Decreased production of CD8 (T8) antigen after immunotherapy

The working mechanism(s) of immunotherapy still remains ill defined. As T cells bearing CD8 antigen possess suppressor/cytotoxic function, this study was conducted to examine the effect of immunotherapy on the production of CD8 antigen. Peripheral blood mononuclear cells (MNC) were obtained from 21 newly diagnosed and 23 hyposensitized (>1 year) asthmatic children and 13 agematched normal children. MNC were stimulated with crude mite extract (Dermatophagoides farinae) for 7 days and with phytohemagglutinin and concanavalin A for 3 days. The CD8 antigen and interleukin-2 receptor (IL-2R) in plasmas and culture supernatants were measured by CELLFREE T8 and IL-2R test kits (T Cell Sciences, USA). The results showed the following. (1) Plasma CD8 antigen was markedly increased in new patients compared to normals (536.7 ± 212.3 vs 222.5 ± 104.0 units/ml;P<0.001) and decreased to normal after immunotherapy (275.7 ± 98.5 units/ml). (2) When stimulated with mite allergen, MNC from both new and hyposensitized patients produced a much greater amount of CD8 antigen compared to those from normals. However, after immunotherapy MNC tended to produce less CD8 antigen, although not to a significant degree. (3) No difference in CD8 antigen production was seen among three groups when lymphocytes were stimulated with mitogens. (4) Production of CD8 antigen paralleled that of IL-2R. Thus, CD8 production was specifically decreased after immunotherapy and this fact reflects a hyposensitized state of T cells after long-term, repeated injection of allergens.     

Prevalence of Childhood Asthma in Taipei, Taiwan, and Other Asian Pacific Countries

Two epidemiological surveys of the prevalence of bronchial asthma in schoolchildren in Taipei, Taiwan, were conducted in 1974 and 1985. The same questionnaire and school, and schoolchildren of the same age (7-15 years), were studied in these two surveys. Bronchial asthma was defined as at least three paroxysmal, recurrent attacks of wheezing and dyspnea in the previous 12 months. A total of 23,678 children were studied in 1974 and 147,373 children in 1985. Data from other Asian Pacific countries were also reviewed.

The results: 1) The questionnaire was able to differentiate asthmatics from nonasthmatics on the basis of differences in methacholine challenge, intracutaneous skin testing, total eosinophil count, total serum IgE, and RAST between the two groups. 2) The prevalence of childhood asthma increased from 1.30% in 1974 to 5.07% in 1985, with boys dominating in both studies. 3) The increase in asthma prevalence could not be explained by air pollution or exposure to new allergens. 4) The prevalence of childhood asthma in the Asian Pacific countries are generally comparable to those of Western countries, and the present study and studies from Japan and New Guinea showed an increasing tendency.

Thus childhood asthma is a major problem in the Asian Pacific countries as well as in Western countries.     

Immunologic evaluation of patients with polychlorinated biphenyl poisoning: Determination of lymphocyte subpopulations

The concentration of serum immunoglobulins and the distribution of different lymphocyte subpopulations were studied in peripheral blood samples obtained from 30 human subjects exposed to PCBs and from 23 normal healthy subjects. PCBs caused decreased concentrations of IgA and IgM but not that of IgG. By using different rosette techniques to enumerate the percentages of lymphocyte subpopulations, we found that the percentages of total T cells, active T cells, and T_μ cells were decreased, while the percentages of B cells and T_γ cells were not affected. Thus, the changes of lymphocyte subpopulations may be responsible for the reported immune deficiency associated with PCB exposure.     

Major histocompatibility complex (MHC) class II restriction,lymphokine production,and IgE regulation of house dust mite-specific T-cell clones

