T-helper Cell Cytokine Research Articles

Immunology of pregnancy. Implications for the mother.

Pregnancy is a unique event in which a genetically and immunologically foreign fetus usually survives to full term without apparent rejection by the mother's immune system. Over the past decade, more information has been gathered to provide insight into the complex immunological mechanisms that allow the fetus to grow and survive in most cases. Whereas the maternal-fetal interface was once felt to be an immunologically privileged site with complete separation between the fetus and the mother, it is now known that recognition of the foreign fetus does occur. However, despite this immunological recognition, several mechanisms have been discovered which may explain why the mother does not reject the foreign fetus. These mechanisms include fetal factors such as trophoblast cell properties and altered MHC Class I expression as well as local maternal factors such as specialized uterine natural killer cells and a shifting of the T-helper cell cytokine profile from a type 1 to a type II array. Other novel immunomodulators are found to be expressed in the local uterine environment to aid in fetal survival. Furthermore, the persistence of fetal cells in the maternal circulation long after pregnancy is over (termed chronic microchimerism) and may have implications for autoimmune diseases. This review presents investigations and developments relevant to an understanding as to why the fetus is not rejected by the maternal immune system.

IV006 Tetramer-guided analysis of M. tuberculosis specific CD8+ T-cells associated with disease activity

We determined T-ceIl cytokine profiles in the epidermis, dermis, and blood of cutaneous T-cell lymphoma to differentiate whether unique cytokine profiles were associated with mycosis fungoides (ME) Versus Sezary syndrome. Punch biopsy specimens from plaque stage MF (n = 7) were compared to Sezary skin (n = 3) after undergoing rapid heat-sa-line separation of epidermis from dermis. Normal adult skin (n = 11), neonatal foreskin (n = 4), untreated psoriatic plaques (n = 6), and normal donor peripheral blood leukocytes (n = 3) were studied as controls. Total RNA was extracted from all s!cm specimens, as well as peripheral blood leukocytes front ME (n = 3) and Sezary patients (n = 7), and was converted to cDNA by reverse transcriptase. Polymerase chain reaction amplification of cDNAs using interleukin 2 (IL-2), IL-4, IL-5, IL-10, and interferon γ- specific primers was used to differentiate Th1-type responses (1L-2+ and interferon γ+) from Th2-type responses (IL-4+, IL-5+, and IL-10+). β-actin specific primers were included as a positive control for mRNA integrity. All MF specimens contained mRNAs for IL-2 and interferon γ limited to epidermis but no IL-4, IL-5, or IL-10. In contrast, Sezary skin and blood showed a cytokine mRNA pattern dominated by IL-4, IL-5, and IL-10. MF blood showed a pattern similar to normal peripheral blood T cells with mixed detection of all T-helper cell cytokine mRNAs. All psoriasis samples contained mRNAs for IL-2 and interferon γ in both epidermis and dermis with no IL-4 or IL-10 in either compartment. These findings demonstrate that the cutaneous lesions of MF are characterized by an epidermal Th1-type cytokine profile, whereas both the blood and skin of patients with Sezary syndrome is characterized by a Th2-type profile. This work suggests that differences in cytokine production may be related to the pathophysiology and clinical presentation in cutaneous T-cell lymphoma.

Respiratory viral infections as promoters of allergic sensitization and asthma in animal models.

Respiratory virus infections can trigger exacerbations of asthma and may also contribute to allergic sensitization to aeroallergens and the development of asthma. Conversely, atopy may predispose to more severe virus-induced airway disease. The animal models reviewed in this article support the hypothesis that respiratory virus infections can promote allergic sensitization and the development of asthma. Respiratory viruses can prevent induction of tolerance and enhance sensitization to inhaled allergens resulting in increased airway inflammation and airway hyperresponsiveness. Probable mechanisms involved in this enhanced sensitization are increased permeability of the airway mucosa to allergens and recruitment of dendritic cells to the respiratory epithelium during acute infection. Factors involved in augmenting the consequences of allergic airway sensitization appear to be T-cells, especially CD8+ T-cells as regulators of this process, interleukin-5 as a pivotal cytokine for eosinophilic airway inflammation and eosinophils themselves as effector cells triggering airway hyperresponsiveness. Depending on the timing of allergen exposure, respiratory virus infections which elicit a significant type 1 T-helper cell cytokine response may also downregulate allergic sensitization. Respiratory virus infections in animals previously sensitized to aeroallergens result in prolonged increases in inflammation and airway responsiveness, indicating that critical interactions between immune responses to allergen sensitization and the responses to infection can lead to more severe disease. Taken together, animal models have proved valuable in generating a number of plausible pathogenetic concepts, and can be used to address a host of unresolved questions regarding the immunology of respiratory virus infections, allergic sensitization and asthma.

