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Investigates the specificity, restriction and effector mechanism of immunoregulatory CD8 T cells. Role of T cells on viral infections and intracellular pathogens; Production of potent immunoregulatory cytokines; Capacity of T cells to regulate induction and effector phases of immune response.

Analyzes the role of CD23 on allergen-induced immunoglobulin E (IgE) levels, pulmonary eosinophilia and bronchial hyperresponsiveness in mice. Sensitization of the mice to ovalbumin resulting in elevated levels of total serum IgE and ovalubumin-specific IgE; Significant increase in the percentage of eosinophils recovered in bronchoalveolar lavage fluid from wild-type and CD23 mice.

Viruses cause asthmatic exacerbations in schoolchildren. We tested the hypothesis that children who wheezed with viral respiratory tract infections secrete higher levels of the type 1 cytokine interferon‐gamma (IFN‐γ) in the peripheral circulation than children who had never wheezed. Blood was taken from 13 children (eight atopic) with episodic wheeze and 11 controls. CD4 and CD8 cells were separated from peripheral blood mononuclear cells and stimulated with phorbol 12‐myrisate 13‐acetate (PMA) and ionomycin for 24 h. IFN‐γ, IL‐4, and IL‐5 were measured in the supernatant by ELISA. IFN‐γ production by CD4 and CD8 cells was lower in children with a history of wheeze (CD4, P=0.046; CD8, P=0.037). These children were then analysed according to atopic status. CD4 and CD8 IFN‐γ production in nonatopic wheezy children was reduced (CD4, P=0.009; CD8, P=0.003). IFN‐γ production by atopic wheezy children was lower than by controls, but the differences were not significant (CD4, P=0.2831; CD8, P=0.1372). CD8 IL‐5 was lower in children who wheezed (P=0.012). Release of IL‐4 and IL‐5 by CD4 cells did not differ between the three groups. We propose that defective IFN‐γ secretion by CD4 and CD8 cells may contribute to viral‐induced wheeze in nonatopic children. [ABSTRACT FROM AUTHOR]

Examines the effect of aspirin in aspirin sensitive patients. Induction of aspirin in patients with a history of urticaria or asthma; Condition of plasma prostaglandin concentration before aspirin administration; Association of aspirin tolerance with other allergic features.

Discusses the role of CD8+s in the regulation of immunoglobulin E (IgE). Role of cytokines; Differential production by T-cell subsets; Castor bean allergy; Effect of ricin on the IgE and IgG antibody responses.

