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Critical, but conditional, role of OX40 in memory T cell-mediated rejection.

Memory T cells can be a significant barrier to the induction of transplant tolerance. However, the molecular pathways that can regulate memory T cell-mediated rejection are poorly defined. In the present study we tested the hypothesis that the novel alternative costimulatory molecules (i.e., ICOS, 4-1BB, OX40, or CD30) may play a critical role in memory T cell activation and memory T cell-mediated rejection. We found that memory T cells, generated by either homeostatic proliferation or donor Ag priming, induced prompt skin allograft rejection regardless of CD28/CD154 blockade. Phenotypic analysis showed that, in contrast to naive T cells, such memory T cells expressed high levels of OX40, 4-1BB, and ICOS on the cell surface. In a skin transplant model in which rejection was mediated by memory T cells, blocking the OX40/OX40 ligand pathway alone did not prolong the skin allograft survival, but blocking OX40 costimulation in combination with CD28/CD154 blockade induced long-term skin allograft survival, and 40% of the recipients accepted their skin allograft for >100 days. In contrast, blocking the ICOS/ICOS ligand and the 4-1BB/4-1BBL pathways alone or combined with CD28/CD154 blockade had no effect in preventing skin allograft rejection. OX40 blockade did not affect the homeostatic proliferation of T cells in vivo, but markedly inhibited the effector functions of memory T cells. Our data demonstrate that memory T cells resisting to CD28/CD154 blockade in transplant rejection are sensitive to OX40 blockade and suggest that OX40 is a key therapeutic target in memory T cell-mediated rejection.

4-1BB Ligand↗

Control of memory CD4 T cell recall by the CD28/B7 costimulatory pathway.

The CD28/B7 costimulatory pathway is generally considered dispensable for memory T cell responses, largely based on in vitro studies demonstrating memory T cell activation in the absence of CD28 engagement by B7 ligands. However, the susceptibility of memory CD4 T cells, including central (CD62L(high)) and effector memory (T(EM); CD62L(low)) subsets, to inhibition of CD28-derived costimulation has not been closely examined. In this study, we demonstrate that inhibition of CD28/B7 costimulation with the B7-binding fusion molecule CTLA4Ig has profound and specific effects on secondary responses mediated by memory CD4 T cells generated by priming with Ag or infection with influenza virus. In vitro, CTLA4Ig substantially inhibits IL-2, but not IFN-gamma production from heterogeneous memory CD4 T cells specific for influenza hemagglutinin or OVA in response to peptide challenge. Moreover, IL-2 production from polyclonal influenza-specific memory CD4 T cells in response to virus challenge was completely abrogated by CTLA4Ig with IFN-gamma production partially inhibited. When administered in vivo, CTLA4Ig significantly blocks Ag-driven memory CD4 T cell proliferation and expansion, without affecting early recall and activation. Importantly, CTLA4Ig treatment in vivo induced a striking shift in the phenotype of the responding population from predominantly T(EM) in control-treated mice to predominantly central memory T cells in CTLA4Ig-treated mice, suggesting biased effects of CTLA4Ig on T(EM) responses. Our results identify a novel role for CD28/B7 as a regulator of memory T cell responses, and have important clinical implications for using CTLA4Ig to abrogate the pathologic consequences of T(EM) cells in autoimmunity and chronic disease.

Abatacept↗

Individual variation in the spatial reference and working memory assessed under allothetic and idiothetic orientation cues in rat.

The present study was designed to examine which kind of memory: reference or working, better correlates with individual variation in rats' spatial learning abilities. To answer this question two groups of rats were trained to an arbitrary criterion in a partially baited 12-arm radial maze under two different experimental conditions: with or without allothetic cues. After 10 days break, rats were examined under the same conditions for memory retention. Within- and between-group variation in the length of training to criterion, and in the frequency of reference and working memory errors were analysed. The present experiment confirmed the facilitating effect of the presence of distal visual cues on place learning in rats. Task-dependent (between-group) differences in the rate of learning were attributed to differences in the frequency of reference memory errors. Conversely, within-group variation in the rate of task acquisition reflected individual variation in the frequency of working memory errors. These results were looked upon from an evolutionary perspective. Low correlation between reference and working memory errors confirms that these two types of memory have different mechanisms. The fact that differences in the rate of learning were not paralleled by the differences in the memory retention supports the notion that memory acquisition and memory retention are two independent processes.