Murine Stress‐triggered Abortion is Mediated by Increase of CD8+ TNF‐α+ Decidual Cells via Substance P

Stress is known to induce abortions in mice and humans. Increased levels of abortogenic type 1 helper T-cell cytokines and decreased levels of pregnancy protective cytokines could be linked to stress-triggered embryonic loss. Stress promotes neurotransmitter substance P (SP) release in tissues. SP increases the production of decidual tumor necrosis factor (TNF)-alpha, whereby the phenotype of these TNF-alpha-producing cells is hypothetical. The objective of the present study was to identify decidual TNF-alpha-producing cell populations that are involved in stress-induced murine abortion. DBA/2J-mated CBA/J female mice were exposed to ultrasonic sound stress on day 5.5 of pregnancy. The mice were randomized and half were treated with the SP NK1-receptor antagonist (SP-RA) RP 67580 (200 microg/mouse). Frequency and cytokine profile of CD8+ cells were evaluated by immunohistochemistry and flow cytometry. Degranulation of uterine mast cells was examined histologically. On day 13.5 of pregnancy, the uteri were removed and the resorption rate was calculated. A mean resorption rate of 38.4% was detected in stressed mice (n = 10) compared to 13.1% in non-stressed control mice (n = 11, P < 0.01). Injection of SP-RA decreased the abortion rate to 18.4% in stressed mice (n = 19, P < 0.01). Flow cytometry revealed a stress-related increase of TNF-alpha+/CD8+ decidual T cells, which could be abrogated by SP-RA (P < 0.05). No significant differences could be observed in numbers of mast cells and total CD8+ cells in situ. Our data suggest that stress-triggered abortion is mediated by SP, and SP receptor blockade abrogates stress-triggered abortion via reduced production of TNF-alpha by CD8+ T cells.

Measurement of T-helper cytokines secreted by cord blood mononuclear cells in response to allergens

It has been proposed that in utero factors may predispose towards the development of childhood atopy. To test this hypothesis, it will be necessary to measure T-helper cell (Th) cytokines secreted by human cord blood mononuclear cells (CBMC) stimulated by allergens. However, to date, it has proven impossible to measure allergen-specific CBMC secretion of the key Th cytokine interleukin-4 (IL-4) using conventional sandwich ELISA techniques. We report for the first time the successful measurement of IL-4 secreted by CBMC stimulated by the allergens timothy grass pollen and house dust mite extract. The method is an adaptation of a novel cell-based ELISA (celELISA), which demonstrated an increased (up to 20-fold) sensitivity to detect IL-4. The method is simple, precise, is no more costly than a conventional ELISA, and can identify individuals in a general population whose CBMC exhibit different cytokine biases in response to allergens. The frequency distribution of IL-4 and interferon-γ (IFN-γ) CBMC responses to allergens in the general population approximates to a log-normal distribution, which will permit the application of linear regression techniques in the identification of in utero factors which influence Th bias.

28] Ultraviolet A-1 irradiation as a tool to study the pathogenesis of atopic dermatitis

Publisher Summary Ultraviolet A (UVA) radiation is widely used for the treatment of skin diseases, including atopic dermatitis) Although the beneficial effects of phototherapy for patients with atopic dermatitis have been appreciated for decades, it has been only recently that the mechanisms by which UVA irradiation improves skin symptoms in these patients have been analyzed. These studies have been made possible through the availability of in situ techniques that allow detection and monitoring of immunomodulatory consequences in lesional skin of patients and their subsequent correlation with the course of atopic dermatitis. From these studies a novel concept concerning the pathogenesis of eczematous skin lesions in atopic dermatitis patients has emerged. It is now generally accepted that cytokines derived from skin-infiltrating T-helper cells are responsible for and contribute to the generation and maintenance of eczematous skin lesions in atopic dermatitis patients. In addition, different T-helper cell cytokines are relevant for different stages of atopic dermatitis. This chapter describes highly sensitive techniques to semiquantitatively assess the expression of T-helper cell-derived, proinflammatory cytokines in lesional skin of patients with atopic dermatitis at the mRNA and protein level. Results obtained by employing these methods have suggested that skin-infiltrating T-helper cells are peferential targets for UVA radiation phototherapy.

