CXCL13/CXCR5 and CCL19/CCR7 play a quite important role in normal physiological conditions, but t... more CXCL13/CXCR5 and CCL19/CCR7 play a quite important role in normal physiological conditions, but the functions of both chemokine/receptor pairs in pathophysiological events are not well-investigated. We have investigated expression and functions of CXCL13/CXCR5 and CCL19/CCR7 in CD23CD5 and CD23CD5 B cells from cord blood (CB) and patients with B cell lineage acute or chronic lymphocytic leukemia (B-ALL or B-CLL). CXCR5
The protein level of transcriptional coactivator p300, an essential nuclear protein, is critical ... more The protein level of transcriptional coactivator p300, an essential nuclear protein, is critical to a broad array of cellular activities including embryonic development, cell differentiation and proliferation. We have previously established that histone deacetylase inhibitor such as valproic acid induces p300 degradation through the 26S proteasome pathway. Here, we report the roles of cellular trafficking and spatial redistribution in valproic acid-induced p300 turnover. Our study demonstrates that p300 is redistributed to the cytoplasm prior to valproic acid-induced turnover. Inhibition of proteasome-dependent protein degradation, does not prevent nucleo-cytoplasmic shuttling of p300, rather sequesters the cytoplasmic p300 to a distinct perinuclear region. In addition, the formation of p300 aggregates in the perinuclear region depends on functional microtubule networks and correlates with p300 ubiquitination. Our work establishes, for the first time, that p300 is also a substrate of the cytoplasmic ubiquitin-proteasome system and provides insight on how cellular trafficking and spatial redistribution regulate the availability and activity of transcriptional coactivator p300.
PURPOSE To prospectively compare the fMRI pattern in PCC and adjacent precuneus (PCC/precuneus) r... more PURPOSE To prospectively compare the fMRI pattern in PCC and adjacent precuneus (PCC/precuneus) regions between the healthy older adults (HC) and patients with aMCI using simplified 4x4 sudoku puzzles as a problem solving paradigm. METHOD AND MATERIALS Thirteen patients with aMCI (mean age 63.62 years ± 7.75, 9 males), and 13 age, gender and education matched HC (mean age 62.62 years±6.99, 9 males) were underwent MRI at 3.0T. Functional imaging was conducted using a single shot echo planar imaging (SS-EPI) sequence sensitive to blood-oxygen-level-dependent (BOLD) contrast. The fMRI task was a simplified 4×4 sudoku puzzle with complexity. The fMRI tasks were divided into two types according to heuristic rule: using “row rule”or “column rule” to solve the puzzle was simple task, whereas using “both row and column rule” was complex task. Data preprocessing were performed with NeuroImaging Software package (NIS). RESULTS The mean accuracy (ACC) on simple task of HC was significantly hig...
Developmental differences in phonological and orthographic processing of Chinese spoken words wer... more Developmental differences in phonological and orthographic processing of Chinese spoken words were examined in 9-year-olds, 11-year-olds and adults using functional magnetic resonance imaging (fMRI). Rhyming and spelling judgments were made to two-character words presented sequentially in the auditory modality. Developmental comparisons between adults and both groups of children combined showed that age-related changes in activation in visuo-orthographic regions depended on a task. There were developmental increases in the left inferior temporal gyrus and the right inferior occipital gyrus in the spelling task, suggesting more extensive visuo-orthographic processing in a task that required access to these representations. Conversely, there were developmental decreases in activation in the left fusiform gyrus and left middle occipital gyrus in the rhyming task, suggesting that the development of reading is marked by reduced involvement of orthography in a spoken language task that do...
