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Postirradiation volatile secretions of mice: syngeneic and allogeneic immune and behavioral effects.

The immune response in immunologically and olfactorily high- and low-reactive CBA and C57Bl/6 mice is almost similarly decreased after exposure to volatile secretions of syngeneic animals exposed to ionizing radiation in a dose of 4 Gy. In the preference/avoidance test intact animals prefer secretions of irradiated syngeneic and allogeneic animals to those of intact animals, while without irradiation animals of both strains prefer syngeneic secretions. C57Bl/6 mice differ from CBA animals by lower sensitivity.

Animal Communication↗

Effects of flavonoids on immune and inflammatory cell functions.

No doubt can remain that the flavonoids have profound effects on the function of immune and inflammatory cells as determined by a large number and variety of in vitro and some in vivo observations. That these ubiquitous dietary chemicals may have significant in vivo effects on homeostasis within the immune system and on the behavior of secondary cell systems comprising the inflammatory response seems highly likely but more work is required to strengthen this hypothesis. Ample evidence indicates that selected flavonoids, depending on structure, can affect (usually inhibit) secretory processes, mitogenesis, and cell-cell interactions including possible effects on adhesion molecule expression and function. The possible action of flavonoids on the function of cytoskeletal elements is suggested by their effects on secretory processes. Moreover, evidence indicates that certain flavonoids may affect gene expression and the elaboration and effects of cytokines and cytokine receptors. How all of these effects are mediated is not yet clear but one important mechanism may be the capacity of flavonoids to stimulate or inhibit protein phosphorylation and thereby regulate cell function. Perhaps the counterbalancing effect of cellular protein tyrosine phosphatases will also be found to be affected by flavonoids. Some flavonoid effects can certainly be attributed to their recognized antioxidant and radical scavenging properties. A potential mechanism of action that requires scrutiny, particularly in relation to enzyme inhibition, is the redox activity of appropriately configured flavonoids. Finally, in a number of cell systems it seems that resting cells are not affected significantly by flavonoids but once a cell becomes activated by a physiological stimulus a flavonoid-sensitive substance is generated and interaction of flavonoids with that substance dramatically alters the outcome of the activation process.

Animals↗

The placebo puzzle: putting together the pieces.

This article outlines and assesses the main theories of the placebo effect and suggests how they might sit together in a larger model of placebo etiology. Among the approaches considered are expectancy theory, emotional change theory, classical conditioning, and the biological approach. Although these are sometimes assumed to be competing models, in many cases they shed light on different pans of the placebo puzzle. Expectancies are the core of most placebo effects in human beings. The effects of expectancies are sometimes unmediated but in other cases are mediated by changes in emotional state, immune system function, perception, or behavior. Although expectancies are implicated in most placebo effects, a small number of placebo effects may be solely attributable to nonconscious contingency learning.

Affect↗

Insect feeding mobilizes a unique plant defense protease that disrupts the peritrophic matrix of caterpillars.

Plants frequently respond to herbivorous insect attack by synthesizing defense proteins that deter insect feeding and prevent additional herbivory. Maize (Zea mays L.) lines, resistant to feeding by a number of lepidopteran species, rapidly mobilize a unique 33-kDa cysteine protease in response to caterpillar feeding. The accumulation of the 33-kDa cysteine protease in the maize mid-whorl was correlated with a significant reduction in caterpillar growth that resulted from impaired nutrient utilization. Black Mexican Sweetcorn callus transformed with mir1, the gene encoding the 33-kDa cysteine protease, expressed the protease and growth of caterpillars reared on the transgenic callus was reduced 60-80%. Scanning electron microscopy was used to examine the effect of plant material expressing the 33-kDa cysteine protease on the structure of the caterpillar peritrophic matrix. Because the peritrophic matrix surrounds the food bolus, assists in digestive processes, and protects the caterpillar midgut from physical and chemical damage, disruption of peritrophic matrix may reduce caterpillar growth. The results indicated that the peritrophic matrix was severely damaged when caterpillars fed on resistant maize plants or transgenic Black Mexican Sweetcorn. The accumulation of the 33-kDa cysteine protease in response to caterpillar feeding, and its ability to damage the insect peritrophic matrix, represents an unusual host-plant resistance mechanism that may have applications in agricultural biotechnology.

Animals↗

The hypothalamic-pituitary-adrenal axis and viral infection.

The hypothalamic-pituitary-adrenal (HPA) axis plays an important immunomodulatory role during viral infection. Activation of the HPA axis ultimately leads to elevated plasma levels of glucocorticoid (GC) hormones with the ability to mediate adaptive behavioral, metabolic, cardiovascular and immune system effects. In this review, we focus on the modulation of anti-viral immunity and viral pathogenesis by the HPA axis.

Animals↗

Human cytotoxic CD8+ T-lymphocyte clones engraft in severe combined immunodeficient (SCID) mice but show diminished function.

