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

Leukocytosis after cerebral injury is well described and may participate in the generation of cerebral damage. However, the mechanisms of brain-induced leukocytosis are still speculative. Since it is known that proinflammatory cytokines are involved in neuroimmunomodulation and since others and we have demonstrated high cytokine levels in the cerebrospinal fluid following injury, we supposed that brain cytokines may also influence leukocyte counts. In order to evaluate this hypothesis, we established an animal model using continuous intracerebroventricular (i.c.v.), intrahypothalamic (i.h.), or intravenous infusion of the proinflammatory cytokines tumor necrosis factor (TNF)-alpha and IL-1beta. Controls received vehicle solution. With this experimental paradigm we could show that i.c.v. and i.h. infusion of IL-1beta but not TNF-alpha dramatically increased neutrophil counts, whereas lymphocytes dropped. Blocking the hypothalamic-pituitary-adrenal (HPA) axis by hypophysectomy abolished the neutrophilia, whereas the lymphopenia remained unchanged. Furthermore, application of the beta2-adrenoreceptor antagonist propranolol prevented the decrease of lymphocytes and diminished the neutrophilia. All parameters normalized within 48 h after termination of infusion. So, our results demonstrate that brain IL-1beta can modify blood leukocyte counts through stimulation of both the sympathetic nervous system (SNS) and the HPA axis.
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PMID:Brain IL-1beta increases neutrophil and decreases lymphocyte counts through stimulation of neuroimmune pathways. 1040 9

This study determined the cytokine profile of CD4+ T-helper cells to elucidate the specific CD4+ T-helper phenotype during the postpartum period. Peripheral blood mononuclear cells were isolated from cows during periods of increased susceptibility (3 d postpartum, n = 7) and decreased susceptibility (mid- to late lactation, n = 6) to mastitis. Isolated mononuclear cells were magnetically separated into CD4(+)-enriched or CD4(+)-depleted populations using specific bovine monoclonal antibodies and were confirmed to be enriched or depleted by flow cytometric analysis. T-helper-1 and T-helper-2 subpopulations were distinguished by cytokine profiles, at both the molecular and protein level, by competitive quantitative reverse transcriptase-polymerase chain reaction and specific bioassays, respectively. The CD4(+)-enriched cultures isolated postpartum had enhanced interleukin-4 and interleukin-10 mRNA transcript expression; cultures isolated during the mid- to late lactating period had enhanced interleukin-2 mRNA transcripts. Depletion of CD4+ lymphocytes decreased, and enrichment of CD4+ lymphocytes increased interferon-gamma transcripts in cultures isolated from mid- to late lactation cows. Interferon-gamma and interleukin-2 bioassays revealed that cytokine secretion paralleled mRNA transcript levels. These data suggest that CD4+ lymphocytes act predominantly as T-helper-2 compared with T-helper-1 within 3 d after calving. Alterations in the T-helper-1 and T-helper-2 responses, and therefore the repertoire of cytokines produced, may be an underlying reason for diminished host immune response during the postpartum period.
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PMID:Shifts in bovine CD4+ subpopulations increase T-helper-2 compared with T-helper-1 effector cells during the postpartum period. 1048 95

Interferon alpha (IFN-alpha) plays a prominent role in the therapy of a variety of diseases. The Fas/FasL system is crucial for the cytotoxic function and the peripheral elimination of activated T lymphocytes (ATC) by a mechanism referred to as activation-induced cell death (AICD). Recent studies suggest a link between IFN-alpha, the 2', 5'- oligoadenylate system and apoptosis. We therefore asked whether IFN-alpha is able to regulate the Fas/FasL pathway and thereby affects AICD. Peripheral blood mononuclear cells (PBMC), purified T cells and ATC of healthy volunteers were stimulated with various agents and the influence of IFN-alpha on Fas/FasL was assessed by mRNA and protein studies. The proportion of ATC undergoing AICD or anti-Fas-induced apoptosis was determined by FITC-annexin V staining and propidium iodide uptake. IFN-alpha upregulated mRNA expression of Fas and FasL in activated PBMC. Furthermore the concentration of the soluble form of FasL (sFasL) was increased in PBMC and T cells co-stimulated with IFN-alpha and various agents, whereas Fas surface expression was enhanced by IFN-alpha alone. IFN-alpha enhanced apoptosis induced by anti-Fas antibody and augmented AICD via the Fas/FasL pathway. IFN-alpha-regulated AICD may contribute to lymphopenia observed during IFN-alpha therapy. Our data further support that IFN-alpha is a multifunctional cytokine with profound effects on the immune cascades.
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PMID:Interferon alpha augments activation-induced T cell death by upregulation of Fas (CD95/APO-1) and Fas ligand expression. 1052 11