Animals↗

Radiotherapeutic effects on brain function: double dissociation of memory systems.

OBJECTIVE: The neurocognitive sequelae of therapeutic cranial irradiation are not well characterized in adults with primary brain tumors. To address this problem, we prospectively examined neuropsychological findings during two phases of radiation effects. BACKGROUND: Investigations of radiation effects have revealed variable outcomes that range from no radiation-associated morbidity to severe cognitive impairment, but have relied on case reports or retrospective studies of late-delayed changes in white matter or in cognition. No reliable radiographic or neurocognitive tools exist to describe the multiple phases of radiation effects. METHOD: Twenty adult patients (median age, 39 years) from a university hospital were treated with radiotherapy (RT) for low-grade primary brain tumors. Prospective longitudinal neuropsychological studies were compared at baseline (after surgery and before irradiation) and at 3, 6, and 12 months after RT to examine early-delayed effects, including verbal memory changes in 20 patients and visual memory changes in 11 patients. We also examined cognitive changes during the late-delayed phase for up to 3 years after RT and determined whether early-delayed memory deficit predicted late-delayed memory deficit in a small subset of patients. A comprehensive neuropsychological battery was used, including verbal and visual memory tests designed to compare learning, storage, and retrieval. RESULTS: Patients demonstrated normal verbal memory at baseline, decrement, and then rebound in verbal retrieval. Deficit at baseline and recovery up to 1 year after RT defined visual memory. Together, these observations constitute a double dissociation of memory functions. No changes over time were observed in other neurocognitive tests or in fatigue or mood measures. Time-dependent patterns of each long-term memory test were examined in relation to lesion site in individual patients. CONCLUSIONS: The double dissociation of memory functions after RT may provide markers for the damaging and facilitative early-delayed effects of RT. Late-delayed effects were not predicted based on early-delayed changes in a small sample.

Adult↗

[The effect of hemodialysis on the virgin CD45RA+, CD45RO- and memory CD45RO+, CD45RA- lymphocyte count in patients with chronic renal failure].

UNLABELLED: The hallmark of immunological memory is a quick and effective response to a repeated antigen exposure. Virgin lymphocytes, with their surface receptors CD45RA+, CD45RO- are produced in primary lymphatic organs, then migrating to secondary lymphatic structures. Memory lymphocytes CD45RO+, CD45RA- produced in these organs migrate to non-lymphatic organs--a possible location of inflammatory process, thus enabling the immunological system to eliminate effectively the same antigen, when repeatedly present. The aim of the study was 1) to test the influence of hemodialysis on the number of virgin lymphocytes and/or memory lymphocytes; 2) whether such impact (if any) depends on the type of dialysis membrane used (cuprophan or polysulphon), 3) if the effect is different in patients with or without diabetes. Overall number of virgin T helper lymphocytes CD45RA+CD4+ was significantly lower in patients with end-stage renal disease, while the number of total CD45RO+, CD45RA- memory lymphocytes was significantly greater among patients with diabetic nephropathy, compared to normal control subjects. After 15 minutes of hemodialysis, number of virgin lymphocytes CD45RA+, CD45RO- (p < 0.001, p < 0.01) and their subclasses, as well as memory lymphocytes CD45RO+, CD45RA- were significantly decreased. After 15 minutes of hemodialysis with polysulphon membrane, the decrease in T virgin cytotoxic, B virgin CD45RA+CD4-, T memory cytotoxic as well as B memory CD45RO+CD4- lymphocytes was significantly lower, when compared with cuprophan membrane (p < 0.02). Among patients treated with cuprophan hemodialysis, the decrease of T helper memory CD45RO+CD4+ lymphocytes was significantly lower in patients with diabetic nephropathy, than in non-diabetic patients. CONCLUSIONS: In all patients with end-stage renal disease, the impact of hemodialysis on the number of memory lymphocytes CD45RO+, CD45RA-, as well as virgin lymphocytes CD45RA+, CD45RO- was shown, but the effect was less profound during hemodialysis with polysulphon membrane, compared to cuprophan. The presence of diabetic nephropathy effects the hemodialysis-induced changes in the number of T memory helper CD45RO+ CD45RO+CD4+ lymphocytes, with no impact on other subclasses of the examined cells.

