Mechanisms for induction of acquired host immunity by neutrophil peptide defensins

Human neutrophil peptide (HNP) defensins were studied to determine their potential effects on adaptive mucosal immunity. Intranasal delivery of HNPs plus ovalbumin (OVA) enhanced OVA-specific serum IgG antibody (Ab) responses. However, OVA-specific IgA Abs were not induced in mucosal secretions or in serum. CD4(+) T cells of intranasally immunized mice displayed higher OVA-specific proliferative responses and elevated production of interferon gamma, interleukin (IL) 5, IL-6, and IL-10 when compared with control groups receiving OVA alone. In vitro, HNPs also enhanced both proliferative responses and T helper (Th) cytokine secretion profiles of CD3epsilon-stimulated spleen- and Peyer's patch-derived naive CD4(+) T cells. HNPs modulated the expression of costimulatory molecules by lipopolysaccharide- or CD3epsilon-stimulated splenic and Peyer's patch B or T cell populations, respectively. These studies show that defensins enhance systemic IgG, but not IgA, Ab responses through help provided by CD4(+) Th1- and Th2-type cytokines and foster B and T cell interactions to link innate immunity with the adaptive immune system.     

Mechanisms of predictive and diagnostic causal induction.

In predictive causal inference, people reason from causes to effects, whereas in diagnostic inference, they reason from effects to causes. Independently of the causal structure of the events, the temporal structure of the information provided to a reasoner may vary (e.g., multiple events followed by a single event vs. a single event followed by multiple events). The authors report 5 experiments in which causal structure and temporal information were varied independently. Inferences were influenced by temporal structure but not by causal structure. The results are relevant to the evaluation of 2 current accounts of causal induction, the Rescorla-Wagner (R. A. Rescorla & A. R. Wagner, 1972) and causal model theories (M. R. Waldmann & K. J. Holyoak, 1992). (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Mechanisms of induction of apoptotic DNA fragmentation

PURPOSE: Despite its common use as an indicator of apoptosis, little is known about the mechanisms controlling apoptotic DNA fragmentation in irradiated cells. This review discusses the pathways of chromatin fragmentation, and the role of both nucleases and chromatin structure in this process. DEFINITIONS: DNA fragmentation linked to apoptosis is a combination of cleavage events excising both large DNA fragments within the range 0.4-1.0 Mbp and 50 kbp followed by random cuts within internucleosomal regions (i.e. DNA laddering). The first two cleavage steps can be detected in virtually all apoptotic cells, but DNA laddering is not ubiquitously observed. Endonucleases that mediate this cleavage of chromatin may be classified by substrate specificity, mode of DNA cleavage and their cofactor requirements. CONCLUSIONS: Three major pathways of DNA fragmentation are proposed and discussed: (1) upregulation of endonucleases, (2) their intranuclear/intracellular redistribution and (3) primary changes of chromatin structure.     

Efficient induction of protective anti-malaria immunity by recombinant adenovirus

The immunogenicity of a previously constructed replication-defective recombinant adenovirus expressing the CS protein of Plasmodium yoelii was compared with that of irradiated sporozoites. We found that immunization of BALB/c mice with a single dose of this recombinant adenovirus induced a much greater CS-specific T-cell response compared with immunization with irradiated sporozoites. More importantly, we found that this recombinant adenovirus induces similar or higher levels of protective immunity than those induced by irradiated sporozoites, eliciting an appreciable resistance to malaria infection.     

Mechanisms of intrathymic tolerance induction to isolated rat hepatocyte allografts

Intrathymic injection of alloantigen in young adult rats is capable of mediating long-lived transplantation tolerance. In this study, we use a well-defined model of isolated hepatocyte transplantation to define the mechanisms of intrathymic induced tolerance. The recipient rats are Nagase analbuminemic rats (NAR) that are deficient in albumin, to allow for following transplant acceptance using metabolic and genetic markers. Tolerance to allogeneic hepatocyte transplants could be mediated by intrathymic injection of live allogeneic splenocytes, lethally irradiated splenocytes, or isolated hepatocytes. Intrathymic injection of live allogeneic splenocytes, but not of hepatocytes or irradiated splenocytes, resulted in donor microchimerism in peripheral lymphoid organs, with preferential expansion of CD4-positive T cells in the recipient spleens. Tolerance could be adoptively transferred from tolerant animals to naive recipients, but only from those animals that had been inoculated with intrathymic donor splenocytes. We conclude that donor microchimerism is found after intrathymic inoculation of live splenocytes, but is not required for tolerance induction and that microchimerism is not an absolute requirement for the generation of regulatory cells.     

