Augmented designs to assess immune response in vaccine trials

This article introduces methods for use in vaccine clinical trials to help determine whether the immune response to a vaccine is actually causing a reduction in the infection rate. This is not easy because immune response to the (say HIV) vaccine is only observed in the HIV vaccine arm. If we knew what the HIV-specific immune response in placebo recipients would have been, had they been vaccinated, this immune response could be treated essentially like a baseline covariate and an interaction with treatment could be evaluated. Relatedly, the rate of infection by this baseline covariate could be compared between the two groups and a causative role of immune response would be supported if infection risk decreased with increasing HIV immune response only in the vaccine group. We introduce two methods for inferring this HIV-specific immune response. The first involves vaccinating everyone before baseline with an irrelevant vaccine, for example, rabies. Randomization ensures that the relationship between the immune responses to the rabies and HIV vaccines observed in the vaccine group is the same as what would have been seen in the placebo group. We infer a placebo volunteer's response to the HIV vaccine using their rabies response and a prediction model from the vaccine group. The second method entails vaccinating all uninfected placebo patients at the closeout of the trial with the HIV vaccine and recording immune response. We pretend this immune response at closeout is what they would have had at baseline. We can then infer what the distribution of immune response among placebo infecteds would have been. Such designs may help elucidate the role of immune response in preventing infections. More pointedly, they could be helpful in the decision to improve or abandon an HIV vaccine with mediocre performance in a phase III trial.     

Naturally occurring genetic variation in the age-specific immune response of Drosophila melanogaster

Immunosenescence, the age‐related decline in immune response, is a well‐known consequence of aging. To date, most studies of age‐related changes in immune response focused on the cellular and physiological bases of this decline; we have virtually no understanding of the genetic basis of age‐related changes in the immune system or if indeed such control exists. We used 25 chromosome substitution lines of Drosophila melanogaster derived from a natural population to address three questions: (i) How is the function of the innate immune system influenced by age? (ii) Is there a genetic basis for phenotypic variation in immune response at different ages? (iii) Is there a genetic basis for differences in the way that age influences the immune function? Virgin females from each line were assayed for immune response using clearance of infection with Escherichia coli at 1 and 4 weeks of age. We found significant genetic variation among lines in immune response at each age. Unexpectedly, when averaged across all lines, the immune response actually improved with age. However, there was significant variation in the effect of age on immune response with 11 lines showing improvement, nine lines showing no change and five exhibiting a decline with age. There was no genetic correlation of immune response across ages suggesting that different loci contribute to variation in immune response at each age. The genetic component of the variation in immune response increased with age, a pattern predicted by the mutation accumulation model of senescence. However, this increase in variation resulted in part from the improvement of the immune response in some lines with age. Thus the observed changes in genetic variation in immune function with age are not entirely explained by the mutation accumulation model.     

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.     

From network-to-antibody robustness in a bio-inspired immune system

Behavioural robustness at antibody and immune network level is discussed. The robustness of the immune response that drives an autonomous mobile robot is examined with two computational experiments in the autonomous mobile robots trajectory generation context in unknown environments. The immune response is met based on the immune network metaphor for different low-level behaviours coordination. These behaviours are activated when a robot sense the appropriate conditions in the environment in relation to the network current state. Results are obtained over a case study in computer simulation as well as in laboratory experiments with a Khepera II microrobot. In this work, we develop a set of tests where such an immune response is externally perturbed at network or low-level behavioural modules to analyse the robust capacity of the system to unexpected perturbations. Emergence of robust behaviour and high-level immune response relates to the coupling between behavioural modules that are selectively engaged with the environment based on immune response. Experimental evidence leads discussions on a dynamical systems perspective of behavioural robustness in artificial immune systems that goes beyond the isolated immune network response.     

Inbreeding and extreme outbreeding cause sex differences in immune defence and life history traits in Epirrita autumnata

Empirical studies in vertebrates support the hypothesis that inbreeding reduces resistance against parasites and pathogens. However, studies in insects have not found any evidence that inbreeding compromises immune defence. Here we tested whether one generation of brother-sister mating or extreme outbreeding (mating between two populations) have an effect on innate immunity and life history traits in the autumnal moth, Epirrita autumnata. We show that the effect of inbreeding on immune response differed between the sexes: whereas in females, inbreeding significantly reduced encapsulation response against nylon monofilament ability, it did not have a significant effect on male immune response. There were also differences in the correlation of the immune response with other traits: in females increased immune response was positively correlated with large size, whereas in males immune response increased with a reduction in development time. Immune response differed significantly among families in males but not in females, both for the inbreeding and extreme outbreeding experiments. In conjunction with the observed immune responses to inbreeding, these data suggest that in males genetic variation for immune response is largely additive or non-directional with respect to dominance, whereas in females variation is much reduced and consists of directional dominance variance. Further, we show that encapsulation response against nylon monofilament is associated with the resistance against real pathogens suggesting that this widely used method to measure the strength of immune defence in insects is also a biologically relevant method.     

