Ratio between the number of Th1 and Th2 lymphocytes in the peripheral blood and concentration of proinflammatory cytokines in lochia of women with postpartum endometritis

We estimated the percentage of CD4⁺ lymphocytes synthesizing IFN-γ and IL-4 in the peripheral blood and measured the concentrations of IL-1, IL-6, and TNF-α in lochia of patients with postpartum endometritis. T lymphocytes with intracellular IFN-γ prevailed in women with physiological course of the postpartum period. The number of cells containing IL-4 increased in patients with postpartum endometritis. On days 5–7 after childbirth the concentrations of proinflammatory cytokines IL-1β and TNF-α in lochia of these patients were higher than in healthy postpartum women (by 1.4 and 2.7 times, respectively). The concentrations of cytokines IL-1β, TNF-α, and IL-6 increased most significantly in patients with postpartum endometritis and active viral infection (by 3.4, 4.2, and 1.6 times, respectively). __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 140, No. 12, pp. 622–624, December, 2005     

Different modulation by histamine of IL-4 and interferon-gamma (IFN-γ) release according to the phenotype of human Th0, Th1 and Th2 clones

Histamine, an important inflammatory mediator in allergic diseases and asthma, has been reported to have modulator effects on T cells, suggesting that the bronchial microenvironment may regulate the function of resident T cells. We examined the effect of histamine on the release of the Th2-associated cytokines IL-4 and IL-5 and the Th1-associated cytokine IFN-γ by 30 CD4⁺ T cell clones from peripheral blood or bronchial biopsy of one atopic subject. Based on the IL-4/IFN-γ ratio, the clones were ascribed to the Th2 (ratio >1), Th0 (ratio 0.1 and 1) or Th1 (ratio <0.1) phenotype. Histamine inhibited IFN-γ production by Th1-like cells (P<0.02, Kruskall–Wallis), especially from bronchial biopsy, but had no effect on IL-4 release. Regarding Th0 clones, histamine inhibited IL-4 production (P<0.02) in a dose-dependent manner and slightly inhibited IFN-γ production, but had no effect on Th2-like cells. Histamine had a heterogeneous and insignificant effect on IL-5 production. The H₂-receptor antagonist ranitidine completely reversed the inhibition of IL-4 and IFN-γ production, whereas the agonist dimaprit mimicked this effect. In contrast, H₁- and H₃-receptor agonists and antagonists had no significant effect. These data demonstrate that histamine has different effects on IL-4 and IFN-γ release by T helper cells according to their phenotype via H₂-receptors. This study extends the immunomodulatory effects of histamine which may contribute to the perpetuation of airway inflammation in asthma.     

Nasal memory T lymphocytes capable of producing IL-4 in the allergic reaction

This paper reports the presence of memory T cells in the nasal mucosa of allergic patients. The demonstration of CD4 +/CD29 + (CD4 +/CD45RO +) T lymphocytes, which are capable of interleukin-4 production, can indicate a complementary cell-mediated regulatory mechanism for mast cell proliferation and IgE synthesis in human nasal allergy. No substantial IgE production can be obtained in the absence of IL-4. Therefore, the existence of IL-4 producing cells on site in the nasal mucosa of allergic subjects probably implies a complementary interaction between cytokines and different immunocompetent nasal cells in the regulation of B cells and IgE synthesis.     

T cell receptor specificities of Toxoplasma gondii-reactive mouse CD4+ T lymphocytes and Th1 clones

The Toxoplasma gondii-directed CD4⁺ T cell response in chronically infected mice was studied with respect to both T cell receptor diversity and antigen specificities. T cell receptor chains Vβ4, 6, 8, 10, and 14 were predominantly found on toxoplasma-reactive CD4⁺ splenocytes. This repertoire was also detected among T. gondii-specific CD4⁺ T cell clones. Analysis of clonotypic cytokine profiles revealed typical Th1 clones secreting interleukin-2, interferon-γ and tumour necrosis factor activity and Th2 clones producing interleukin-4 and interleukin-10. Five distinct toxoplasma antigens (p26, p40, p55, p58 and p60) were detected in electrophoretically separated toxoplasma lysate by five individual Th1 clones. Parallel testing of CD4⁺ T lymphocytes from infected mice confirmed that these specificities constitute the peak immunogenic fractions of toxoplasma lysate. The expression patterns of two clonotypic, T cell-stimulatory parasite antigens were studied in detail. While p55 was expressed by mouse-virulent and avirulent T. gondii isolates and in both the tachyzoite and bradyzoite stages, p58 was detected only in virulent strains from intraspecies subgroup I. Thus, we describe the heterogeneity of toxoplasmic immunodominant T cell antigens including a 58-kDa group I-restricted molecule which may provide a marker for virulent isolates. Received: 3 February 1997     

Eosinophil locomotion and the release of IL-3 and IL-5 by allergen-stimulated mononuclear cells are effectively downregulated in vitro by budesonide