Antitumor immunity induction by intracellular hyperthermia using magnetite cationic liposomes

Induction of antitumor immunity to T-9 rat glioma by intracellular hyperthermia using functional magnetic particles was investigated. Magnetite cationic liposomes (MCLs), which have a positive surface charge, were used as heating mediators for intracellular hyperthermia. Solid T-9 glioma tissues were formed subcutaneously on both femurs of female F344 rats, and MCLs were injected via a needle only into the left solid tumors (treatment side). The rats were then divided into two groups, which received no irradiation, or irradiation for 30 min given three times at 24-h intervals with an alternating magnetic field (118 kHz, 384 Oe). On the treatment side, the tumor tissue disappeared completely in many rats exposed to the magnetic field. The tumor tissue on the opposite side also disappeared completely, even though MCLs were not injected into the right solid tumors. To examine whether a long-lasting and tumor-specific immunity could be generated, the rats that had been cured by the hyperthermia treatment were rechallenged with T-9 cells 3 months later. After a period of transient growth, all tumors disappeared. Furthermore, immunocytochemical assay revealed that the immune response induced by the hyperthermia treatment was mediated by both CD8+ and CD4+ T cells and accompanied by a marked augmentation of tumor-selective cytotoxic T lymphocyte activity. These results suggest that our magnetic particles are potentially effective tools for hyperthermic treatment of solid tumors, because in addition to killing of the tumor cells by heat, a host immune response is induced.     

Oligomannose-coated liposomes as an adjuvant for the induction of cell-mediated immunity

Rats were exposed prenatally to the coplanar congener 3,3',4,4'-tetrachlorobiphenyl (TCB). The amount of long-term potentiation (LTP) was measured in slices from the visual cortex and hippocampus of the adult males as well as of controls. While in the cortical slices from the controls a stable LTP could be induced, LTP was inhibited in the TCB-exposed rats. In hippocampal slices, the amount of LTP was not significantly different between the two groups. Our results suggest that the visual cortex of adult animals is functionally altered by TCB if the exposure takes place during embryonic development.     

IL-12 is an effective adjuvant for induction of mucosal immunity

OBJECTIVE: To define those physiologic and clinical variables that have a positive or negative predictive value in discriminating survivors from nonsurvivors with traumatic injuries and a Trauma Score of 5 or less. METHODS: A retrospective review of 2,622 trauma patients transported by an air medical service from the scene of injury to a Level I trauma center was performed. Demographic, physiologic, and clinical variables were evaluated. RESULTS: One hundred thirty-six patients were studied; 14 patients survived trauma resuscitation. Survivors had statistically significant improvement in the Glasgow Coma Scale from the field to arrival in the emergency room. Revised Trauma Score, probability of survival, pulse, respiratory rate, cardiac rhythm, central nervous system activity, and signs of life were statistically more favorable in survivors. CONCLUSION: In patients who survived to discharge, signs of central nervous system activity in the field was a positive predictor of survival, and severe head injury served as a negative predictor of survival.     

The role of macrophages in the induction and regulation of immunity elicited by exogenous antigens

Different delivery vehicles may target to different antigen presenting cells (APC) because of their composition, size and/or physical properties. In this study, we examined the priming of cytotoxic T lymphocyte (CTL) responses to a soluble exogenous protein in vivo, using various delivery vehicles. In addition, we determined the role of macrophages as APC in vivo for each of these delivery vehicles by comparing the induction of antigen-specific CTL and serum antibodies in normal and macrophage-depleted mice. Influenza A virus-derived virosomes, liposomes and monophosphoryl lipid A/squalene (MPLSQ) efficiently induced antigen-specific CTL as well as antibody responses, of which virosomes proved to be the most efficient inducers. In mice that were immunized with cell-associated antigen, strong CTL responses but no antigen-specific antibodies were detectable, while aluminium hydroxide and aluminium phosphate elicited antigen-specific antibodies but no CTL responses. Elimination of macrophages in vivo before immunization abrogated CTL responses induced with liposomes and MPL/SQ, but did not affect induction of antigen-specific CTL with virosomes or cell-associated antigen. Importantly, serum antibody levels were not altered after macrophage depletion, regardless of the delivery vehicle used, suggesting that in the absence of macrophages, other APC may phagocytose the exogenous antigens for major histocompatibility complex (MHC) class II processing and presentation. These results suggest that soluble exogenous antigens delivered in different carrier systems may be processed differently by different APC in vivo for MHC class I- or class II-restricted presentation.     