Does the strength of an immune response reflect its energetic cost?

The energetic cost of immune responses has been proposed to be an important basis for trade-offs between life-history traits, such as between survival and reproduction. A critical assumption of this hypothesis is that the magnitude of the energetic cost increases with the strength of an immune response, so that energy can be saved by partly suppressing a response. Here, we test this assumption experimentally. The immune system of great tits Parus major was experimentally activated by injecting different doses of phytohemagglutinin (PHA) in the wing web. We found the resting metabolic rate of immune challenged birds to increase by 5%. However, although great tits injected with a high dose had a stronger immune response, this was not paralleled by a higher metabolic rate. Thus, we found the energetic cost of the immune response to be relatively low and not dose-dependent. This suggests to us that the energetic cost of immune responses cannot form the basis for trade-offs between life-history traits.     

Is Hypothalamic GABA Involved in Immune Function in Relation to Dietary Protein During Aging?

Hypothalamic GABAergic activity and immune response in spleen were not significantly changed with the increase of age from 3 to 6 months in adult male albino rats. Further increase of age from 6 to 9 months increased the GABAergic activity and decreased the cell viability in spleen without any change in its T-lymphocyte cytotoxicity. Consumption of low protein diet (LPD) for a short-term period (STP; 7 consecutive days) increased the hypothalamie GABAergic activity without changing the immune response in 3 months old rats. When supplemented for a long-term period (LTP; 30 consecutive days) to 3 months old rats, a reduction of hypothalamie GABAergic activity and the immune response was observed. Intake of high protein diet (HPD) for both STP and LTP increased the GABAergic activity and immune response, but the increase of GABAergic activity in hypothalamus under STP was greater than that observed under LTP. In 6 months old rats consumption of LPD for STP reduced the GABAergic activity without any alteration of its immune response. Long-term supplementation of this LPD to the same age group increased GABAergic activity and the mitotic activity of spleen cells without any alteration of the functional activity of the T-cells in spleen. Consumption of HPD for STP failed to produce any change in hypothalamic GABAergic activity and the immune response of 6 months old rats. Supplementation of HPD for LTP reduced the hypothalamic GABAergic activity and the immune response of the same age group. The reduction in hypothalamic GABAergic activity without any change in the immune response was observed following the supplementation of low protein diet to 9 months old rat for STP. Intake of the LPD for LTP also reduced the hypothalamie GABAergic activity and the mitotic activity of the spleen cells without any alteration of the functional activity of the T-cells in spleen of 9 months old rats. Supplementation of HPD for STP to this aged rat, on the other hand, failed to produced any change in hypothalamic GABAergic activity and the immune response. Intake of HPD for LTP by this aged rats increased the hypothalamie GABAergic activity along with the immune response. The results of this study, thus, suggest that hypothalamic GABAergic activity during aging is an index of immune response and it is modulated following the short- and long-term consumption of protein poor and protein rich diet.     

Ontogeny of Toll-Like Receptor Mediated Cytokine Responses of South African Infants throughout the First Year of Life

The first year of life represents a time of marked susceptibility to infections; this is particularly true for regions in sub-Saharan Africa. As innate immunity directs the adaptive immune response, the observed increased risk for infection as well as a suboptimal response to vaccination in early life may be due to less effective innate immune function. In this study, we followed a longitudinal cohort of infants born and raised in South Africa over the first year of life, employing the most comprehensive analysis of innate immune response to stimulation published to date. Our findings reveal rapid changes in innate immune development over the first year of life. This is the first report depicting dramatic differences in innate immune ontogeny between different populations in the world, with important implications for global vaccination strategies.     

Heat shock proteins as potential targets in the therapy of inflammatory arthritis

Whether heat shock proteins (hsp) will be therapeutic targets in arthritis depends on their role in pathogenesis. In this article, three possibilities are considered. Firstly, an excessive immune response to bacterial hsp could be arthritogenic — as may occur in reactive arthritis. In these circumstances therapy would be directed to down-regulating this immune response, or altering the nature of the immune response e.g. by changing cytokine production from interferon-g to IL-4. However this approach depends on the immune response to bacterial hsp not being critical for control of the bacterial infection. Secondly, an immune response to bacterial hsp may induce autoimmunity by cross-reactivity, e.g. with the homologous human. This could also be modulated in the same way with a lower likelihood of interfering with control of the infectious agent, since only a component of the immune response against the bacterial hsp will be cross-reactive with self. Thirdly, recent experiments raise the possibility that joint inflammation might be controlled by T cells which recognizes self hsp, particularly hsp60. Therapies might enhance this response; protection from experimental arthritis by prior immunization with hsp60 is well established. Whether similar approaches will be viable after arthritis is established remains to be seen.     