Background Treatment of aliergic asthma with inhaled corticosteroids, such as budesonide (BDN), results in downregulation of T-cell activation and of eosinophil recruitment. Objective Since blood concentrations of BDN, although significantly lower than those measured in the lung, may still have anti-inflammatory effects, we evaluated the activity of BDN in vitro on: allergen-induced release of lymphokines involved in eosinophil chemotaxis (i.e. IL-3 and IL-5), at drug concentrations similar to those obtained in vivo in the lung (10^?8 M), and eosinophil locomotion, at ‘systemic concentrations’ of the drug (10^?10 M and 10^?9M). Methods Twenty-three atopic asthmatic subjects (atopics) sensitized to Dermatophagoides pteronyssinus (Dp) and seven non-atopic healthy subjects (controls) were studied. Purified blood mononuclear cells (BMC) were stimulated with Dp, with or without BDN 10^?8 M and, after 6 days, the supernatants were collected and frozen to test their ehemotactie activity toward purified blood eosinophils and their levels of interleukin (IL)-3 and IL-5 by immunoassay. BMC were then pulsed for additional 18h with [³H]thymidine to evaluate allergen-induced T-cell proliferation. In addition, to test possible direct effects of ‘systemic concentrations’ of the drug on eosinophil locomotion, blood eosinophils were incubated for 1 h with BDN (10^?10 M and 10^?9 M) prior to test their ehemotactie response toward recombinant human IL-3 and IL-5. Results Stimulation of BMC from atopies with Dp induced a statistically significant increase in [H]thymidine incorporation (P < 0.05); secretion of ehemotactie factors for eosinophils (P < 0.001) and the release of IL-3 and IL-5 (P < 0.005 and P < 0.05 respectively). BDN, at the concentration of 10^?8 M, was able to significantly down-regulate T-cell proliferation (P < 0.05), the secretion of ehemotactie factors for eosinophils (P < 0.001) and the release of IL-3 and IL-5 (P < 0.01 and P < 0.05 respectively). Similarly, “systemic concentrations” of BDN (10^?10 M and 10^?9 M) totally inhibited the ehemotactie response of blood eosinophils toward recombinant human IL-3 and IL-5 (P < 0.005). Conclusions Concentrations of BDN similar to those obtained in vivo are effective in inhibiting both the release of eosinophils chemotaxins by allergen-activated mononuclear cells and eosinophil locomotion.     

Human Th1 and Th2 lymphocytes: their role in the pathophysiology of atopy

In human beings, as in mice, two distinct patterns of cytokine secretion have been defined among CD4+ helper T-cell clones. Human type 1 helper (Th1), but not type 2 helper (Th2), cells produce interleukin-2 (IL-2), gamma-interferon (IFN-gamma), and tumor necrosis factor-beta, whereas Th2, but not Th1, cells secrete IL-4 and IL-5, but not IL-2 or IFN-gamma. Other cytokines, such as IL-3, IL-6, GM-CSF, or TNF-alpha, are produced by both Th1 and Th2 cells. Th0 cells, a third Th subset, show combined production of Th1- and Th2-type cytokines. The different cytokine patterns are associated with different functions. In general, Th2 cells provide an excellent helper function for B-cell antibody production, particularly of the IgE class. On the other hand, Th1 cells are responsible for delayed type hypersensitivity reactions and are cytolytic for autologous antigen-presenting cells, including B cells. Most allergen- or helminth-antigen-specific human CD4+ T-cell clones exhibit a Th2 phenotype, whereas most clones specific for bacterial antigens show a Th1 profile. Allergen-specific Th2 cells seem to play a crucial role in atopy. These cells induce IgE production via IL-4 and favor the proliferation, differentiation, and activation of eosinophils via IL-5. In addition, Th2-derived IL-3 and IL-4 are mast-cell growth factors that act in synergy, at least in vitro. Recent evidence indicates that allergen-specific Th2 cells are selectively enriched in tissues affected by allergic inflammation, such as the bronchial mucosa of subjects with allergic asthma.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of Th1 and Th2 lymphocytes and cytokines produced by these cells in suppression of immune reactions during subacute poisoning with anticholinesterase toxicants

Experiments on Wistar rats showed that subacute poisoning with anticholinesterase toxicants zarin and agent VX (daily subcutaneous injections in 1/7 LD₅₀ for 6 days) led to suppression of cellular and humoral immune reactions and to a decrease in blood concentrations of cytokines (IL-2, IL-4, IFN-γ) with a reduction of the IFN-γ/IL-4 and IL-2/IL-4 ratios, which attests to more pronounced decrease in Th1 lymphocyte function in comparison with Th2 cells. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 144, No. 7, pp. 62–64, July, 2007     

The Th1/Th2 cytokine balance changes with the progress of the immunopathological lesion of Sjogren's syndrome