Neural structures change with age but there is no consensus on the exact processes involved. This... more Neural structures change with age but there is no consensus on the exact processes involved. This study tested the hypothesis that white and grey matter in the language network changes during aging according to a "last in, first out" process. The fractional anisotropy (FA) of white matter and cortical thickness of grey matter were measured in 36 participants whose ages ranged from 55 to 79 years. Within the language network, the dorsal pathway connecting the mid-to-posterior superior temporal cortex (STC) and the inferior frontal cortex (IFC) was affected more by aging in both FA and thickness than the other dorsal pathway connecting the STC with the premotor cortex and the ventral pathway connecting the mid-to-anterior STC with the ventral IFC. These results were independently validated in a second group of 20 participants whose ages ranged from 50 to 73 years. The pathway that is most affected during aging matures later than the other two pathways (which are present at b...
The ability to draw numerical inductive reasoning requires two key cognitive processes, identific... more The ability to draw numerical inductive reasoning requires two key cognitive processes, identification and extrapolation. This study aimed to identify the neural correlates of both component processes of numerical inductive reasoning using event-related fMRI. Three kinds of tasks: rule induction (RI), rule induction and application (RIA), and perceptual judgment (Jud) were solved by twenty right-handed adults. Our results found that the left superior parietal lobule (SPL) extending into the precuneus and left dorsolateral prefrontal cortex (DLPFC) were commonly recruited in the two components. It was also observed that the fronto-parietal network was more specific to identification, whereas the striatal-thalamic network was more specific to extrapolation. The findings suggest that numerical inductive reasoning is mediated by the coordination of multiple brain areas including the prefrontal, parietal, and subcortical regions, of which some are more specific to demands on only one of ...
Effective literacy education in deaf students calls for psycholinguistic research revealing the c... more Effective literacy education in deaf students calls for psycholinguistic research revealing the cognitive and neural mechanisms underlying their written language processing. When learning a written language, deaf students are often instructed to sign out printed text. The present fMRI study was intended to reveal the neural substrates associated with word signing by comparing it with picture signing. Native deaf signers were asked to overtly sign in Chinese Sign Language (CSL) common objects indicated with written words or presented as pictures. Except in left inferior frontal gyrus and inferior parietal lobule where word signing elicited greater activation than picture signing, the two tasks engaged a highly overlapping set of brain regions previously implicated in sign production. The results suggest that word signing in the deaf signers relies on meaning activation from printed visual forms, followed by similar production processes from meaning to signs as in picture signing. The...
Although much has been known about how humans psychologically perform data-driven scientific disc... more Although much has been known about how humans psychologically perform data-driven scientific discovery, less has been known about its brain mechanism. The number series completion is a typical data-driven scientific discovery task, and has been demonstrated to possess the priming effect, which is attributed to the regularity identification and its subsequent extrapolation. In order to reduce the heterogeneities and make the experimental task proper for a brain imaging study, the number magnitude and arithmetic operation involved in number series completion tasks are further restricted. Behavioral performance in Experiment 1 shows the reliable priming effect for targets as expected. Then, a factorial design (the priming effect: prime vs. target; the period length: simple vs. complex) of event-related functional magnetic resonance imaging (fMRI) is used in Experiment 2 to examine the neural basis of data-driven scientific discovery. The fMRI results reveal a double dissociation of the...
PURPOSE Healthy ageing has become one of today’s biggest international challenges. However, theor... more PURPOSE Healthy ageing has become one of today’s biggest international challenges. However, theories debate about how neural structures change with age. This study aimed to elucidate this debate by examining the white and grey matter in a large-scale neural network for high cognitive function (i.e., language). METHOD AND MATERIALS Twenty right-handed native Mandarin speakers participated (age ranged from 50 to 73, Mean 61 years, S.D. = 7.23, 11 males and 9 females). They were assessed by the MMSE (>=28, Mean = 29, S.D. = 0.74), and no participant had cognitive complaints or positive signs in the neurological examination. Structural images (T1-MP-RAGE sequence) and DTI were acquired on a 3T scanner (Siemens Trio). All DTI images were processed following the TBSS pipeline, part of FMRIB Software Library. Whole brain FA skeletons were regressed with ages using a general linear model method. Statistical parametric maps were thresholded at a voxel-wise p < 0.001 (uncorrected). Cort...