Use of Human CD4 Transgenic Mice for Studying Immunogenicity of HIV-1 Envelope Protein gp120

HIV-1 envelope protein, gp120, is a major immunogenic protein of the AIDS virus. A specific feature of this protein is its interaction with the receptor protein, human CD4, an important component of the immune system. This interaction might affect the immunogenic properties of the gp120 and modulate the immune response towards HIV. To test this hypothesis we used human CD4-transgenic mice for immunization with gp120. The dynamics of the immune response towards gp120, CD4 and other proteins was followed. The results show that the primary immune response to gp120 (two weeks) developed somewhat faster in CD4-transgenic mice versus non-transgenic mice. Both animals, however, ultimately mounted the same level of response over time. The primary immune response to gp120 when complexed with soluble CD4 before the immunization, developed similarly in both groups. The secondary immune response was earlier and markedly stronger in non-transgenic mice compared with the transgenic mice where a less efficient memory response to gp120 was observed. The ability of gp120 to directly interact with CD4+ helper lymphocytes appears to affect the humoral response towards this antigen. Moreover, these effects illustrate how viral modulation of these cells may in turn lead to potentially different states of immunological equilibrium.     

Immunology of Dermatophytosis

The immune response to infection by dermatophytes ranges from a non-specific host mechanism to a humoral and cell-mediated immune response. The currently accepted view is that a cell-mediated immune response is responsible for the control of dermatophytosis. Indeed, some individuals develop a chronic or recurrent infection mediated by the suppression of a cell-mediated immune response. The immune response to Trichophyton is unusual in that this fungus can elicit both immediate hypersensitivity (IH) and delayed-type hypersensitivity (DTH) in different individuals when they are submitted to a skin test reaction. Understanding the nature and function of the immune response to dermatophytes is an exciting challenge that might lead to novel approaches in the treatment and immunological prophylaxis of dermatophytosis.     

Senescence in immune priming and attractiveness in a beetle

Age‐related decline in immune activity is referred to as immunosenescence and has been observed for both the adaptive immune response of vertebrates and the innate immune system of invertebrates. Because maintaining a basic level of immune defence and mounting an immune response is costly, optimal investment in immune function should vary over a wide range of individual states such as the individual’s age. In this study, we tested whether the immune response and immunological priming within individuals become less efficient with age using mealworm beetles, Tenebrio molitor, as a model organism. We also tested whether ageing and immunological priming affected the odours produced by males. We found that young males of T. molitor were capable of mounting an immune response a sterile nylon monofilament implant with the potential to exhibit a simple form of immune memory through mechanisms of immune priming. Older males did not increase their immune response to a second immune challenge, which negatively affected their sexual attractiveness and remaining life span. Our results indicate that the immune system of older males in T. molitor is less effective, suggesting complex evolutionary trade‐offs between ageing, immune response and sexual attractiveness.     

抗系统性白念珠菌感染的先天性免疫

白念珠菌是引起浅部、深部真菌感染常见的病原菌.先天免疫反应在宿主抗系统性白念珠菌感染中起主导作用.介导宿主抗念珠菌感染的先天性免疫包括一系列真菌识别受体及免疫效应细胞.宿主对系统性白念珠菌感染的免疫反应是决定患者预后的关键.本文就宿主抗系统性白念珠菌感染的先天性免疫机制进行综述.     

Immune proteasomes and immunity

A lot of facts that require understanding have been accumulated since immune proteasomes were discovered and their relationship with the immune response was established. For example, why are immune proteasomes present in all studied mammalian organs and tissues, including nonlymphoid tissues? What is responsible for differences in the ratio of immune to constitutive proteasomes in different organs? Are the functions of immune proteasomes related to the immune response alone, as was shown initially, or not? Are immune proteasomes formed simultaneously in different organs during ontogenesis? An attempt is made in this review to answer these and other related questions.     