Expression of type-1 and type-2 cytokines at the mRNA level in labial salivary glands (LSG) of patients with Sjogren's syndrome (SS), as reported by several groups, have generated conflicting results. In the present study we have directly examined the production of IL-4, IL-13 and IFN-gamma by lymphocytes infiltrating the LSG of 44 consecutive patients referred for SS evaluation. Cytokines production was evaluated following in vitro culture of LSG in the presence of IL-2. IFN-gamma and IL-13 were detected in the majority of SN (24/44 and 26/44, respectively) while IL-4 was present in 5/44 SN. The presence of IFN-gamma was significantly higher in SS patients, as opposed to patients who did not fulfil the criteria for SS (P < 0.01). In addition, almost all cultured lymphocytes expressed mRNA for IFN-gamma (17/19 cultures) and IL-13 (18/19) while IL-4 mRNA was also expressed at high frequency (14/19 cultures). Interestingly, the IFN-gamma mRNA copies in cultured lymphocytes correlated significantly with the intensity of lymphocytic infiltration as evaluated by Chisholm's score (P < 0.01). Furthermore, RT-PCR of RNA extracted from whole LSG from 14 SS patients also demonstrated the presence of all cytokines in the majority of the cases and the prevalence of IFN-gamma in LSG with high-grade infiltration. Because IL-13 was produced by the majority of the cultured LSG, IgE production was also evaluated. Interestingly, IgE was detected in 21/44 LSG culture SN and mainly in those biopsies that had Chisholm's score less than 0.5 (P < 0.05). We conclude that lymphocytes infiltrating the LSG are capable of producing both Th1 and Th2 cytokines and that the balance between them shifts in favour of Th1 in LSG with high infiltration score and in patients with SS.     

Human in vivo-activated CD45R0(+) CD4(+) T cells are susceptible to spontaneous apoptosis that can be inhibited by the chemokine CXCL12 and IL-2, -6, -7, and -15

The number of T cells that have undergone proliferation after antigen stimulation in vivo must be controlled to prevent excessive accumulation of T cells, autoimmunity, and T cell neoplasia. We describe here that primary human adenotonsillar memory phenotype CD45R0(+) CD4(+) T cells, but not adenotonsillar naive-phenotype CD45RA(+) CD4(+) T cells, or peripheral blood naive or memory CD4(+) T cells, express high levels of activation-associated antigens CD38, CD69, CD71, and HLA-DR. These in vivo-activated CD45R0(+) CD4(+) T cells were susceptible to spontaneous and rapid apoptosis in vitro. Apoptosis could not be inhibited by the disruption of Fas-Fas ligand engagement or by the pan-caspase inhibitor ZVAD. Cross-linking of the T cell antigen receptor did not rescue cells from apoptosis. Apoptosis could be partially inhibited by the chemokine CXCL12/SDF-1, by IL-6, and by the IL-2 receptor common gamma chain-signaling cytokines IL-2, -7, and -15. Inhibitors of phosphatidylinositol 3-kinase accelerated apoptosis. We conclude that after in vivo activation of CD45R0(+) CD4(+) T cells, the cells experience a period of intrinsically elevated sensitivity to apoptosis and that multiple external signals control their survival.     

Interleukin 2 leads to dose-dependent expression of the alpha chain of the IL-2 receptor on CD25-negative T lymphocytes in the absence of exogenous antigenic stimulation

Expression of the alpha chain of the interleukin 2 receptor on T lymphocytes is restricted, increasing in the setting of activation, particularly after antigenic stimulation via the TCR. The effects of IL-2 in vitro on the expression of CD25 and proliferation as well as the cytokine induction in CD25-depleted T cells were studied. CD25-depleted and PBMC of healthy donors were cultured for 7 days with 0, 10, or 100 IU/ml of IL-2. Phenotypic analysis and measurement of cytokines in the culture supernatants were performed. IL-2 led to a dose-dependent induction of the IL-2R alpha chain on both CD4 and CD8 T lymphocytes. In the CD25-depleted cultures, IL-2 treatment (100 IU/ml) increased the percentage of CD4 T cells expressing CD25 by 30.6% (P = 0.05) and of CD8 T cells by 48.2% (P = 0.01) on day 7 compared to no treatment. In the PBMC cultures the increase on day 7 was 36.4% for CD4 (P = 0.01) and 50.8% (P = 0.025) for CD8 T lymphocytes. The patterns of cytokine induction in the CD25-depleted and control cultures were similar with increases of IFN-gamma, GM-CSF, IL-16, TNF alpha, and soluble IL-2 receptor in the IL-2-containing cultures. CFSE experiments demonstrated the proliferative capacity of both CD25-positive and -negative T cells. Interleukin 2 alone can lead to a dose-dependent induction of the alpha chain of its receptor on resting CD4 and CD8 T lymphocytes. IL-2 as a sole stimulant is also associated with generation of a cytokine milieu that includes IFN-gamma, GM-CSF, IL-16, and TNF alpha.