Cancer stem cells (CSCs) represent a small subset of tumor cells which have the ability to self-r... more Cancer stem cells (CSCs) represent a small subset of tumor cells which have the ability to self-renew and generate the diverse cells that comprise the tumor bulk. They are responsible for local tumor recurrence and distant metastasis. However, they are resistant to conventional radiotherapy and chemotherapy. Novel immunotherapeutic strategies which specifically target CSCs may improve the efficacy of cancer therapy. To immunologically target CSC phenotypes, innate immune responses to CSCs have been reported using NK cells and γδT cells. To target CSC specifically, in vitro CSC-primed T cells have been successfully generated and shown targeting of CSCs in vivo after adoptive transfer. Recently, CSC-based dendritic cell vaccine has demonstrated significant induction of anti-CSC immunity both in vivo in immunocommpetent hosts and in vitro as evident by CSC reactivity of CSC vaccine-primed antibodies and T cells. In addition, identification of specific antigens or genetic alterations in...
Cerebral cortex (New York, N.Y. : 1991), Jan 19, 2014
Alzheimer's disease (AD) is associated not only with regional gray matter damages, but also w... more Alzheimer's disease (AD) is associated not only with regional gray matter damages, but also with abnormalities in functional integration between brain regions. Here, we employed resting-state functional magnetic resonance imaging data and voxel-based graph-theory analysis to systematically investigate intrinsic functional connectivity patterns of whole-brain networks in 32 AD patients and 38 healthy controls (HCs). We found that AD selectively targeted highly connected hub regions (in terms of nodal functional connectivity strength) of brain networks, involving the medial and lateral prefrontal and parietal cortices, insula, and thalamus. This impairment was connectivity distance-dependent (Euclidean), with the most prominent disruptions appearing in the long-range connections (e.g., 100-130 mm). Moreover, AD also disrupted functional connections within the default-mode, salience and executive-control modules, and connections between the salience and executive-control modules. T...
Computer methods and programs in biomedicine, 2014
Current electrocardiogram (ECG) signal quality assessment studies have aimed to provide a two-lev... more Current electrocardiogram (ECG) signal quality assessment studies have aimed to provide a two-level classification: clean or noisy. However, clinical usage demands more specific noise level classification for varying applications. This work outlines a five-level ECG signal quality classification algorithm. A total of 13 signal quality metrics were derived from segments of ECG waveforms, which were labeled by experts. A support vector machine (SVM) was trained to perform the classification and tested on a simulated dataset and was validated using data from the MIT-BIH arrhythmia database (MITDB). The simulated training and test datasets were created by selecting clean segments of the ECG in the 2011 PhysioNet/Computing in Cardiology Challenge database, and adding three types of real ECG noise at different signal-to-noise ratio (SNR) levels from the MIT-BIH Noise Stress Test Database (NSTDB). The MITDB was re-annotated for five levels of signal quality. Different combinations of the 1...
Accurate foetal electrocardiogram (FECG) morphology extraction from non-invasive sensors remains ... more Accurate foetal electrocardiogram (FECG) morphology extraction from non-invasive sensors remains an open problem. This is partly due to the paucity of available public databases. Even when gold standard information (i.e derived from the scalp electrode) is present, the collection of FECG can be problematic, particularly during stressful or clinically important events.In order to address this problem we have introduced an FECG simulator based on earlier work on foetal and adult ECG modelling. The open source foetal ECG synthetic simulator, fecgsyn, is able to generate maternal-foetal ECG mixtures with realistic amplitudes, morphology, beat-to-beat variability, heart rate changes and noise. Positional (rotation and translation-related) movements in the foetal and maternal heart due to respiration, foetal activity and uterine contractions were also added to the simulator.The simulator was used to generate some of the signals that were part of the 2013 PhysioNet Computing in Cardiology ...