Adult↗

[Interactions between the hippocampus and the amygdala in synaptic plasticity processes. A key to understanding the relations between motivation and memory].

INTRODUCTION: Memory is initially stored as a transitory change that can become consolidated and converted into a long term memory trace. Consolidation largely depends on the emotional state. It is known that the hippocampus plays a role in the consolidation process of certain types of memory and that the amygdala might modulate the consolidation of the memory traces in other parts of the brain. The interaction between these two structures is crucial in many forms of learning and memory. METHOD: The hippocampus, as well as the amygdala, display a type of synaptic plasticity known as long term potentiation (LTP), which is considered to be a cellular memory mechanism. Recently, it has been reported that the consolidation of the hippocampal LTP may be modulated, like memory, by the emotional state and by the activation of the basolateral amygdala. These findings, taken as a whole, can help to explain how the processes of consolidation of memory take place. At the same time they also constitute a more physiological model of the learning and memory processes, which will provide us with a more accurate understanding of the mechanisms behind the consolidation of the memory.

Amygdala↗

Inhibition of conditioned stimulus pathway phosphoprotein 24 expression blocks the development of intermediate-term memory in Hermissenda.

Studies of memory consolidation have identified multiple phases or stages in the formation of memories. The multiple components of memory can be broadly divided into the three phases; short-term, intermediate-term, and long-term. Although molecular changes underlying short- and long-term memory have been examined extensively, the molecular mechanisms supporting the formation of intermediate-term memory are poorly understood. In several examples of cellular and synaptic plasticity, intermediate memory depends on translation but not transcription. One-trial conditioning in Hermissenda results in the development of intermediate memory that is associated with enhanced cellular excitability and the phosphorylation of a 24 kDa protein referred to as conditioned stimulus pathway phosphoprotein (Csp24). Using amino acid sequences derived from Csp24 peptide fragments, a full-length cDNA was cloned and shown to contain multiple beta-thymosin-like domains. The expression of Csp24 and the development of enhanced excitability, a characteristic of intermediate memory, were blocked by antisense oligonucleotide-mediated downregulation of Csp24 without affecting the induction of immediate enhanced excitability, a characteristic of short-term memory. These results demonstrate that the synthesis of Csp24 is required for the development and maintenance of intermediate memory.

Action Potentials↗

[Subjective and objective assessment of memory functions in patients with schizophrenia treated with olanzapine].

Schizophrenic patients often complain of intellectual functioning impairment. The aim of this survey was to define the subjective memory loss by means of objective tests. The tests were carried out in three steps: before the admission to the clinic, after 6 weeks of hospitalisation, and after approximately 12 months from the beginning of the olanzapine treatment, 36 patients were examined (9 female, 27 male) aged 20-53 (X = 25.4). The following tests were applied: PANSS, Memory Questionnaire (Squire, Zouzounis 1988), subscales: Digit span and Similarities of the Wechsler Intelligence Scale, subtest for Long-term memory of the Choynowski's Memory Scale, Diagnosis of Brain Damages (Weidlich, Lamberti), Clock Completion Test, Decroly Box. The subjective assessment of memory functioning improved during the treatment with olanzapine. Before the hospitalisation and after 6 weeks of treatment patients' memory complaints were associated with the visuospatial memory. After 12 month of the olanzapine therapy the memory complaints were associated with audioverbal memory. Age, level of education and objective intensity of psychopathological symptoms did not influence patients' subjective assessment of memory functioning.