Mechanisms of cell interaction during primary embryonic induction studied in transfilter experiments

The transmission mechanisms operative at different stages of neutralisation during primary embryonic induction of the newt Triturus vulgaris were studied in experiments employing Nuclepore filters placed between interactive tissue explants. The transmission time of the neuralising effect was determined with 0.2 mum Nuclepore filter. In another series of experiments the transformation of neuralised ectoderm by archenteron roof mesoderm into other parts of the CNS was studied. Although sufficiently long induction times were used no transformation into hindbrain structures could be induced across filters with pore sizes from 0.1 mum to 1.0 mum. However, electron microscopy demonstrated cytoplasmic penetration into 0.6 mum filters at 15 h of induction. The results speak against free long-range diffusion of inductive material at the stage of transformation of the neuralised ectoderm to more caudal parts of CSN and warrant a more detailed structural study of the transmission phenomenon in question.     

Location of induction and expression of protective immunity against Fasciola hepatica at the gut level: a study using an ex vivo infection model with ligated gut segments

PURPOSE: We developed a semiautomatic class solution to irradiate centrally located Stage III non-small cell lung cancer (NSCLC), involving a beam intensity modulation technique and optimization using a biophysical cost function. METHODS AND MATERIALS: Treatment for 10 patients with Stage III NSCLC was planned, using a conventional three- or four-beam three-dimensional (3D) technique and two techniques involving, respectively, seven (BIM1) and five (BIM2) noncoplanar beam incidences with intensity modulation. Two planning target volumes were defined: PTV1 included macroscopic tumor volume and PTV2 included macroscopic and microscopic disease. Beams were divided into beam parts (segments) and their outlines were defined during virtual simulation. Optimization using a biophysical cost function determined beam weights, segment weights, and wedge angles. Biological end points included tumor control probability of both target volumes (TCP1 and TCP2) and normal tissue complication probability (NTCP) of heart, lung, and spinal cord. The resulting uncomplicated local control probability (UCLP) was calculated. Physical end points included dose at PTV1 expressed as a dose minimum and dose maximum. Target-dose inhomogeneity was constrained in all plans. RESULTS: Concerning tumor evaluation, TCP1 was 74% (range 54-89%) for the 3D plan, 78.0% (range 62-94%) for BIM1, and 86.0% (range 59-93%) for BIM2. TCP1*TCP2 was, respectively, 67.0% (range 39-81%), 73.0% (range 56-94%), and 81.0% (range 54-93%). Minimum doses to PTV1 were 85, 80, and 88 Gy with the three respective techniques, while dose maxima were 89, 101, and 100 Gy. NTCPs of lung were 45.0% (range 11-75%) for 3D, 19.5% (range 8-59%) for BIM1, and 24.5% (range 3-61%) for BIM2. NTCPs of heart and spinal cord were comparable for all techniques. ULCPs were 37.0% (range 9-73%), 52.5% (range 22-86%), and 60.0% (range 20-85%), respectively. Applying physical limits to ensure clinical safety, minimum doses at PTV1 were recalculated. These were 72, 71, and 74 Gy for 3D, BIM1, and BIM2, respectively. CONCLUSION: The BIM2 plan is a candidate class solution for dose escalation studies in centrally located Stage III NSCLC.     

Evidence for postsynaptic induction and expression of NMDA receptor independent LTP

Whole cell/patch-clamp and extracellular field potential recordings were used to study the induction and expression of N-methyl-D-aspartate (NMDA) receptor independent long-term potentiation (LTP) in area CA1 of the in vitro rat hippocampus. Induction of NMDA receptor independent LTP was prevented by manipulations that inhibited postsynaptic depolarization during tetanic stimulation: direct hyperpolarization of postsynaptic neurons and bath application of an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and kainate receptor antagonist. NMDA receptor independent LTP also was blocked by intracellular application of the lidocaine derivative, N-(2,6-dimethylphenylcarbamoylmethyl)triethylammonium bromide (QX-314), to CA1 pyramidal neurons. These results complement the previous findings that NMDA receptor independent LTP was inhibited by postsynaptic injections of the calcium chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid and also was inhibited by a L-type voltage-dependent calcium channel antagonist (nifedipine). Collectively, these data make a strong case for the postsynaptic induction of this form of LTP. This paper also provides evidence for postsynaptic expression of NMDA receptor independent LTP. In an experiment where AMPA- and NMDA-receptor-mediated excitatory postsynaptic potentials (EPSPs) were isolated pharmacologically, LTP was found for only the AMPA-receptor-mediated EPSPs. In a separate experiment, paired-pulse facilitation (PPF) was measured during NMDA receptor independent LTP. Although there was an initial decrease in PPF, suggesting a posttetanic increase in the probability of glutamate release, the change in PPF decayed within 30-40 min of the tetanic stimulation, whereas the magnitude of the LTP was constant over this same time period. In addition, the LTP, but not the corresponding change in PPF, was blocked by the metabotropic glutamate receptor antagonist (+/-)-alpha-methyl-4-carboxyphenylglycine. These results are accounted for most easily by a selective increase in postsynaptic AMPA receptor function, but one type of presynaptic modification-an increase in the number of release sites without an overall change in the probability of release-also could account for these results (assuming that the level of glutamate release before LTP induction fully saturated NMDA, but not AMPA, receptors). One possible presynaptic modification, an increase in axon excitability, was ruled out by analysis of the presynaptic fiber volley, which was not increased at any time after LTP induction.     