International journal of biological sciences, 2007
Administration of anti-4-1BB mAb has been found to be a potent adjuvant when combined with other ... more Administration of anti-4-1BB mAb has been found to be a potent adjuvant when combined with other therapeutic approaches, e.g. chemotherapy, cytokine therapies, anti-OX40 therapy, and peptide or DC vaccines. However, the adjuvant effect of anti-4-1BB mAb administration in adoptive T cell therapy of cancer has not been fully evaluated. In this report, effector T cells were generated in vitro by anti-CD3/anti-CD28 activation of tumor-draining lymph node (TDLN) cells and used in an adoptive immunotherapy model. While T cells or anti-4-1BB alone showed no therapeutic efficacy in mice bearing macroscopic 10-day pulmonary metastases, T cells plus anti-4-1BB mediated significant tumor regression in an anti-4-1BB dose dependent manner. Mice bearing microscopic 3-day lung metastases treated with T cells alone demonstrated tumor regression which was significantly enhanced by anti-4-1BB administration. NK cell depletion abrogated the augmented therapeutic efficacy rendered by anti-4-1BB. Cell t...
Using murine tumor-draining lymph node (TDLN) cells, we investigated the polarization effect of 4... more Using murine tumor-draining lymph node (TDLN) cells, we investigated the polarization effect of 4-1BB (CD137) during CD28 costimulation in generating antitumor T cells. Costimulation of TDLN cells through the newly induced 4-1BB molecules, CD3, and CD28 using monoclonal antibodies significantly enhanced cell proliferation. The greater cell yield with 4-1BB signaling appeared to be related to the inhibition of activation-induced cell death. Activation of TDLN cells through 4-1BB in addition to CD3/CD28 signaling shifted T-cell responses toward a type 1 cytokine pattern because 4-1BB ligation plus CD3/CD28 stimulation significantly augmented type 1 cytokine (e.g., IFN-gamma) and granulocyte macrophage colony-stimulating factor secretion. By contrast, type 2 cytokine (e.g., interleukin 10) secretion by the activated TDLN cells was significantly reduced. The in vivo antitumor reactivity of TDLN cells activated through 4-1BB in conjunction with CD3/CD28 pathways was examined using an ado...
CXCL13/CXCR5 and CCL19/CCR7 play a quite important role in normal physiological conditions, but t... more CXCL13/CXCR5 and CCL19/CCR7 play a quite important role in normal physiological conditions, but the functions of both chemokine/receptor pairs in pathophysiological events are not well-investigated. We have investigated expression and functions of CXCL13/CXCR5 and CCL19/CCR7 in CD23CD5 and CD23CD5 B cells from cord blood (CB) and patients with B cell lineage acute or chronic lymphocytic leukemia (B-ALL or B-CLL). CXCR5
The protein level of transcriptional coactivator p300, an essential nuclear protein, is critical ... more The protein level of transcriptional coactivator p300, an essential nuclear protein, is critical to a broad array of cellular activities including embryonic development, cell differentiation and proliferation. We have previously established that histone deacetylase inhibitor such as valproic acid induces p300 degradation through the 26S proteasome pathway. Here, we report the roles of cellular trafficking and spatial redistribution in valproic acid-induced p300 turnover. Our study demonstrates that p300 is redistributed to the cytoplasm prior to valproic acid-induced turnover. Inhibition of proteasome-dependent protein degradation, does not prevent nucleo-cytoplasmic shuttling of p300, rather sequesters the cytoplasmic p300 to a distinct perinuclear region. In addition, the formation of p300 aggregates in the perinuclear region depends on functional microtubule networks and correlates with p300 ubiquitination. Our work establishes, for the first time, that p300 is also a substrate of the cytoplasmic ubiquitin-proteasome system and provides insight on how cellular trafficking and spatial redistribution regulate the availability and activity of transcriptional coactivator p300.