Adult↗

Activation of mitogen-activated protein kinase/extracellular signal-regulated kinase in hippocampal circuitry is required for consolidation and reconsolidation of recognition memory.

Consolidation and reconsolidation of long-term memory have been shown to be dependent on the synthesis of new proteins, but the specific molecular mechanisms underlying these events remain to be elucidated. The mitogen-activated protein kinase (MAPK) pathway can trigger genomic responses in neurons, leading to changes in protein synthesis, and several studies have identified its pivotal role in synaptic plasticity and long-term memory formation. In this study, we analyze the involvement of this pathway in the consolidation and reconsolidation of long-term recognition memory, using an object recognition task. We show that inhibition of the MAPK pathway by intracerebroventricular injection of the MEK [MAPK/extracellular signal-regulated kinase (ERK)] inhibitor UO126 blocks consolidation of object recognition memory but does not affect short-term memory. Brain regions of the entorhinal cortex-hippocampal circuitry were analyzed for ERK activation, and it was shown that consolidation of recognition memory was associated with increased phosphorylation of ERK in the dentate gyrus and entorhinal cortex, although total expression of ERK was unchanged. We also report that inhibition of the MAPK pathway blocks reconsolidation of recognition memory, and this was shown to be dependent on reactivation of the memory trace by brief reexposure to the objects. In addition, reconsolidation of memory was associated with an increase in the phosphorylation of ERK in entorhinal cortex and CA1. In summary, our data show that the MAPK kinase pathway is required for both consolidation and reconsolidation of long-term recognition memory, and that this is associated with hyperphosphorylation of ERK in different subregions of the entorhinal cortex-hippocampal circuitry.

Animals↗

Role of neuropeptides in antidepressant and memory improving effects of venlafaxine.

The aim of this study has been to investigate the effects of vasopressin and oxytocin on antidepressive and memory improving effects of venlafaxine. Male Wistar rats weighing 180-200 g were used in the study. Venlafaxine (20 mg/kg) was administered po 30 min before the test once, and for 7 and 14 days in the chronic experiments. Oxytocin (1 microg/kg) ip and vasopressin (1 microg/kg) sc were administered only once on the test day, 60 min before the tests. The animals were subjected to Porsolt's test for testing antidepressant activity, and their memory functions (working and spatial memory) were evaluated in the maze test and Morris Water Maze test. Antidepressant effects of venlafaxine could be observed already after single drug administration and the effect was maintained during 7 days of drug administration. Oxytocin also exhibited antidepressant activity, and concurrent administration of venlafaxine and oxytocin helped to maintain antidepressant activity of venlafaxine. Vasopressin was devoid of antidepressant action, yet concurrent administration of vasopressin and venlafaxine did not suppress antidepressant activity of the latter. In the chronic experiment, there was no shortening of passive swimming time. Venlafaxine improved memory in the labyrinth test and in the spatial memory test, whereas oxytocin did not affect memory of the tested animals. Joint administration of venlafaxine and oxytocin did not produce memory improving effect observed after administration of venlafaxine only. Vasopressin improved memory and joint administration of venlafaxine and vasopressin maintained the memory improving effect induced by vasopressin. The regulatory role of neuropeptides and new antidepressant drugs, e.g. venlafaxine in mood status and memory functions may depend on the interactions between monoaminergic and neuropeptidergic systems.

Animals↗

Memory impairment in patients with cirrhosis.

