Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024312 (lymphopenia)
 4,859 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin-18 (IL-18) is a pleiotropic cytokine that enhances Th1 or Th2 immune response. We show a novel mechanism of gastric cancer cells that allows their immune escape utilizing IL-18. All 4 gastric cancer cell lines, but not colon lines, constitutively expressed IL-18 receptors and IL-18 dose-dependently enhanced their in vitro proliferation accompanied by nuclear factor kappaB activation. When IL-18-pretreated gastric cancer cells were cultured with cytokine-activated peripheral blood killer lymphocytes, the antitumor machineries, perforin or interferon-gamma production of killer lymphocytes decreased, resulting in a decreased susceptibility of cancer cells to killer lymphocytes. Furthermore, gastric cancer cells cultured with IL-18 showed an increased expression of a granzyme B inhibitor, protease inhibitor 9. IL-18 injections into severe combined immuno-deficient mice intraperitoneally inoculated with gastric cancer cells consistently decreased the mouse survival time. Our results indicate that gastric cancers exploit IL-18 to grow/invade and evade immunosurveillance in the hosts.
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PMID:Exploitation of interleukin-18 by gastric cancers for their growth and evasion of host immunity. 1604 75

Loss of existing T cell populations is a significant clinical problem following cytoreductive therapies or in disease states such as HIV. Characterization of the pathways of T cell regeneration, their limitations and regulation, is central to the development of new approaches for the correction of T cell lymphopenia. Recently, there has been an increasing appreciation that subsets of T cells differ not only in requirements for homeostasis, but in the mechanisms of initial generation and later reconstitution of lost populations. In this issue, Cox et al. determine that variations in cytokine/chemokine levels may affect the biology of T cell recovery which impacts on the development of treatment strategies for lymphopenia.
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PMID:Reconstitution of the lymphocyte compartment after lymphocyte depletion: a key issue in clinical immunology. 1623 Dec 85

Outcomes for infants with severe combined immunodeficiency (SCID) would be improved by universal newborn screening, but there are not yet screening tests of sufficient accuracy for the disorder. In a pilot study, we assessed the ability of a two-tiered strategy to improve accuracy. Dried blood samples from patients were assessed with two tests for lymphopenia: interleukin-7, a T-cell growth cytokine, and TRECs, a byproduct of T-cell receptor recombination. IL-7 screening has a specificity of 96.1% and TRECs have a specificity of 92.3%. Combining these tests in a two-tiered strategy increases specificity to 100% (97-100% CI). Sensitivity was 85% for IL-7 screening and 100% for TREC screening. A two-tiered strategy may be of sufficient accuracy to enable universal SCID screening, and should be assessed in a prospective trial.
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PMID:Two-tiered universal newborn screening strategy for severe combined immunodeficiency. 1626 Jan 63

The peripheral lymphocyte pool size is governed by homeostatic mechanisms. Thus, grafted T cells expand and replenish T cell compartments in lymphopenic hosts. Lymphopenia-driven proliferation of naive CD8+ T cells depends on self-peptide/MHC class I complexes and the cytokine IL-7. Lymphopenia-driven proliferation and maintenance of memory CD8+ T cells are MHC independent, but are believed to require IL-7 and contact with a bone marrow-derived cell that presents the cytokine IL-15 by virtue of its high affinity receptor (IL-15Ralpha). In this study we show that optimal spontaneous proliferation of grafted naive and memory CD8+ T cells in mice rendered lymphopenic through gene ablation or irradiation requires the presence of CD11chigh dendritic cells. Our results suggest a dual role of CD11chigh dendritic cells as unique APC and cytokine-presenting cells.
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PMID:CD11chigh dendritic cell ablation impairs lymphopenia-driven proliferation of naive and memory CD8+ T cells. 1627 95