PURPOSE To prospectively compare the fMRI pattern in PCC and adjacent precuneus (PCC/precuneus) r... more PURPOSE To prospectively compare the fMRI pattern in PCC and adjacent precuneus (PCC/precuneus) regions between the healthy older adults (HC) and patients with aMCI using simplified 4x4 sudoku puzzles as a problem solving paradigm. METHOD AND MATERIALS Thirteen patients with aMCI (mean age 63.62 years ± 7.75, 9 males), and 13 age, gender and education matched HC (mean age 62.62 years±6.99, 9 males) were underwent MRI at 3.0T. Functional imaging was conducted using a single shot echo planar imaging (SS-EPI) sequence sensitive to blood-oxygen-level-dependent (BOLD) contrast. The fMRI task was a simplified 4×4 sudoku puzzle with complexity. The fMRI tasks were divided into two types according to heuristic rule: using “row rule”or “column rule” to solve the puzzle was simple task, whereas using “both row and column rule” was complex task. Data preprocessing were performed with NeuroImaging Software package (NIS). RESULTS The mean accuracy (ACC) on simple task of HC was significantly hig...
Developmental differences in phonological and orthographic processing of Chinese spoken words wer... more Developmental differences in phonological and orthographic processing of Chinese spoken words were examined in 9-year-olds, 11-year-olds and adults using functional magnetic resonance imaging (fMRI). Rhyming and spelling judgments were made to two-character words presented sequentially in the auditory modality. Developmental comparisons between adults and both groups of children combined showed that age-related changes in activation in visuo-orthographic regions depended on a task. There were developmental increases in the left inferior temporal gyrus and the right inferior occipital gyrus in the spelling task, suggesting more extensive visuo-orthographic processing in a task that required access to these representations. Conversely, there were developmental decreases in activation in the left fusiform gyrus and left middle occipital gyrus in the rhyming task, suggesting that the development of reading is marked by reduced involvement of orthography in a spoken language task that do...
Neural structures change with age but there is no consensus on the exact processes involved. This... more Neural structures change with age but there is no consensus on the exact processes involved. This study tested the hypothesis that white and grey matter in the language network changes during aging according to a "last in, first out" process. The fractional anisotropy (FA) of white matter and cortical thickness of grey matter were measured in 36 participants whose ages ranged from 55 to 79 years. Within the language network, the dorsal pathway connecting the mid-to-posterior superior temporal cortex (STC) and the inferior frontal cortex (IFC) was affected more by aging in both FA and thickness than the other dorsal pathway connecting the STC with the premotor cortex and the ventral pathway connecting the mid-to-anterior STC with the ventral IFC. These results were independently validated in a second group of 20 participants whose ages ranged from 50 to 73 years. The pathway that is most affected during aging matures later than the other two pathways (which are present at b...
The ability to draw numerical inductive reasoning requires two key cognitive processes, identific... more The ability to draw numerical inductive reasoning requires two key cognitive processes, identification and extrapolation. This study aimed to identify the neural correlates of both component processes of numerical inductive reasoning using event-related fMRI. Three kinds of tasks: rule induction (RI), rule induction and application (RIA), and perceptual judgment (Jud) were solved by twenty right-handed adults. Our results found that the left superior parietal lobule (SPL) extending into the precuneus and left dorsolateral prefrontal cortex (DLPFC) were commonly recruited in the two components. It was also observed that the fronto-parietal network was more specific to identification, whereas the striatal-thalamic network was more specific to extrapolation. The findings suggest that numerical inductive reasoning is mediated by the coordination of multiple brain areas including the prefrontal, parietal, and subcortical regions, of which some are more specific to demands on only one of ...
Effective literacy education in deaf students calls for psycholinguistic research revealing the c... more Effective literacy education in deaf students calls for psycholinguistic research revealing the cognitive and neural mechanisms underlying their written language processing. When learning a written language, deaf students are often instructed to sign out printed text. The present fMRI study was intended to reveal the neural substrates associated with word signing by comparing it with picture signing. Native deaf signers were asked to overtly sign in Chinese Sign Language (CSL) common objects indicated with written words or presented as pictures. Except in left inferior frontal gyrus and inferior parietal lobule where word signing elicited greater activation than picture signing, the two tasks engaged a highly overlapping set of brain regions previously implicated in sign production. The results suggest that word signing in the deaf signers relies on meaning activation from printed visual forms, followed by similar production processes from meaning to signs as in picture signing. The...