To elucidate the regulatory mechanism of human IgE synthesis, we have cloned house dust mite (Dermatophagoides pteronyssinus; Dp)-specific T-cell clones from three asthmatic children and three healthy individuals. Twelve clones were cloned from each group. All of these clones were CD3⁺, CD4⁺, CD8^–, and HLA-DR⁺. After stimulation with allergen in the presence of antigen presenting cells (APCs), half of the T-cell clones from asthmatic children and one-third of those from normals produced interleukin 4 (IL-4). None of the patients' clones produced interferon r (IFN-r), while 10 of 12 normals' clones did. After stimulation with calcium ionophore A23187 and phorbol myristic acetate (PMA), the production of IL-4 was markedly increased in both patients and normals. However, only 3 of the 12 patients' clones produced IFN-r, while all of the normals' clones did. The T-cell clones of both patients and normals produced comparable IL-2. To study the kinetics of lymphokine productions, a HLA-DRw12-restricted T-cell clone (FYD 3.1) was stimulated, respectively, with a combination of A23187 and PMA, phytohemagglutinin (PHA), or Dp antigen in the presence of APCs. Maximal IL-2 and IL-4 productions were detected 12 hr after A23187 and PMA stimulation, whereas IFN-r could not be detected even 36 hr after stimulation. When stimulated with PHA, the production of IFN-r peaked on the fourth day, but IL-4 was not detected. After stimulation with Dp antigen and APCs, IL-4 and IL-2 were detected on the second and third days, but IFN-r was not detected. The IgE production by autologous purified B cells in the presence of allergen or IL-4 was found to be augmented by the FYD 3.1 T-cell clones. IFN-r was observed to counteract the effects of the T-cell clones and IL-4. Thus, the secretory patterns of lymphokine and kinetics of lymphokine production of allergen-specific T-cell clones can be used to explore the regulatory mechanism of human IgE synthesis.     

Characterization of histamine-releasing activity: Role of cytokines and IgE heterogeneity

Histamine-releasing factors (HRFs) are a group of cytokines that cause histamine release (HR) from basophils and mast cells. The concept of the priming effect of cytokines and the heterogeneity of IgE involved in the HRF-induced HR have been emphasized in recent years. In this study, we performed a series of experiments to elucidate the above-mentioned hypotheses. The stock HRF were obtained by stimulating mononuclear cells (MNC) with phytohemagglutinin (PHA). Maximal activity was observed 36 hr after culture. By gel filtration, HRF was eluted with a peak activity ranging from 12 to 18 KD. A large portion (75%) of HRF activity could be neutralized by a combination of antibodies against interleukin 1 (IL-1), IL-3, IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor-alpha (TNF-). The stimulation of basophils with 100 ng/ml each of IL-3, IL-6, IL-7, GM-CSF, or TNF- alone caused 10% HR; however, when the cells were pretreated with 10 ng/ml of either IL-3, IL-6, IL-7, IL-8, TNF-, or GM-CSF and then stimulated with anti-IgE, a marked increase in HR was regularly observed. The combination of 100 ng/ml each of IL-1, IL-3, IL-8, GM-CSF, and TNF- could induce only about 20% HR; furthermore, such combinations did not have an additive or synergistic priming effect on anti-IgE-induced HR compared to the effect of single cytokines. Stripping of surface-bound IgE with lactic acid markedly reduced the capacity of basophils to release histamine in response to MNC-HRF and anti-IgE. Passive sensitization of IgE-stripped basophils with high-HRF responders' serum could restore their responsiveness to both MNC-HRF and anti-IgE, but passive sensitization with low-HRF responders' serum could restore responsiveness to anti-IgE only. Moreover, passage of MNC-HRF through high-, but not low-HRF, responders' IgE-Sepharose columns significantly reduced the HR activity of MNC-HRF. Finally, although the eluant could induce only 10% HR, the majority of its HR activity could be restored by the addition of effluent but not by the mixture of IL-1, IL-3, IL-8, GM-CSF, and TNF-, suggesting the presence of a complex interaction among those cytokines. In summary, MNC-HRF contained at least two types of HRF activity; one was IgE dependent and the other was IgE independent. Cytokines such as IL-1, IL-3, IL-8, GM-CSF, and TNF- showed a priming effect on histamine release induced by MNC-HRF, although another unidentified cytokine(s) may be also involved.     

Exposure to a high concentration of mite allergen in early infancy is a risk factor for developing atopic dermatitis: A 3-year follow-up study

