in immature individuals. — The persistence of tolerance seems to be dependent on the continuous presence of the tolerogen. — The various known hypotheses of the development of immunological tolerance are discussed and a new one is presented. This theory is based on the following premises: (a) The phagocytic function of macrophages is a necessary step for the evocation of the immunological response. After phagocytosis and processing, the antigenicity of the antigen is increased. (b) Antigens of small or missing adjuvanticity can react directly with lymphocytes to block their immune response. Such antigens are not or to a lesser extent taken up by macrophages. (c) Blocked lymphocytes cannot be activated by antigens previously processed by macrophages. Once activated, lymphocytes can no longer be blocked. Considering the kinetics of these simultaneous processes of phagocytosis and blocking reactions, the phenomena of high and low zone tolerance as well as partial tolerance can be explained.
Article
Formation of ring zones in virus-infected animal tissues 2. Analysis of the phenomenon of annular zone formation in the chorioallantois of the chick embryo infected with fowl pox virus La formation de zones annulaires dans le tissu animal infecté par un virus. 2eme communication: analyse du phénomène de la formation de zones annulaires dans la membrane chorio-allantoidienne de l'embryon de poulet infecté par le virus de la variole aviaire La formacion de la zona anular en los tejidos animales infectados por virus 2a Communicación: Anàlisis del fenómeno de formacion de la zona anular en las membranas corioalantoideas del embrión de pollo infectadas con difteroviruela aviar
Chapter
Biological “Laws” of Transplantation.The mechanism of the immunological responseAntibodiesInflammationThe passive transfer of immunityThe route of immunizationResponse to pharmacologically active compoundsThe antigenic stimulus; antigenic transformationsThe prolongation of the life of homograftsThe action of adrenal hormonesThe effect of pregnancyExposure to foreign cells in foetal life: “actively acquired tolerance’.ReferencesDiscussion
Article
The research briefly summarized here covers 38 years of work in cellular immunology, chiefly devoted to understanding how antigen subserves the antithetical functions of stimulating antibody formation and inducing tolerance. The three interlocking themes running through the work are the development of methods to beat the problem of heterogeneity among lymphocytes by studying single cells and single clones; critical pursuit of antigen-trapping patterns within lymphoid tissues and analysis of consequent cellular events; and construction of models of tolerance that permit the detection of events subtler than direct purging of the B cell repertoire. One of the best features of this adventure has been its international character, the interaction with colleagues in many countries, and the influence that this work, despite its entirely fundamental character, has exerted in the practical world of preventive and clinical medicine.
Article
Experiments were carried out to determine the relative susceptibility of guinea pigs at different ages to the virus of epidemic influenza. From a correlation of these studies on the mature fetus, the newborn, and the adult animal, with previously reported findings on the immature fetus, we draw two conclusions: first, that there is a gradually increasing resistance to infection with this virus during intrauterine development, with but little change thereafter; and second, that at the time of birth there is a sudden loss of infectibility by routes other than the intranasal. These results illustrate then the benefits which may accrue if one projects into the period of antenatal life studies dealing with the age factor in relation to susceptibility to infection. It is implied that data collected from observations of the postnatal animal alone are of necessity incomplete and may be misleading.
Article
A small mouse stock in which lymphocytic choriomeningitis is endemic has been observed over a period of 4 years. The disease has persisted during that time, but it has become so mild that it can no longer be recognized by clinical observation. In spite of this fact, all of the stock mice tested, both young and old, carried considerable amounts of virus in their organs and blood. The females readily transmit the infection to their offspring. Intrauterine infection has become the only mode of transmission of the disease in contrast to the situation in 1935 when a certain number of mice were born virus-free and became infected by contact shortly after birth. The present mildness of the disease appears to be due to two factors, namely, the change in its mode of transmission just mentioned, and a shift in the severity of the disease with regard to the age of the host at the time of infection. This shift has occurred gradually since 1935 when the mice infected in utero were the only ones to become sick. Since 1937, however, the virus is quite harmless for such animals and produces symptoms only in suckling mice from the virus-free stock exposed to contact infection. Evidence is presented which suggests that the shift in the severity of the disease was caused by a decrease of the pathogenicity of the virus for embryonic mouse tissue and a concurrent increase of the resistance to intrauterine infection of the mice from the infected stock. Another change noted concerned the communicability of the experimental disease. In contrast to observations made in 1935 the experimental infection of mature mice from the virus-free colony is now very rarely transmitted by contact to healthy mice, young or old. Suckling mice from the same stock infected by intranasal instillation of virus, however, readily transmit the disease and continue to do so as they grow up. The same is true for mice infected naturally. The reason for this discrepancy has not been ascertained, but it has been shown that naturally infected mice capable of transmitting the disease in general discharge large amounts of virus through the nose for a longer period of time than mature mice infected experimentally which fail to transmit their infection. It may likewise be of significance in this connection that the virus can lose its communicability by animal passage. A marked change (chiefly climatic and dietary) in the environmental conditions of the infected stock failed to influence the course and character of the epidemic.
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