Although much has been known about how humans psychologically perform data-driven scientific disc... more Although much has been known about how humans psychologically perform data-driven scientific discovery, less has been known about its brain mechanism. The number series completion is a typical data-driven scientific discovery task, and has been demonstrated to possess the priming effect, which is attributed to the regularity identification and its subsequent extrapolation. In order to reduce the heterogeneities and make the experimental task proper for a brain imaging study, the number magnitude and arithmetic operation involved in number series completion tasks are further restricted. Behavioral performance in Experiment 1 shows the reliable priming effect for targets as expected. Then, a factorial design (the priming effect: prime vs. target; the period length: simple vs. complex) of event-related functional magnetic resonance imaging (fMRI) is used in Experiment 2 to examine the neural basis of data-driven scientific discovery. The fMRI results reveal a double dissociation of the...
PURPOSE Healthy ageing has become one of today’s biggest international challenges. However, theor... more PURPOSE Healthy ageing has become one of today’s biggest international challenges. However, theories debate about how neural structures change with age. This study aimed to elucidate this debate by examining the white and grey matter in a large-scale neural network for high cognitive function (i.e., language). METHOD AND MATERIALS Twenty right-handed native Mandarin speakers participated (age ranged from 50 to 73, Mean 61 years, S.D. = 7.23, 11 males and 9 females). They were assessed by the MMSE (>=28, Mean = 29, S.D. = 0.74), and no participant had cognitive complaints or positive signs in the neurological examination. Structural images (T1-MP-RAGE sequence) and DTI were acquired on a 3T scanner (Siemens Trio). All DTI images were processed following the TBSS pipeline, part of FMRIB Software Library. Whole brain FA skeletons were regressed with ages using a general linear model method. Statistical parametric maps were thresholded at a voxel-wise p < 0.001 (uncorrected). Cort...
Cancer stem cells (CSCs) represent a small subset of tumor cells which have the ability to self-r... more Cancer stem cells (CSCs) represent a small subset of tumor cells which have the ability to self-renew and generate the diverse cells that comprise the tumor bulk. They are responsible for local tumor recurrence and distant metastasis. However, they are resistant to conventional radiotherapy and chemotherapy. Novel immunotherapeutic strategies which specifically target CSCs may improve the efficacy of cancer therapy. To immunologically target CSC phenotypes, innate immune responses to CSCs have been reported using NK cells and γδT cells. To target CSC specifically, in vitro CSC-primed T cells have been successfully generated and shown targeting of CSCs in vivo after adoptive transfer. Recently, CSC-based dendritic cell vaccine has demonstrated significant induction of anti-CSC immunity both in vivo in immunocommpetent hosts and in vitro as evident by CSC reactivity of CSC vaccine-primed antibodies and T cells. In addition, identification of specific antigens or genetic alterations in...
Cerebral cortex (New York, N.Y. : 1991), Jan 19, 2014
Alzheimer's disease (AD) is associated not only with regional gray matter damages, but also w... more Alzheimer's disease (AD) is associated not only with regional gray matter damages, but also with abnormalities in functional integration between brain regions. Here, we employed resting-state functional magnetic resonance imaging data and voxel-based graph-theory analysis to systematically investigate intrinsic functional connectivity patterns of whole-brain networks in 32 AD patients and 38 healthy controls (HCs). We found that AD selectively targeted highly connected hub regions (in terms of nodal functional connectivity strength) of brain networks, involving the medial and lateral prefrontal and parietal cortices, insula, and thalamus. This impairment was connectivity distance-dependent (Euclidean), with the most prominent disruptions appearing in the long-range connections (e.g., 100-130 mm). Moreover, AD also disrupted functional connections within the default-mode, salience and executive-control modules, and connections between the salience and executive-control modules. T...