Adaptation of the T cell activation threshold may be one mechanism to control autoreactivity. To investigate its occurrence in vivo, we engineered a transgenic mouse model with increased TCR-dependent excitability by expressing a Zap70 gain-of-function mutant (ZAP-YEEI) in postselection CD8 thymocytes and T cells. Increased basal phosphorylation of the Zap70 substrate linker for activation of T cells was detected in ZAP-YEEI-bearing CD8 T cells. However, these cells were not activated, but had reduced levels of TCR and CD5. Moreover, they produced lower cytokine amounts and showed faster dephosphorylation of linker for activation of T cells and ERK upon activation. Normal TCR levels and cytokine production were restored by culturing cells in the absence of TCR/spMHC interaction, demonstrating dynamic tuning of peripheral T cell responses. The effect of avidity for self-ligand(s) on this sensory adaptation was studied by expressing ZAP-YEEI in P14 or HY TCR transgenic backgrounds. Unexpectedly, double-transgenic animals expressed ZAP-YEEI prematurely in double-positive thymocytes, but no overt alteration of selection processes was observed. Instead, modifications of TCR and CD5 expression due to ZAP-YEEI suggested that signal tuning occurred during thymic maturation. Importantly, although P14 x ZAP-YEEI peripheral CD8 T cells were reduced in number and showed lower Ag-induced cytokine production and limited lymphopenia-driven proliferation, the peripheral survival/expansion and Ag responsiveness of HY x ZAP-YEEI cells were enhanced. Our data provide support for central and peripheral sensory T cell adaptation induced as a function of TCR avidity for self-ligands and signaling level. This may contribute to buffer excessive autoreactivity while optimizing TCR repertoire usage.
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PMID:CD8 T cell sensory adaptation dependent on TCR avidity for self-antigens. 1630 46

To evaluate morphological characteristics and development of the immune system at different ages in neonatal pigs, 4 piglets were euthanized at 7, 14, and 18 d of age for collection of blood, bile, and intestinal tissue for morphological measurements. Blood was collected for differential cell counts, lymphocyte blastogenesis, immunoglobulin (Ig) concentrations, cytokine concentrations, and flow cytometric analysis. Bile was collected for quantification of Ig-A and Ig-M. Villus width and crypt depth from duodenum sections, as well as ileum crypt depth, were reduced (P < or = 0.08) in 18-d-old pigs compared with 7-d-old pigs. No age-related differences (P > or = 0.11) were observed in the number of goblet cells with neutral and acidic mucins, serum or enteric Ig concentrations, IL-2, IL-4, spontaneous lymphocyte proliferation, or leukocyte concentrations. When measured as counts per minute (cpm) and as a stimulation index (SI), lymphocyte proliferation responses to phytohaemagglutinin increased (P = 0.05) between 7 and 14 d of age; no changes (P = 0.10) occurred at 18 d of age. No age-related changes (P = 0.39) were observed in response to pokeweed mitogen (PWM) when measured as cpm; however, the SI from PWM-induced lymphocytes decreased (P = 0.04) 4-fold between 7 and 18 d of age. The CD4+:CD8+ and populations of lymphocytes expressing CD2+CD4+CD8- (T helper cells) and CD25+CD4+CD8- (activated T helper cells) were greater (P > or = 0.04) at 7 d of age than at 14 and 18 d. Populations of T lymphocytes, cytotoxic T cells (CD2+CD4-CD8+), activated lymphocytes (CD25+), and activated cytotoxic T cells (CD25+CD4-CD8+) were greater (P > or = 0.02) in 18-d-old pigs compared with 7-d-old pigs, whereas CD2+CD4-CD8- [double negative cells] were lower (P = 0.08) in 18-d-old pigs compared with 14-d-old pigs. The percentage of CD2+ T cells was 8.4% at 7 d of age, and by the time the pigs reached 18 d of age, the percentage of CD2+ T cells was 33.8%. Moreover, the percentage of gammadelta T cells was greater (P = 0.02) in 18-d-old pigs than in 7-d-old pigs (74.8 vs. 46.1%, respectively). Results indicate that the porcine immune system and gut are continuously changing as the young pig matures. Changes occurred in lymphocyte phenotypic expression and functional capabilities, as well as morphology and mucin production, and their role may be to further protect the neonate from antigenic challenge as protection from passive immunity declines.
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PMID:Ontogeny of T lymphocytes and intestinal morphological characteristics in neonatal pigs at different ages in the postnatal period. 1647 48

We compared the kinetics of T-cell recovery after extensive ex vivo and in vivo T-cell depleted autologous stem cell transplantation (SCT) for multiple sclerosis (MS; n=8) with unmodified SCT for hematological malignancies (HM; n=39). Both patient group showed a very protracted recovery of 'naive' CD4(+), 45R0(-) ( approximately CD45RA(+)) T-cells. Within the 'primed' CD4(+), 45R0(+) T-cells, the 'central memory' cells expressing the CD62L and CD27 markers were the slowest to recover. The repopulating T-cells were highly activated, as shown by increased expression of HLA-DR and the apoptosis marker CD95. The capability of CD4(+) and CD8(+) T-cells to produce IFN-gamma, IL-2 and TNF-alpha had reached normal ranges from 2 months post SCT onwards. Unexpectedly, the kinetics of T-cell recovery between 3 and 12 months post transplant was similar in T-depleted and unmodified SCT. Before SCT, the HM patients showed lymphopenia of all T-cell subsets, upregulated HLA-DR and CD95 expression and increased cytokine responses. We suggest that the similar kinetics of T-cell recovery in the two patient groups may be explained by the susceptibility to apoptosis of the activated CD4(+) T-cells in the autografts of the HM patients. This susceptibility to apoptosis would interfere with a swift and sustained CD4(+) T-cell regeneration post SCT.
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PMID:T-lymphocyte reconstitution following rigorously T-cell-depleted versus unmodified autologous stem cell transplants. 1651 23