Stability and Hopf bifurcation for a five-dimensional virus infection model with Beddington–DeAngelis incidence and three delays

In this paper, the dynamical behaviours for a five-dimensional virus infection model with three delays which describes the interactions of antibody, cytotoxic T-lymphocyte (CTL) immune responses and Beddington–DeAngelis incidence are investigated. The reproduction numbers for virus infection, antibody immune response, CTL immune response, CTL immune competition and antibody immune competition, respectively, are calculated. By using the Lyapunov functionals and linearization method, the threshold conditions on the local and global stability of the equilibria for infection-free, immune-free, antibody response, CTL response and interior, respectively, are established. The existence of Hopf bifurcation with immune delay as a bifurcation parameter is investigated by using the bifurcation theory. Numerical simulations are presented to justify the analytical results.     

猪胞内劳森菌感染的免疫应答与检测技术研究进展

胞内劳森菌(Lawsonia intracellularis, LI)常引起猪精神不振、食欲减退、血样下痢或突然死亡,严重损害养猪业。猪群感染该菌在肠道诱导免疫应答的研究较少。因该菌胞内寄生,基于细菌不同感染阶段动物免疫应答特点,检测方法会有所侧重。本文重点阐述了胞内劳森菌感染后机体免疫应答的特点,并对其检测技术进行综述,以期为新型检测技术研发及疫病防控提供参考。     

Immune proteasomes and immunity

A lot of facts that require understanding have been accumulated since immune proteasomes were discovered and their relationship with the immune response was established. For example, why are immune proteasomes present in all studied mammalian organs and tissues, including nonlymphoid tissues? What is responsible for differences in the ratio of immune to constitutive proteasomes in different organs? Are the functions of immune proteasomes related to the T-cell immune response alone, as was shown initially, or not? Are immune proteasomes formed simultaneously in different organs during ontogenesis? An attempt is made in this review to answer these and other related questions.     

Suppression of antigen-specific lymphocyte activation in modeled microgravity

Various parameters of immune suppression are observed in lymphocytes from astronauts during and after a space flight. It is difficult to ascribe this suppression to microgravity effects on immune cells in crew specimens, due to the complex physiological response to space flight and the resultant effect on in vitro immune performance. Use of isolated immune cells in true and modeled microgravity in immune performance tests, suggests a direct effect of microgravity on in vitro cellular function. Specifically, polyclonal activation of T-cells is severely suppressed in true and modeled microgravity. These recent findings suggest a potential suppression of oligoclonal antigen-specific lymphocyte activation in microgravity. We utilized rotating wall vessel (RWV) bioreactors as an analog of microgravity for cell cultures to analyze three models of antigen-specific activation. A mixed-lymphocyte reaction, as a model for a primary immune response, a tetanus toxoid response and a Borrelia burgdorferi response, as models of a secondary immune response, were all suppressed in the RWV bioreactor. Our findings confirm that the suppression of activation observed with polyclonal models also encompasses oligoclonal antigen-specific activation.     

Pathogen responses to host immunity: the impact of time delays and memory on the evolution of virulence

Current analytical models of the mammalian immune system typically assume a specialist predator-prey relationship between invading pathogens and the active components of the immune response. However, in reality, the specific immune system is not immediately effective following invasion by a novel pathogen. First, there may be an explicit time delay between infection and immune initiation and, second, there may be a gradual build-up in immune efficacy (for instance, during the period of B-cell affinity maturation) during which the immune response develops, before reaching maximal specificity to the pathogen. Here, we use a novel theoretical approach to show that these processes, together with the presence of long-lived immune memory, decouple the immune response from current pathogen levels, greatly changing the dynamics of the pathogen-immune system interaction and the ability of the immune response to eliminate the pathogen. Furthermore, we use this model to show how distributed primary immune responses combine with immune memory to greatly affect the optimal virulence of the pathogen, potentially resulting in the evolution of highly virulent pathogens.     

Control of Drosophila Blood Cell Activation via Toll Signaling in the Fat Body

The Toll signaling pathway, first discovered in Drosophila, has a well-established role in immune responses in insects as well as in mammals. In Drosophila, the Toll-dependent induction of antimicrobial peptide production has been intensely studied as a model for innate immune responses in general. Besides this humoral immune response, Toll signaling is also known to activate blood cells in a reaction that is similar to the cellular immune response to parasite infections, but the mechanisms of this response are poorly understood. Here we have studied this response in detail, and found that Toll signaling in several different tissues can activate a cellular immune defense, and that this response does not require Toll signaling in the blood cells themselves. Like in the humoral immune response, we show that Toll signaling in the fat body (analogous to the liver in vertebrates) is of major importance in the Toll-dependent activation of blood cells. However, this Toll-dependent mechanism of blood cell activation contributes very little to the immune response against the parasitoid wasp, Leptopilina boulardi, probably because the wasp is able to suppress Toll induction. Other redundant pathways may be more important in the defense against this pathogen.