Computer methods and programs in biomedicine, 2014
Current electrocardiogram (ECG) signal quality assessment studies have aimed to provide a two-lev... more Current electrocardiogram (ECG) signal quality assessment studies have aimed to provide a two-level classification: clean or noisy. However, clinical usage demands more specific noise level classification for varying applications. This work outlines a five-level ECG signal quality classification algorithm. A total of 13 signal quality metrics were derived from segments of ECG waveforms, which were labeled by experts. A support vector machine (SVM) was trained to perform the classification and tested on a simulated dataset and was validated using data from the MIT-BIH arrhythmia database (MITDB). The simulated training and test datasets were created by selecting clean segments of the ECG in the 2011 PhysioNet/Computing in Cardiology Challenge database, and adding three types of real ECG noise at different signal-to-noise ratio (SNR) levels from the MIT-BIH Noise Stress Test Database (NSTDB). The MITDB was re-annotated for five levels of signal quality. Different combinations of the 1...
Accurate foetal electrocardiogram (FECG) morphology extraction from non-invasive sensors remains ... more Accurate foetal electrocardiogram (FECG) morphology extraction from non-invasive sensors remains an open problem. This is partly due to the paucity of available public databases. Even when gold standard information (i.e derived from the scalp electrode) is present, the collection of FECG can be problematic, particularly during stressful or clinically important events.In order to address this problem we have introduced an FECG simulator based on earlier work on foetal and adult ECG modelling. The open source foetal ECG synthetic simulator, fecgsyn, is able to generate maternal-foetal ECG mixtures with realistic amplitudes, morphology, beat-to-beat variability, heart rate changes and noise. Positional (rotation and translation-related) movements in the foetal and maternal heart due to respiration, foetal activity and uterine contractions were also added to the simulator.The simulator was used to generate some of the signals that were part of the 2013 PhysioNet Computing in Cardiology ...
International journal of biological sciences, 2007
Administration of anti-4-1BB mAb has been found to be a potent adjuvant when combined with other ... more Administration of anti-4-1BB mAb has been found to be a potent adjuvant when combined with other therapeutic approaches, e.g. chemotherapy, cytokine therapies, anti-OX40 therapy, and peptide or DC vaccines. However, the adjuvant effect of anti-4-1BB mAb administration in adoptive T cell therapy of cancer has not been fully evaluated. In this report, effector T cells were generated in vitro by anti-CD3/anti-CD28 activation of tumor-draining lymph node (TDLN) cells and used in an adoptive immunotherapy model. While T cells or anti-4-1BB alone showed no therapeutic efficacy in mice bearing macroscopic 10-day pulmonary metastases, T cells plus anti-4-1BB mediated significant tumor regression in an anti-4-1BB dose dependent manner. Mice bearing microscopic 3-day lung metastases treated with T cells alone demonstrated tumor regression which was significantly enhanced by anti-4-1BB administration. NK cell depletion abrogated the augmented therapeutic efficacy rendered by anti-4-1BB. Cell t...
Using murine tumor-draining lymph node (TDLN) cells, we investigated the polarization effect of 4... more Using murine tumor-draining lymph node (TDLN) cells, we investigated the polarization effect of 4-1BB (CD137) during CD28 costimulation in generating antitumor T cells. Costimulation of TDLN cells through the newly induced 4-1BB molecules, CD3, and CD28 using monoclonal antibodies significantly enhanced cell proliferation. The greater cell yield with 4-1BB signaling appeared to be related to the inhibition of activation-induced cell death. Activation of TDLN cells through 4-1BB in addition to CD3/CD28 signaling shifted T-cell responses toward a type 1 cytokine pattern because 4-1BB ligation plus CD3/CD28 stimulation significantly augmented type 1 cytokine (e.g., IFN-gamma) and granulocyte macrophage colony-stimulating factor secretion. By contrast, type 2 cytokine (e.g., interleukin 10) secretion by the activated TDLN cells was significantly reduced. The in vivo antitumor reactivity of TDLN cells activated through 4-1BB in conjunction with CD3/CD28 pathways was examined using an ado...
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