BACKGROUND AND AIM: Subclinical hepatic encephalopathy (HE) in cirrhotic patients is usually characterized by memory impairment and psychomotor slowing. Our aim was to investigate memory status in cirrhotic patients with and without clinically overt HE. MATERIAL AND METHODS: Thirty-two cirrhotic patients (10 female and 22 male) aged 49 +/- 17 years and 20 healthy subjects (six female and 14 male) aged 46 +/- 12 years were included in the study. Memory status was defined by Wechsler Memory Scale, verbal memory process and complex memory process tests. RESULTS: Grade-1 HE was detected in 7 (22%) patients with cirrhosis. We detected 36 to 92% decrement in various memory tests in cirrhotic patients without HE as compared to healthy subjects. The scores for all psychometric testing results were significantly lower in cirrhotic patients without HE as compared to healthy subjects. We detected 42.9 to 100% decrement in various memory tests in cirrhotic patients with HE than cirrhotic patients without HE. However, there was no statistical significant difference between cirrhotic patients with and without HE. There was no statistical significant difference in cirrhotic patients with Child-Pugh A, B, and C. CONCLUSION: In conclusion, memory status was influenced in which patients with cirrhosis yet has a normal mental and neurological status to routine clinical examination (subclinical HE). Occasionally, decreased memory performance may adversely affect the satisfaction and lifestyle of these patients. Therefore, subclinical HE is an important social problem.

Aged↗

[Memory problems among elderly patients in general practice: the importance of caregiver information].

INTRODUCTION: The aim was to describe and analyse signs that make caregivers suspect memory problems among elderly patients in general practice. METHODS: This prospective study was conducted in October and November 2002 among all patients aged 65 or older who consulted a GP in a total of 17 practices in Copenhagen inner city. The patients who agreed to participate were asked to complete a questionnaire regarding memory, quality of life, etc. Their GP completed a questionnaire independently, and a MMSE was subsequently given to the patient. Where consent was obtained from a patient, a postal questionnaire regarding the patient's memory was mailed to a caregiver chosen by the patient. RESULTS: Out of 775 patients 62% (483) gave consent to contact a caregiver. Among the caregivers who received the questionnaire a total of 74% returned the questionnaire. A total of 88 (26%) of the caregivers suspected that the patient had memory problems. Predictors for caregiver suspicion of memory problems were: patient had complained about memory problems to caregiver (OR 21.7), caregiver had received information for other sources that the patient suffered from memory problems (OR 5.0), a MMSE in the interval between 0-24 (OR 4.5) and a low quality of life (OR 3.1). Furthermore, if the patient was male, caregivers were more likely to report memory problems. CONCLUSION: Memory impairment is commonly observed by caregivers, but is rarely discussed with a GP. The results indicate that more focus on the possibility of memory impairment among elderly patients is important in general practice.

Aged↗

[Working memory: neuropsychological and neurobiological issues].

Working memory denotes an ability to remember information for a short-time and to manipulate it. The memory allows including correct information depending on the situation, to keep the information on present activities for a while and enables changing the reaction according to new criteria. The relation between working memory and efficiency of complex cognitive processes and also with the control of emotional processes, plasticity of behaviour and consciousness was demonstrated. Working memory is connected with the activity of the dorsolateral prefrontal cortex of the brain. Recently, it has been shown, that working memory disturbances play an important role in the aetiopathogenesis of psychiatric disturbances such as schizophrenia, bipolar affective disorder or obsessive-compulsive disorder. Working memory disturbances are also shown in a proportion of healthy first-degree relatives of patients with schizophrenia or bipolar disorders. Working memory disturbances are presently regarded as a cognitive endophenotypic marker of vulnerability to these illnesses. In recent years, an association between working memory abilities and activity of different neurotransmitters, especially with the dopaminergic system in the brain, has been shown. Molecular genetic studies show an association between working memory abilities and polymorphism of the dopaminergic system genes in schizophrenia and polymorphism of BDNF gene in bipolar affective disorders. So far not much data about the genetics of working memory in healthy subjects has been gathered. Currently in Poland such research is carried on in the Clinical Neuropsychology Unit Nicolaus Copernicus University, Collegium Medicum in Bydgoszcz in cooperation with the Department of Adult Psychiatry and Laboratory of Psychiatric Genetics University of Medical Sciences in Poznań.