The detection and quantification of specific T lymphocytes against human cytomegalovirus (HCMV) has proven an important laboratory marker in the monitoring of patients after stem cell transplantation (SCT). In these patients HCMV infections may cause severe disease and death. However, the determination of HCMV-specific T lymphocytes may be limited by lymphopenia occurring after transplantation. We evaluated a commercial test kit for the reliable determination of HCMV-specific T lymphocyte development in lymphopenic patients after stem cell transplantation. Using a whole blood protocol for the flow cytometric detection of antigen-specific CD4(+) T-helper and CD8(+) cytotoxic T lymphocytes this test kit measures intracellular cytokine production after stimulation with HCMV antigen. The measurement of HCMV-specific T lymphocytes was feasible when at least 3,000 CD4(+) or 1,000 CD8(+) T cells could be counted by flow cytometry. Detection of HCMV-specific T lymphocytes was possible, on average, 67 (SD+/-61) days after transplantation for CD4(+) cells and 27 (SD+/-13) days for CD8(+) cells, thus being still within the critical time for HCMV reactivation. In conclusion, the use of modern test kits permits the measurement of HCMV-specific T lymphocytes in stem cell transplant recipients and may be included in the HCMV monitoring system after SCT.
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PMID:Flow cytometric analysis of virus-specific T lymphocytes: practicability of detection of HCMV-specific T lymphocytes in whole blood in patients after stem cell transplantation. 1653 Jul 82

Destruction of peripheral lymphocytes and detrimental alterations in hematopoietic precursors are associated with influenza virus infection in birds and humans. A prominent feature among H5N1 influenza-virus-infected patients with a severe or fatal outcome was found to be lymphopenia and reactive hemophagocytosis. We show here that NS1 protein from human H5N1 influenza isolate A/HK/156/97 reduces both systemic and pulmonary pro-inflammatory cytokines in an in vivo mouse model and protects against bone marrow lymphocyte depletion, an effect which has been shown to be mediated by TNFalpha. These data suggest that the outcome of disease-associated lymphohematopoietic pathogenesis with a pathogenic influenza A virus may depend on the balance between the virus-replication-induced generation of pro-inflammatory cytokines which are a crucial component of the host's anti-viral defense and the ability of the NS1 protein, with or without the interaction of other virus proteins, to counteract such cytokine-mediated adverse effects.
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PMID:Influenza virus NS1 protein protects against lymphohematopoietic pathogenesis in an in vivo mouse model. 1654 18

Autologous transfer of anti-CD3/anti-CD28 (CD3/CD28)-activated CD4(+) T cells may benefit patients receiving autologous stem cell transplant with severe CD4 lymphopenia. Interleukin (IL)-15, an IL-2-like cytokine that promotes T cell survival may enhance immune reconstitution in conjunction with adoptive immunotherapy. We investigated the effect of IL-15 on effector and regulatory function of CD3/CD28-activated CD4(+) T cells. IL-15 upregulated CD45RO and CD25 whereas it down regulated CD62L expression of CD3/CD28-stimulated CD4(+) T cells. Both type 1 (IFN-gamma, tumor necrosis factor (TNF)-alpha) and type 2 (IL-5 and IL-10) production by CD3/CD28-activated CD4(+) T cells was further enhanced by IL-15. Co-culture experiments revealed that CD3/CD28-activated CD4(+) T cells down regulated proliferation of autologous peripheral blood lymphocytes (PBLs) and CD8(+) PBL subsets upon TCR ligation, a contact-dependent effect that was further enhanced by pretreatment with IL-15. Flow cytometric analysis of cell mixture with carboxyfluorescein diacetate succinimidyl ester and Annexin-V-PE staining revealed that CD3/CD28+IL-15-activated CD4(+) T cells showed increased apoptosis over CD4(+) T cells stimulated with CD3/CD28 alone. Taken together, pretreatment of CD3/CD28-activated CD4(+) T cells with IL-15 may increase regulatory function but may aggravate activation-induced apoptosis of CD3/CD28 CD4(+) T cells.
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PMID:Effect of interleukin-15 on effector and regulatory function of anti-CD3/anti-CD28-stimulated CD4(+) T cells. 1656 41


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