Therapeutic potential of melatonin in immunodeficiency states, viral diseases, and cancer.

Maintenance of health depends on the ability to respond appropriately to environmental stressors via reciprocal interactions between the body and the brain. In this context, it is well recognized that the pineal hormone melatonin (MLT) plays an important role. T-helper cells bear G-protein-coupled MLT cell membrane receptors and, perhaps, MLT nuclear receptors. Activation of MLT receptors enhances the release of T-helper cell cytokines, such as gamma-interferon and interleukin-2 (IL-2), as well as activation of novel opioid cytokines which crossreact immunologically with both interleukin-4 and dynorphin B. MLT has been reported also to enhance the production of interleukin-1, interleukin-6 and interleukin-12 in human monocytes. These mediators may counteract secondary immunodeficiencies, protect mice against lethal viral and bacterial diseases, synergize with IL-2 against cancer and influence hematopoiesis. Hematopoiesis is influenced by MLT-induced-opioids (MIO) acting on kappa 1-opioid receptors present on bone marrow macrophages. Clinically, MLT could amplify the anti-tumoral activity of low dose IL-2, induce objective tumor regression, and prolong progression-free time and overall survival. MLT seems to be required for the effectiveness of low dose IL-2 in those neoplasias that are generally resistant to IL-2 alone. Similar findings were obtained in a study in which MLT was combined with gamma-interferon in metastatic renal cell carcinoma. In addition, MLT in combination with low-dose IL-2 was able to neutralize the surgery-induced lymphocytopenia in cancer patients. IL-2 treatment in patients results in activation of the immune system and creates the most suitable biological background for MLT. The finding that MLT stimulates IL-12 production from human monocytes only if incubated in presence of IL-2 further supports this concept. On the other hand, high concentrations of MLT have been found in human breast cancer tissue. The MLT concentration, which was 3 orders of magnitude higher than that present in the plasma, correlated positively with good prognostic markers such as estrogen receptor status and nuclear grade. Whether this relates to the immunoneuroendocrine action of MLT remains to be established. Clinical studies are needed on the effect of MLT in combination with IL-2 or other cytokines in cancer patients and viral diseases including HIV-infected patients.

Reciprocal age-related patterns of allergen-specific T-cell immunity in normal vs. atopic infants.

By adulthood there is almost universal immunological memory to aeroallergens, and the presence of allergic disease appears to be related to the nature of the underlying T-helper (Th) cell cytokine responses. The hypothesis of this study is that adult patterns of allergen specific Th-cell memory (Th-2 polarized in atopics vs. Th1 in non-atopics) can be determined in early infancy. Mononuclear cell cytokine responses to house-dust mite were measured at 6-monthly intervals from birth to 2 years of age, using ELISA (IL-10, IL-13, IFN-gamma) and sqRT/PCR (IL-4, IL-5, IL-9, IFN-gamma) in normal infants (n = 14) with no family history or allergic symptoms, and infants with a family history and definite atopy by 2 years (n = 16). Both normals and atopics showed low-level Th2 skewed allergen-specific responses at birth with little accompanying IFN-gamma. The Th2 responses to house-dust mite were higher in normal newborns, who then show a rapid downregulation of these responses in the first year of life. Atopic infants instead show a consolidation of their neonatal patterns of Th2 polarized allergen specific immunity. Earlier studies indicate that neonates at high risk of atopy display diminished capacity for production of the Th1 cytokine IFN-gamma. The present study suggests for the first time that neonates who subsequently develop atopy also initially have reduced capacity to mount Th2 responses. However, in contrast to non-atopics who selectively downregulate their fetal Th2 polarized allergen-specific responses, atopic children display age-associated upregulation of Th2 immunity.