Bipolar Disorder↗

Memory for two types of spatial location: effects of instructions, age, and format.

Three experiments, with old persons (59-80 years) and college students (17-30 years) in Experiments 1 and 2 and with college students (17-24 years) in Experiment 3, investigated the differences between two types of spatial location memory: memory for the location of individual items in an array and memory for occupied, as opposed to unoccupied, locations in an array. Young persons performed better than old persons on both measures of location memory. However, an effect of instructions (intentional vs. incidental for spatial location) was consistently obtained for memory for occupied, as opposed to unoccupied, locations, whereas no effect of instructions was obtained for memory for individual item locations. In addition, item location memory was superior for objects as opposed to matched words (Experiment 2), whereas occupied location memory was not affected by presentation format (Experiments 2 and 3). These differences indicate that spatial memory is a complex process whose properties are affected by variations in stimulus characteristics and task demands. It was concluded that the distinction of Hasher and Zacks (1979) between automatic and effortful processes is not adequate for understanding spatial memory. A recognition of the complex nature of spatial processing suggests a resolution of discrepancies in the literature based upon differences in stimulus characteristics, task demands, and the effectiveness of task-appropriate mnemonic strategies.

Adolescent↗

Induction of IgG memory responses with polyvinylpyrrolidone (PVP) is antigen dose dependent.

Irradiated recipients of spleen cells from mice primed with a very low dose (0.0025 microgram) of the thymus-independent (TI) antigen polyvinylpyrrolidone (PVP) produced PVP-specific IgG memory responses after secondary challenge with a T-dependent (TD) form of PVP, PVP-HRBC. The IgG memory responses induced by low doses of PVP were similar in magnitude to those induced by the TD antigen PVP-HRBC. The induction of IgG memory by the TI form of antigen was markedly dependent on the dose of PVP used to prime donor mice. Spleen cells from mice primed with an amount of PVP (0.25 microgram) that induces an optimal primary IgM response did not produce significant IgG antibody after challenge with PVP-HRBC. The inability of higher doses of PVP to induce IgG memory may be due, at least in part, to the fact that such doses of PVP were found to induce tolerance in PVP-specific B cells and could suppress the induction of memory induced by PVP-HRBC. Low doses of PVP did not interfere with the induction of memory by PVP-HRBC. Expression of IgG memory responses in recipients of PVP-HRBC or low-dose PVP-primed cells was found to be T cell dependent. Moreover, only primed T cells could reconstitute the response of recipients of primed B cells, suggesting that the ability of PVP to induce IgG memory may be related to its ability to prime T helper cells. Expression of the IgG memory response in recipient mice also required the use of a TD antigen for secondary challenge, i.e., mice challenged with PVP did not develop IgG. The inability of PVP to elicit IgG antibody was due in part to the fact that 0.25 microgram PVP was tolerogenic, i.e., it could interfere with the expression of memory in mice simultaneously challenged with both PVP and PVP-HRBC.

Animals↗

Memory effectors: a potent, IL-4-secreting helper T cell population that develops in vivo after restimulation with antigen.