Cyclophosphamide (CY), an alkylating cytostatic drug, is known for its ability to accelerate a number of experimental autoimmune diseases including spontaneous diabetes in NOD mice. The mechanism(s) by which CY renders autoreactive lymphocytes more pathogenic is largely unknown, but it has been postulated that the drug preferentially depletes regulatory (suppressor) T cells. It has been suggested that in cell-mediated autoimmune diseases, Th2-like lymphocytes secreting IL-4 and/or IL-10 provide protection, while Th1-like cells secreting IFN-gamma are pathogenic. In this study, we analysed the effects of CY on autoimmune diabetes and cytokines in two mouse models: the spontaneous diabetes of NOD mice and the diabetes induced in C57BL/KsJ mice by multiple injections of low dose streptozotocin (LD-STZ). In both models, CY induced severe lymphopenia and accelerated the progression to hyperglycemia. This was associated with changes in splenic cytokine patterns indicating a shift towards the IFN-gamma-secreting phenotype. We provide here evidence that IFN-gamma producers are relatively resistant to depletion by CY and that Th0 clones can be shifted towards Th1. However, direct exposure of T lymphocytes to CY may not be a necessary condition for exacerbation of diabetes; NOD.scid mice treated with CY before adoptive transfer of NOD splenocytes developed diabetes at a higher rate than did controls. Thus, the acceleration of diabetes by CY seems to be a complex event, which includes the relatively high resistance of IFN-gamma producers to the drug, their rapid reconstitution, and a Th1 shift of surviving T cell clones.
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PMID:Acceleration of autoimmune diabetes by cyclophosphamide is associated with an enhanced IFN-gamma secretion pathway. 1058 54

Sepsis remains a serious clinical problem despite intense efforts to improve survival. Experimental animal models of sepsis have responded dramatically to immunotherapy blocking the activity of cytokines. Despite these preclinical successes, human clinical trials have not demonstrated any improvement in survival. We directly compared the mortality, morbidity, and immunopathology in two models of sepsis, one due to lipopolysaccharide (LPS) and the other to cecal ligation and puncture (CLP). BALB/c mice were injected intraperitoneally with 250 microg of LPS or subjected to CLP with an 18-gauge needle. Both models yielded similar mortality (> 85%) and morbidity. Additionally, neutropenia and lymphopenia developed in both groups. Plasma and peritoneal levels of cytokines (TNF, IL-1, IL-6, and the chemokines KC and MIP-2) were measured at 1.5, 4, and 8 h after challenge. LPS induced substantially higher levels of cytokines in both compartments with peak levels between 1.5 and 4 h that began to decline at 8 h. In contrast, cytokine levels in the CLP model were continuing to increase at the 8 h-time point and often exceeded the LPS-induced values at this time. Our data demonstrate that the LPS and CLP models have similar mortality but significant differences in the kinetics and magnitude of cytokine production. Immunotherapy for sepsis based on cytokine production after LPS challenge is misdirected because the LPS model does not accurately reproduce the cytokine profile of sepsis.
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PMID:Comparison of the mortality and inflammatory response of two models of sepsis: lipopolysaccharide vs. cecal ligation and puncture. 1067 Aug 40

During the acute phase of infection with influenza A virus, the degree of lymphopenia correlates with severity of disease. Factors that contribute to T-cell activation during influenza virus infection may contribute to this observation. Since the immune response is initiated when dendritic cells (DC) interact with T cells, we have established an in vitro system to examine the effects of influenza virus infection on DC function. Our results show that allogeneic T-cell proliferation was dependent on the dose of A/PR/8/34 used to infect DC, with enhanced responses at low, but not high, multiplicities of infection. The lack of enhancement at high virus doses was not primarily due to the increased rate of DC apoptosis, but required viral replication and neuraminidase (NA) activity. Clusters that formed between DC or between DC and T cells were also dependent on the viral dose. This change in cellular interaction may oppose T-cell proliferation in response to DC infected with high doses of PR8, since the increased contact between DC resulted in the exclusion of T cells. The enhanced alloreactive T-cell response was restored by neutralization of transforming growth factor beta1 (TGF-beta1). It is likely that NA present on viral particles released from DC infected with high doses of PR8 activates TGF-beta1. Future studies will determine the mechanism by which TGF-beta1 modifies the in vitro T-cell response and address the contribution of this cytokine to the lymphopenia observed in severe disease.
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PMID:Dose-dependent changes in influenza virus-infected dendritic cells result in increased allogeneic T-cell proliferation at low, but not high, doses of virus. 1082 50