Exogenous IL-3 enhances IL-10 production in [formula omitted]-infected mice

We determined T-ceIl cytokine profiles in the epidermis, dermis, and blood of cutaneous T-cell lymphoma to differentiate whether unique cytokine profiles were associated with mycosis fungoides (ME) Versus Sezary syndrome. Punch biopsy specimens from plaque stage MF (n = 7) were compared to Sezary skin (n = 3) after undergoing rapid heat-sa-line separation of epidermis from dermis. Normal adult skin (n = 11), neonatal foreskin (n = 4), untreated psoriatic plaques (n = 6), and normal donor peripheral blood leukocytes (n = 3) were studied as controls. Total RNA was extracted from all s!cm specimens, as well as peripheral blood leukocytes front ME (n = 3) and Sezary patients (n = 7), and was converted to cDNA by reverse transcriptase. Polymerase chain reaction amplification of cDNAs using interleukin 2 (IL-2), IL-4, IL-5, IL-10, and interferon γ- specific primers was used to differentiate Th1-type responses (1L-2+ and interferon γ+) from Th2-type responses (IL-4+, IL-5+, and IL-10+). β-actin specific primers were included as a positive control for mRNA integrity. All MF specimens contained mRNAs for IL-2 and interferon γ limited to epidermis but no IL-4, IL-5, or IL-10. In contrast, Sezary skin and blood showed a cytokine mRNA pattern dominated by IL-4, IL-5, and IL-10. MF blood showed a pattern similar to normal peripheral blood T cells with mixed detection of all T-helper cell cytokine mRNAs. All psoriasis samples contained mRNAs for IL-2 and interferon γ in both epidermis and dermis with no IL-4 or IL-10 in either compartment. These findings demonstrate that the cutaneous lesions of MF are characterized by an epidermal Th1-type cytokine profile, whereas both the blood and skin of patients with Sezary syndrome is characterized by a Th2-type profile. This work suggests that differences in cytokine production may be related to the pathophysiology and clinical presentation in cutaneous T-cell lymphoma.

Disruption of Th1/Th2 cytokine balance by cocaine is mediated by corticosterone

Cocaine has been shown to affect immune function through the release of corticosterone. Acute administration of both cocaine and corticosterone produces an enhancement of the T-dependent antibody response to sheep erythrocytes. The T-independent antibody response to DNP-ficoll is not enhanced under identical conditions, suggesting that the T-cell is involved as a cellular target. We examined T-helper cell cytokine production following in vivo cocaine administration and found an increase in IL-4 and IL-10; while IL-2 and IFN-γ were unaffected. The rise in Th2 cytokines is consistent with an enhanced T-dependent antibody response, a measure of humoral immunity. Because previous results showed that the enhancement by cocaine is mediated via corticosterone, the direct effects of corticosterone on Th1/Th2 in vitro cytokine production were investigated. Th1 cytokines, IL-2 and IFN-γ, were dose-dependently suppressed by corticosterone at physiologic concentrations. In contrast Th2 cytokines, IL-4 and IL-10, exhibited a biphasic dose response curve, whereby an enhancement was observed at low doses, followed by suppression at higher doses. In order to determine the consequences of this apparent shift towards a Th2 response on a Th1 response, we looked at the delayed-type hypersensitivity response to sheep erythrocytes. This measure of cell-mediated immunity was not significantly affected by acute cocaine, however, corticosterone administration resulted in a significant suppression. These results indicate that corticosterone can produce a shift towards a Th2 predominate response, possibly at the expense of Th1-mediated responses.

Production of T-helper cell subsets and cytokines by lymphocytes from patients with chronic mucocutaneous candidiasis.

Chronic mucocutaneous candidiasis (CMC) is a heterogeneous group of disorders characterized by recurrent and persistent superficial candidal infections. Cytokine-induced dysregulation of T-helper cell function has been described in other immune-deficient states but has not been studied in CMC patients. We studied T-helper cell subsets by flow cytometry and cytokine production by stimulated lymphocytes in six CMC patients, two healthy pediatric controls, and five healthy adult controls. Peripheral blood lymphocytes were stimulated in vitro with phytohemagglutinin or Candida albicans extract, and the production of interleukin-2R (IL-2R), IL-4, IL-10, and gamma interferon in the supernatants was measured by enzyme-linked immunosorbent assay. CMC patients had a decrease in the CD29+/CD29+ cell population compared with the numbers in controls (P < 0.02). The percentage of CD4+/CD45RA+ cells was greater in patients than in controls, but the difference was not significant. There was no difference in the production of IL-10 or gamma interferon by the patient lymphocytes. CMC patients produced more IL-4 than the controls (P < 0.001), whereas the controls tended to produce more IL-2R than the patients (P = 0.19). These findings support the concept that a decrease in CD4+/CD29+ T-helper inducer cells along with T-helper cell dysregulation may lead to defective memory responses to antigens in CMC patients and a decrease in cell-mediated immunity due to inhibition of TH1 cells by increased levels of IL-4.