The cause of allergy is multi-factorial, and the development of an allergic disease seems to be the result of an interaction between genetic and environmental factors. The goal for preventing the development of allergic diseases is to avoid sensitization to allergens. The aim of this work was to study whether or not exposure to environmental allergens early in infancy would influence the occurence of various allergic diseases in later life. On an annual basis, a total of 931 healthy newborns were followed-up until they reached 3 years of age. The occurence of allergic diseases was recorded by trained medical students during visits. Measurement of Dermatophagoides pteronyssinus (Der p 1) concentration in house dust was performed when each baby was 18 and 36 months old. Total and specific immunoglobulin E (IgE) antibodies against Der p 1, cow's milk, and egg white were evaluated at birth and at 18 months of age. The following results were obtained: at 3 years of age, 10.4% had bronchial asthma (BA), 21.4% atopic dermatitis (AD), 7.0% urticaria, and 46.8% had experienced wheezing; higher family allergy scores led to a higher incidence of AD (p=0.0012); exposure to a mite allergen concentration of 1 µg/g of dust may be associated with a higher incidence of AD (p=0.0156); the presence of Der p 1 IgE antibody at 18 months of age was associated with a higher incidence of BA (p=0.0001); and children sensitized to egg whites at 18 months of age had an increased risk of developing AD at 3 years of age (p=0.0187). Hence, early exposure to mite allergen is a risk factor for the development of atopic dermatitis, but seems not to be related to the development of bronchial asthma. Early sensitization to egg whites increases the risk of developing AD. The early detection of serum Der p 1 IgE antibody is associated with a higher incidence of bronchial asthma.     

The effect of liu-wei-di-huang wan on cytokine gene expression from human peripheral blood lymphocytes

Liu-Wei-Di-Huang Wan (LWDHW) has been used by traditional Chinese doctors to treat asthma patients. This study was to examine the potential effect of this decoction on the regulation of T helper (Th)1- and Th2-type cytokine gene expression in vitro. Peripheral blood mononuclear cells (PBMC) were activated with mitogen for 24 hours in the presence or absence of LWDHW extracts. Concentrations of different cytokines in the culture supernatants were determined with ELISA. RNA isolated from cultured cells was subjected to RT-PCR analysis. The results showed that the expression of all cytokines (Th2-type: IL-4, IL-5, IL-10, or IL-13 and Th1-type: IL-2 and IFN-gamma) examined was inhibited at both RNA and protein levels by LWDHW. Since the cell viability was similar in all cultures, the reduction of cytokine production was not due to the toxicity of LWDHW. Moreover, the cells either retained or increased their capacity to respond to mitogen stimulation after incubation with the LWDHW decoction. Therefore, the data suggest that LWDHW functioned directly on cytokine gene expression from activated PBMC.     

Decreased production of interleukin-2 receptors after immunotherapy to house dust

The magnitude of the T-cell immune response depends on both the amount and the duration of interaction between interleukin 2 (IL-2) and interleukin-2 receptors (IL-2R). In a previous study, we found that IL-2 production was decreased after immunotherapy. In order to delineate further the mechanisms for the decreased lymphoproliferative response after immunotherapy,in vitro production of soluble IL-2R (SIL-2R) was studied in 18 normal children and 21 newly diagnosed and 26 hyposensitized (>2 years) asthmatic children. The results indicate that immunotherapy may modulate the immunobiologic functions of T cells through its effect on IL-2R production, and IL-2R production after allergen challenge may be used to judge the outcome of immunotherapy. However, the implication of such an alteration in the pathogenesis of atopy and the working mechanism of immunotherapy still need further study.     

Interleukin 2 therapy in severe atopic dermatitis

Interleukin 2 (IL-2) at a dose of 10,000 to 20,000 U/kg/q 8 hr was given for 9–12 days to six patients with cases of severe atopic dermatitis (AD) which were refractory to conventional therapy. After IL-2 therapy, the clinical symptoms and signs of eczema including pruritus, scratching, papulovesicles, and lichenification were much improved, but all of them recurred 2–6 weeks after stopping treatment. Adverse reactions were similar to those reported previously, but all of them subsided after discontinuation of therapy. Laboratory findings showed decreased T-cell subsets, especially CD4+ cells, and increased IL-2R+ (CD25) cells, but there was no significant change in serum IL-2, serum IgE, orin vitro IgE production. Immunopathological studies of the skin biopsies showed decreased mononuclear-cell infiltration, depletion of CD4+ cells, and enhanced expression of CD25 and HLA-DR antigens. As lymphokine-activated killer (LAK)-cell activity against cultured fibroblasts was similar in patients with AD and in normals and CD1+ Langerhans cells were not decreased after IL-2 therapy, we speculate that the depletion of helper/inducer CD4+ cells and hence abrogation of the exaggerated antigen processing and cellular activation in diseased skin are the explanation for the transient efficacy of IL-2 in the treatment of atopic dermatitis.