Mice with severe combined immunodeficiency (SCID) provide an in vivo model for studying interactions between human tumor cells and effector cells of the immune system. We studied the behavior of human alloreactive cytotoxic T lymphocytes (CTLs) in SCID mice, including the migration pattern of CD8+ or CD4+ CTL clones to various murine tissues, their engraftment in the absence or presence of recombinant human interleukin 2 (rhIL-2) compared with the engraftment of lymphokine activated killer (LAK) cells, and the in vitro as well as the in vivo function of the engrafted CTL clones. The polymerase chain technique using T-cell-receptor-gamma specific primers revealed the presence of human CD8+ CTL clones in the blood, lungs, and liver of mice receiving rhIL-2 for 14 days, for at least 18 days after intravenous inoculation. Human T cells were transiently detected in the bone marrow, lymph nodes, thymus, and spleen. Although the three CD8+ CTL clones and two CTL lines tested required rhIL-2 for their engraftment, the four LAK cell populations also engrafted in the absence of rhIL-2. In contrast to CD8+ T cells, only low frequencies (<1%) of CD4+ cells could be detected in the blood of the SCID mouse. Engrafted human T cells recovered from the murine blood showed absent or diminished cytotoxicity in vitro against human target cells in five or six experiments, respectively. In addition, when the antitumor activity of engrafted CD8+ clones was investigated in vivo using a xenotransplantation model of human B-cell lymphoma in SCID mice, no significant prolongation of the mean survival time of six treated animals was observed compared with animals treated with rhIL-2 alone. Our results illustrate that although in vitro primed and cultured human CD8+ T cells engraft in SCID mice, their in vitro and in vivo function is impaired.

Animals↗

Analysis of nonlinear properties of immune network reactions.

On the basis of biochemical reaction dynamics, the temporal behavior of the immune network system was analyzed theoretically to promote the analysis of quantitative changes in the reactions of immune disorders and organ substitution. The idiotype immune network reaction system was expressed by 64 nonlinear differential equations that comprised four kinds of antibodies and B-cell subpopulations. All four kinds of antibodies decreased rapidly. With the progress of the reactions, they have increased gradually. The single and double bound antibodies increased rapidly from the onset of the reaction. The single-bound antibodies did not show a definite increase after the rapid increasing phase. The antibody-antibody complex increased parallel with the double bound antibodies. The effects of rate constant expand to all the immune complexes in the network system. The double bound antibodies and antibody-antibody complexes were oscillatory functions of a given antibody. Therefore, the idiotypic immune network system must be a chaotic one. The present theoretical method is available to evaluate the total ability of immune reaction system that operates as a network system.

Antibodies↗

Regulation of autoimmune disease physiological and therapeutic.

An important question is how the immune system can control the behavior of autoimmune effector lymphocytes. My colleagues and I have investigated this question in four models. Three models of organ specific autoimmune diseases were studied using the specific autoimmune lines or clones of T lymphocytes functionally involved in the disease process. The fourth model was an anti-idiotypic network triggered spontaneously by autoantibodies. This article reviews the evidence indicating that healthy individuals can carry potentially virulent autoimmune T lymphocytes without symptoms. This carrier state of autoimmunity implies the existence of natural mechanisms of counter-autoimmunity. One natural element appears to be clones of suppressor-inducer T lymphocytes that arise in the course of the autoimmune response. We have discovered that autoimmune effector T lymphocytes can serve as inducers of their own suppression either artificially, by manipulating the T cell membrane, or naturally, by exposing the individual to very low concentrations of some effector T cell clones. Regarding the regulation of autoreactive B lymphocytes, we have observed that spontaneous generation of anti-idiotypic antibodies may have a particular bias for autoantibody idiotypes. Counter-autoimmunity appears to involve recognition of the self-reactive lymphocyte receptors resulting in the activation of suppressor cells. These suppressor cells can prevent disease or cause remission of established disease.

Animals↗

Immunity, inflammation, and remodeling in the airway epithelial barrier: epithelial-viral-allergic paradigm.

The concept that airway inflammation leads to airway disease has led to a widening search for the types of cellular and molecular interactions responsible for linking the initial stimulus to the final abnormality in airway function. It has not yet been possible to integrate all of this information into a single model for the development of airway inflammation and remodeling, but a useful framework has been based on the behavior of the adaptive immune system. In that paradigm, an exaggeration of T-helper type 2 (Th2) over Th1 responses to allergic and nonallergic stimuli leads to airway inflammatory disease, especially asthma. In this review, we summarize alternative evidence that the innate immune system, typified by actions of airway epithelial cells and macrophages, may also be specially programmed for antiviral defense and abnormally programmed in inflammatory disease. Furthermore, this abnormality may be inducible by paramyxoviral infection and, in the proper genetic background, may persist indefinitely. Taken together, we propose a new model that highlights specific interactions between epithelial, viral, and allergic components and so better explains the basis for airway immunity, inflammation, and remodeling in response to viral infection and the development of long-term disease phenotypes typical of asthma and other hypersecretory airway diseases.