Mechanisms underlying induction of homosynaptic long-term depression in area CA1 of the hippocampus

The mechanisms responsible for long-lasting, activity-dependent decreases in synaptic efficacy are not well understood. We have examined the initial steps required for the induction of long-term depression (LTD) in CA1 pyramidal cells by repetitive low frequency (1 Hz) synaptic stimulation. This form of LTD was synapse specific, was saturable, and required activation of post-synaptic NMDA receptors. Loading CA1 cells with the Ca2+ chelator BAPTA prevented LTD, whereas lowering extracellular Ca2+ resulted in the induction of LTD by stimulation that previously elicited long-term potentiation. Following LTD, synaptic strength could be increased to its original maximal level, indicating that LTD is reversible and not due to deterioration of individual synapses. Induction of homosynaptic LTD therefore requires an NMDA receptor-dependent change in postsynaptic Ca2+ which may be distinct from that required for long-term potentiation.     

Effects of induction of anti-embryonation and anti-fecundity immunity on liver granuloma formation in mice infected with Schistosoma japonicum

Coronal T2-weighted magnetic resonance imaging (MRI) has been reported to be a useful technique for the localization of both spontaneous and traumatic CSF (cerebro spinal fluid) fistulae. We reviewed the magnetic resonance imaging (MRI) scans of 50 patients with temporal lobe epilepsy in whom such sequences were routinely acquired to determine if this asymptomatic population fulfilled any of the criteria for the diagnosis of a CSF fistula. We found that a large proportion did and conclude that using MRI as the initial radiological investigation in the localization of CSF fistulae is of such low specificity that it is of little or no value.     

Serotype-dependent induction of pulmonary neutrophilia and inflammatory cytokine gene expression by reovirus

Reovirus type 3 Dearing (T3D) causes a prominent neutrophil influx, substantially greater than seen with reovirus type 1 Lang (T1L) in a rat model of viral pneumonia. We sought to measure reovirus-mediated increases in chemokine mRNA expression in pulmonary cells. We found that the neutrophilia induced by T1L and T3D infection in vivo correlated directly with increased levels of chemokine mRNA expression in T3D-infected compared with those of T1IL-infected lungs. In vitro, reovirus-infected normal alveolar macrophages (AMs) and the rat AM cell line NR8383 expressed greater levels of macrophage inflammatory protein 2, KC, and tumor necrosis factor alpha mRNA. A synergism between reovirus and lipopolysaccharide was also detected for macrophage inflammatory protein 2 and KC mRNA expression. Tumor necrosis factor protein secretion was also increased to a greater extent by T3D than by T1L in primary rat AMs and the NR8383 cells. We conclude that the virus-mediated inflammatory cytokine induction suggests a role for these cytokines in the neutrophil influx observed in the rat reovirus pneumonia model.     

Presynaptic induction and expression of homosynaptic depression at Aplysia sensorimotor neuron synapses

The cellular mechanisms underlying the induction and expression of homosynaptic depression at the glutamatergic synapse between Aplysia sensory and motor neurons were studied in dissociated cell culture. Intracellular microelectrodes were used to stimulate action potentials in the presynaptic sensory neuron and record the depolarizing EPSP from the motor neuron. Homosynaptic depression (HSD) was induced by repeatedly stimulating the sensory neuron at rates as low as one action potential per minute. Activation of postsynaptic Glu receptors was neither sufficient nor necessary to induce HSD. Thus, repeated applications of exogenous Glu did not depress the synaptically evoked EPSP. Moreover, normal HSD was observed when the sensory neuron was stimulated during a period when the Glu receptors were blocked with the antagonist DNQX. The induction of HSD is thus likely to occur within the presynaptic terminal. We explored the role of presynaptic calcium in the induction of HSD by injecting the sensory neuron with EGTA, a relatively slow calcium chelator that does not alter rapid release but effectively buffers the slow residual calcium transient thought to be important for plasticity. EGTA had little effect on HSD, indicating that residual Cai is not involved. HSD does not appear to involve a decrease in presynaptic calcium influx, because there was no change in the presynaptic calcium transient, measured by calcium indicator dyes, during HSD. We conclude that HSD is induced and expressed in the presynaptic terminal, possibly by a mechanism directly coupled to the release process.