In vitro and in vivo, tryptophan degradation was found to be associated with T cell functional loss and tolerance induction. In systemic lupus erythematosus (SLE) besides the Th2-type cytokine interleukin-10, Th1-type cytokines including interferon-gamma (IFN-gamma) are expressed especially during exacerbation of the disease. IFN-gamma stimulates the enzyme indoleamine (2,3)-dioxygenase (IDO) converting tryptophan to the metabolite kynurenine which in macrophages is subsequently degraded to other, partly neurotoxic compounds like quinolinic acid, and finally to nicrotinamides. We measured kynurenine and tryptophan concentrations in the sera of 55 SLE patients. In these patients, the concentrations of tryptophan (median, interquartile range: 53.9, 45.7-64.1 microM) were lower (p < 0.0001), and the kynurenine concentrations (2.45, 1.75-3.40 microM) were increased (p < 0.0005) compared to healthy blood donors (70.0, 63.8-80.6; 1.80, 1.45-2.27 microM, respectively). Also the kynurenine per tryptophan quotients (K/T), which allow to estimate IDO activity, were significantly higher in patients than in normals (0.043, 0.033-0.062 vs. 0.027, 0.021-0.030; p < 0.0001), indicating enhanced IDO-induced tryptophan degradation in SLE. There was no significant relationship between tryptophan, kynurenine and the SLEDAI, and also the correlation of K/T with SLEDAI was rather weak (rs = 0.243, p < 0.05). Higher K/T was found in patients presenting with serositis (p = 0.01), decrease of complement (c3, c4; p < 0.01) and blood count change (anemia, leucopenia, lymphopenia; p = 0.032) than in patients without such disease manifestations. The significant correlation found between K/T and neopterin (rs = 0.808, p < 0.001), a marker of immune activation, points to a role of immune activation to be responsible for tryptophan degradation in SLE patients.
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PMID:Enhanced tryptophan degradation in systemic lupus erythematosus. 1083 18

CVID is a primary immune disorder in which hypogammaglobulinaemia may be associated with a number of T cell defects including lymphopenia, anergy, impaired lymphocyte proliferation and deficient cytokine secretion. In this study we show that T cells of CVID subjects, in comparison with control T cells, undergo spontaneous apoptosis in culture and markedly accelerated apoptosis after gamma-irradiation. Although costimulation of the CD28 receptor following engagement of the TCR/CD3 receptor normally provides a second signal necessary for IL-2 secretion, CD28 costimulation in CVID does not significantly increase IL-2 production, nor does this combination of activators enhance the survival of irradiated CVID T cells, as it does for cultured normal T cells. Addition of IL-2 enhances CVID T cell survival, suggesting that the IL-2 signalling pathways are normal. CVID T cells have similar expression of Bcl-2 to control T cells. CD3 stimulation up-regulates T cell expression of bcl-xL mRNA for normal T cells, but anti-CD28 does not augment bcl-xL expression for CVID subjects with accelerated apoptosis. Defects of the CD28 receptor pathway, leading to cytokine deprivation and dysregulation of bcl-xL, could lead to poor T cell viability and some of the cellular defects observed in CVID.
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PMID:Enhanced apoptosis of T cells in common variable immunodeficiency (CVID): role of defective CD28 co-stimulation. 1084 30

A case of Evans' syndrome with IgM deficiency and lymphopenia was studied before and after splenectomy. The lymphopenia was as a result of profound reduction of CD4 and CD8 cells. Study of cytokine secretion before splenectomy revealed a spontaneous Th1- and Th2-type cytokine production, and complete suppression of transforming growth factor (TGF)-beta. After splenectomy, the patient achieved clinical remission, the natural killer (NK) cell number increased and the pattern of cytokine production showed normalization of interleukin (IL)-2, IL-4, IL-10, TGF-beta and abolition of interferon (IFN)-gamma production. We conclude that splenectomy had a beneficial effect owing to an increase in NK cells and an associated increase in TGF-beta production.
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PMID:Th1 and Th2 cytokines in a patient with Evans' syndrome and profound lymphopenia. 1105 90

Interleukin (IL)-7 is known to up-regulate thymopoietic pathways of T-cell regeneration. Recent work also has shown it to potently enhance thymic-independent peripheral expansion and to restore immunocompetence in athymic T-cell-depleted hosts. We hypothesized that endogenous IL-7 could contribute to the restoration of T-cell homeostasis following T-cell depletion. To analyze this, we evaluated circulating IL-7 levels and lymphocyte subsets in multiple clinical cohorts with T-cell depletion of varying etiologies. In pediatric (n = 41) and adult (n = 51) human immunodeficiency virus-infected CD4-depleted patients, there were strong inverse correlations between IL-7 levels and CD4 counts (r = -0.77, P <.0001, and r = -0.68, P <.0001). Declines in IL-7 were temporally correlated with recovery of CD4 counts. Similar patterns were observed in CD4-depleted patients receiving cancer chemotherapy (r = -0.65, P =.009). Therefore, in 2 disparate clinical scenarios involving CD4 depletion, IL-7 levels dynamically respond to changes in CD4 T-cell number, making this cytokine uniquely suited as a candidate regulator of T-cell homeostasis. Furthermore, in patients with idiopathic CD4 lymphopenia, a much weaker relationship between IL-7 levels and peripheral blood CD4 counts was observed, suggesting that an impaired IL-7 response to CD4 depletion may contribute to the impaired lymphocyte homeostasis observed in this population. In light of the known effects of IL-7 on T-cell regeneration, we postulate that increased availability of IL-7 could play a critical role in restoring T-cell homeostasis following T-cell depletion.
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PMID:A potential role for interleukin-7 in T-cell homeostasis. 1134 21


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