Animals↗

Molecular genetic analysis of glucocorticoid signaling using the Cre/loxP system.

Glucocorticoids (GC) are involved in a plethora of physiological processes that range from the regulation of the stress response and the control of the immune system to modulation of behavior. Most GC effects are mediated by the glucocorticoid receptor (GR) via activation and repression of gene expression. Whereas in most cases activation requires DNA binding of the receptor, repression is usually mediated by protein-protein interaction with other transcription factors. To decipher the molecular mode of action of GR, mice were generated by gene targeting carrying a point mutation in one of the dimerization domains, thus abrogating DNA binding by GR. Analysis of these mice demonstrated that thymocyte apoptosis and stress erythropoiesis require the DNA binding-dependent function of GR, whereas lung development and the anti-inflammatory activity of GR are mediated by protein-protein interaction. Furthermore, to study the role of GC in the brain, mice were generated specifically lacking GR function in the nervous system. Using these mice we demonstrated that GR is essential for the regulation of the HPA-axis and the stress response, as well as for the control of emotional behavior. Taken together, gene targeting using the Cre/loxP system proved to be highly valuable for the analysis of both molecular mechanism and tissue-specific functions of the GR.

Animals↗

Immunoenhancing property of dietary whey protein in mice: role of glutathione.

The spleen cells immune response to sheep red blood cells of C3H/HeJ mice fed a 20 g whey protein/100 g diet is substantially higher than that of mice fed an equivalent casein diet of similar nutritional efficiency. The present study indicates that the observed immunoenhancing effect of the whey protein mixture is dependent on the overall amino acid pattern resulting from the contribution of all its protein components. Whey protein contains substantially more cysteine than casein. Dietary cysteine is considered to be a rate limiting substrate for the synthesis of glutathione which is necessary for lymphocyte proliferation. Our studies show that enhancement of host humoral immune response is associated with greater and more sustained production of splenic glutathione during the antigen driven clonal expansion of the lymphocyte in whey protein fed mice in comparison to mice fed the equivalent casein or the cysteine-enriched casein diet. Hence the efficiency of dietary cysteine in inducing supernormal glutathione levels is greater when it is delivered in the whey protein than as free cysteine. Administration of S-(n-butyl) homocysteine sulfoximine, which reduces splenic glutathione level by half, produces a 4-5 fold drop in the humoral immune response of whey protein diet-fed mice. This is further evidence of the important role of glutathione in the immunoenhancing effect of dietary whey protein.

Animals↗

Interactions between the neuroendocrine and immune systems: common hormones and receptors.

The studies reviewed here support a molecular basis for bidirectional communication between the immune and neuroendocrine systems. The main findings can be summarized as follows: First, cells of the immune system can synthesize biologically active neuroendocrine peptide hormones. Second, immune cells also possess receptors for many of these peptides. Third, these same neuroendocrine hormones can influence immune function; and fourth, lymphokines can influence neuroendocrine tissues. Although recent studies have begun to unravel the biochemistry of bidirectional communication between the immune and neuroendocrine systems, there are still missing parts in this puzzle. Among the important questions that must be resolved are the identification of factors that trigger the synthesis of neuroendocrine hormones by immune cells. Are these events operating similar to or in balance with pituitary cells? Drugs that interfere with either pathway may be useful. Second, it will be of value to understand the factors controlling neuroendocrine hormone receptor expression on immune cells. A better understanding of the spectrum of positive and negative regulatory events for both systems may determine the ultimate behavior of immune and neuroendocrine cells. In addition, since leukocytes can produce hormones and also have receptors for the same hormones (e.g., ACTH and GH), it is possible that these immunocytes may also influence their own function in an autocrine-like fashion. We have postulated that the immune system can serve as a sensory organ for external stimuli that cannot be detected by the nervous system (Blalock 1984). Thus, the immune system recognizes stimuli such as bacteria, viruses or tumors, whereas the nervous system detects classical sensory stimuli. The contribution of extrapituitary sites of hormone production and function may provide new clues to define psychological and/or pathological states in the pathophysiology of infectious diseases and tumors.

Animals↗

Immunomorphological characteristics of animals with different levels of orientation and exploratory behavior.

We revealed some relationships between the level of orientation and exploratory behavior, functional activity of the immune system, and structural and functional organization of the CNS in animals. Significant differences in brain morphology and expression of cytokine IL-1 beta, type I IL-1 receptor, and erythropoietin receptor genes in brain cells were detected in (CBA x C57Bl/6)F1 mice with different initial levels of orientation and exploratory behavior. Immunocompetent cells of mice with high and low levels of exploratory behavior differ by spontaneous and mitogen-induced proliferative activity. The formation of humoral and cellular immune response in these animals causes opposite changes in exploratory behavior and the type of these changes depends on the initial level of this behavioral reaction.

Animals↗