Resting CD4+ memory T cells from the spleens of mice primed more than 6 wk earlier with KLH in adjuvant produce IL-2 and IL-3, but only low levels of IL-4 and IFN-gamma, and undetectable IL-5 after specific restimulation in vitro. In contrast, when previously primed mice are boosted by i.v. injection of soluble KLH, a CD4+ T cell population develops in the spleen that can produce greatly increased levels of IL-4, and variably increased IL-2, IFN-gamma, and/or IL-3. The ability of these memory effector Th cells to be restimulated to secrete cytokines is maximal by 3 days after in vivo boosting with Ag, and declines rapidly thereafter. Memory effector Th are induced in the spleens of KLH-primed mice that have been depleted of precursor T cells by thymectomy more than 25 wk previously, suggesting that they are derived from a memory T cell population. Cell separation on the basis of CD45RB or MEL-14, surface markers that are down-regulated on memory CD4+ cells, indicates that memory effector Th are in the CD45RBlo and MEL-14- subsets of CD4+ T cells. The frequency of KLH-specific splenic CD4+ T cells with the capacity to secrete cytokines in limiting dilution cultures is very low in unprimed mice (1/3 x 10(4) to 1/9 x 10(4)), but increases as much as 50-fold after priming. IL-2, but not IL-4, can be detected in the supernatants of stimulated unprimed CD4+ T cells. Both IL-2- and IL-4-producing cells are readily detected after priming, and frequencies of IL-2-secreting cells (1/250 to 1/4000) are up to ninefold greater than those for IL-4 secreting cells. Boosting elicits variable (two to eightfold) increases in the frequencies of both IL-2- and IL-4-producing CD4+ T cells. However, high IL-4 titers associated with memory effector Th function can be obtained when significant frequency changes are not detected after boosting. The data suggest that reactivation of resting memory Th in vivo induces their differentiation into effector Th with the capacity to secrete much higher levels of IL-4. Although the capacity to produce high levels of IL-4 is associated with both primary and memory CD4+ effector populations, memory effector Th are the higher producers.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

Administration of lanthanum chloride following a reminder induces a transient loss of memory retrieval in day-old chicks.

Lanthanum chloride (5.0 mM) administered immediately after a visual reminder presented to day-old chickens between 7.5 min and 48 h following a single trial passive avoidance learning task produced an immediate but transient loss of memory on retention test, an effect not observed in the absence of a reminder. The duration of the transient deficit was relatively stable with lanthanum chloride consistently inducing a loss of memory that was evident 5 min after the reminder, with recovery by 10-15 min. The results suggest that, for a period of at least up to 48 h after passive avoidance training, the activation of memory retrieval by a reminder stimulus may lead to processes which are sensitive to inhibition by the calcium channel antagonist lanthanum chloride. These results extend previously reported findings implicating the involvement of glutamate-sensitive channels in a transient memory process that is also activated as a result of a reminder stimulus, but that is no longer present 48 h after training. The glutamate-sensitive mechanism appears to be a secondary mechanism activated following memory retrieval and to be dependent on the level of memory consolidation that the memory for the original experience has undergone. The results presented here suggest that lanthanum chloride, a calcium channel antagonist, inhibits memory retrieval in the day-old chick. This effect implicates calcium channel mediated processes in immediate memory recall. Further, the results suggest the lanthanum inhibits a primary mechanism, that precedes that glutamate-sensitive mechanism identified previously and that both are dependent on the activation of memory retrieval by a reminder.

Animals↗

Memory T cell development in the absence of specific antigen priming.

Numerous studies have shown that memory T cell development is Ag dependent and specific. In the present study, we show that memory responses can be made against an Ag to which there has been no prior exposure. In unimmunized DO11.10 mice, which carry alpha and beta transgenes that encode a TCR specific for OVA, CD45RB(low) memory cells express the transgenic TCR. These cells can be stimulated by OVA to proliferate and perform typical memory functions, such as secrete diverse lymphokines and provide cognate help to B cells, despite the fact that the mice were never exposed to OVA. Thus, memory cells can be generated in the absence of specific Ag. The data also demonstrate that the transgenic TCR-bearing memory T cells possess endogenous TCR alpha-chains, which permit the expression of a second TCR. In DO11.10/RAG(-/-) mice, the endogenous alpha-chains are eliminated, and the T cells can only express the transgenic TCR. In these mice, no memory cells were observed. Thus, it is the additional TCR that appears to drive memory cell generation. Once induced, memory function may be triggered through the transgenic receptor. Since dual TCR-bearing cells have been shown to exist in nontransgenic mice and humans, our results provide evidence that one mechanism for the maintenance of memory responses to a specific Ag is through stimulation of the second TCR by another Ag. Further, these findings have important implications for understanding aberrant immune responses, such as those that occur in autoimmunity.

Animals↗