Mycosis Fungoides Exhibits a Th1-Type Cell-Mediated Cytokine Profile Whereas Sezary Syndrome Express a Th2-Type Profile

We determined T-cell cytokine profiles in the epidermis, dermis, and blood of cutaneous T-cell lymphoma to differentiate whether unique cytokine profiles were associated with mycosis fungoides (MF) versus Sezary syndrome. Punch biopsy specimens from plaque stage MF (n = 7) were compared to Sezary skin (n = 3) after undergoing rapid heat-saline separation of epidermis from dermis. Normal adult skin (n = 11), neonatal foreskin (n = 4), untreated psoriatic plaques (n = 6), and normal donor peripheral blood leukocytes (n = 3) were studied as controls. Total RNA was extracted from all skin specimens, as well as peripheral blood leukocytes from MF (n = 3) and Sezary patients (n = 7), and was converted to cDNA by reverse transcriptase. Polymerase chain reaction amplification of cDNAs using interleukin 2 (IL-2), IL-4, IL-5, IL-10, and interferon gamma-specific primers was used to differentiate Th1-type responses (IL-2+ and interferon gamma +) from Th2-type responses (IL-4+, IL-5+, and IL-10+). beta-actin specific primers were included as a positive control for mRNA integrity. All MF specimens contained mRNAs for IL-2 and interferon gamma limited to epidermis but not IL-4, IL-5, or IL-10. In contrast, Sezary skin and blood showed a cytokine mRNA pattern dominated by IL-4, IL-5, and IL-10. MF blood showed a pattern similar to normal peripheral blood T cells with mixed detection of all T-helper cell cytokine mRNAs. All psoriasis samples contained mRNAs for IL-2 and interferon gamma in both epidermis and dermis with no IL-4 or IL-10 in either compartment. These findings demonstrate that the cutaneous lesions of MF are characterized by an epidermal Th1-type cytokine profile, whereas both the blood and skin of patients with Sezary syndrome is characterized by a Th2-type profile. This work suggests that differences in cytokine production may be related to the pathophysiology and clinical presentation in cutaneous T-cell lymphoma.

IL-4 down-regulates IL-2-, IL-3-, and GM-CSF-induced cytokine gene expression in peripheral blood monocytes

IL-4, a product of the T-helper 0 (Th0) and 2 (Th2) subset, was originally described as a B-cell stimulatory factor and has subsequently been found to suppress IL-1 alpha, IL-1 beta, IL-6, IL-8, and TNF-alpha gene expression in monocytes stimulated with LPS, and to upregulate IL-1 receptor antagonist (IL1-RA) gene expression. In this study we investigated the effect of IL-4 on the expression of cytokine genes in monocytes evoked by other T-helper cell cytokines: IL-2, IL-3, and GM-CSF. IL-4 down-regulated mRNA accumulation of the proinflammatory cytokines IL-1 beta, IL-8, and TNF-alpha in monocytes stimulated with IL-2, IL-3, and GM-CSF. IL-4 also suppressed the IL-2-induced IL-6 mRNA expression. Temporal analysis of the IL-4 down-regulatory effect on the IL-2-, IL-3-, or GM-CSF-induced proinflammatory cytokine gene expression in monocytes provided evidence that IL-4 acts predominantly on the post-transcriptional level. This was supported by the observation that the down-regulatory capacity of IL-4 appeared to be dependent on de novo protein synthesis. IL-4 did not exert significant influence on the induction of expression of IL-1-RA or various CSFs by IL-2, IL-3, and GM-CSF.(ABSTRACT TRUNCATED AT 250 WORDS)