Interleukin-4 (IL-4) is antagonistic for many of the activities of interferon-γ (IFN-γ) and, as well as suppressing the development of T-helper type-1 (Th1) cells, has been reported to block directly the synthesis of IFN-γ in human lymphocytes. However, IL-4 transgenic mice produce increased amounts of IFN-γ as well as IL-4. We have compared the ability of rat IL-4 to regulate IFN-γ secretion in short-term cultures of spleen cells with its effect on the differentiation of T lymphocytes into IFN-γ-producing, or Th1-type, cells. Normal rat spleen cells were stimulated using a variety of mitogens and ovalbumin antigen, with or without IL-4, for 12-24 hr and the levels of IFN-γ in the supernatants measured by enzyme-linked immunosorbent assay (ELISA). The results show that when normal rat splenocytes were stimulated with phytohaemaulutinin (PHA) or concavalin A (Con A), IL-4 enhanced secretion of IFN-γ after 12-24 hr. This enhancement was also apparent when splenocytes from animals immunized 10 days previously with alum-precipitated ovalbumin were stimulated with ovalbumin in vitro, and appeared to be mediated primarily via CD+ T cells. In contrast, when spleen cells were maximally stimulated with phorbol myristate acetate (PMA) and ionomycin, addition of IL-4 had no effect on the amount of IFN-γ secreted. When splenocytes were stimulated with Con A for 4 days in the presence of IL4, and restimulated with PMA and ionomycin, IFN-γ secretion was greatly suppressed. Our results indicate that IL-4 exerts differential effects on IFN-γ secretion and on the development of IFN-γ-producing lymphocytes.Interleukin-4 (IL-4) is antagonistic for many of the activities of interferon-γ (IFN-γ) and, as well as suppressing the development of T-helper type-1 (Th1) cells, has been reported to block directly the synthesis of IFN-γ in human lymphocytes. However, IL-4 transgenic mice produce increased amounts of IFN-γ as well as IL-4. We have compared the ability of rat IL-4 to regulate IFN-γ secretion in short-term cultures of spleen cells with its effect on the differentiation of T lymphocytes into IFN-γ-producing, or Th1-type, cells. Normal rat spleen cells were stimulated using a variety of mitogens and ovalbumin antigen, with or without IL-4, for 12-24 hr and the levels of IFN-γ in the supernatants measured by enzyme-linked immunosorbent assay (ELISA). The results show that when normal rat splenocytes were stimulated with phytohaemaulutinin (PHA) or concavalin A (Con A), IL-4 enhanced secretion of IFN-γ after 12-24 hr. This enhancement was also apparent when splenocytes from animals immunized 10 days previously with alum-precipitated ovalbumin were stimulated with ovalbumin in vitro, and appeared to be mediated primarily via CD+ T cells. In contrast, when spleen cells were maximally stimulated with phorbol myristate acetate (PMA) and ionomycin, addition of IL-4 had no effect on the amount of IFN-γ secreted. When splenocytes were stimulated with Con A for 4 days in the presence of IL4, and restimulated with PMA and ionomycin, IFN-γ secretion was greatly suppressed. Our results indicate that IL-4 exerts differential effects on IFN-γ secretion and on the development of IFN-γ-producing lymphocytes. [ABSTRACT FROM AUTHOR]

Ricin has been shown to enhance IgE production in the rat, probably through inhibition of suppressor T lymphocytes. We have studied further the effects of tic-in on IgE titre and have determined its effects on antigen-induced airway inflammation and hyperreactivity in the Brown Norway rat. Immunization with ovalbumin (l-100 μg, intraperitoneally) produced dose-related increases in serum antigen-specific IgE titre. Ricin augrnented the total IgE titre and caused about a 10-fold increase in the peak antigen-specific IgE titre. In sensitized animals, antigen challenge (three times with aerosolized ovalbumin every second day) caused a significant influx of eosinophils and neutrophils and significant airway hyperreactivity 24 hr after the third challenge. In sensitized animals that had also received ricin, the eosinophil and neutrophil influx was further significantly potentiated and a significant influx of lymphocytes also occurred. Thus, there was a relationship between the degree of sensitization and the magnitude of the inflammatory response. However, the enhanced airway inflammation in ricin-treated animals was not accompanied by a further enhancement of airway hyperreactivity. The present study demonstrates that ricin enhances IgE production and augments an antigen-induced inflammatory pathology but does not potentiate antigen-induced airway hyperreactivity. [ABSTRACT FROM AUTHOR]

Certain strains of rats infested with the nematode parasite Nippostrongulus brasiliensis mount vigorous, persistent immunoglobulin E (IgE) responses. In the absence of parasites, adjuvants such as Bordatella pertussis or Al(OH)3 are needed to produce IgE responses to soluble antigens. These are short-lived, even in high IgE responder strains. In this study we have produced long-lived IgE responses in both low (Wistar) and high (Brown Norway) IgE responder strains of rats by repeated injections of ricin, a toxic lectin from castor beans, and phospholipase A2 (PLA2), a bee venom protein. Total IgE levels rose from 30 ± 20 ng/ml to 39,000 ± 7500 ng/ml in the Wistar rats compared with an increase from 120 ± 100 ng/ml to 47,000 ± 8000 ng/ml in the Brown Norway rats. An even greater (104-fold) increase was seen in PLA2-specific IgE antibody levels. Total and PLA2-specific IgE started to fall 6 weeks after treatment was stopped in the Wistar and after 12 weeks in the Brown Norway rats. The duration of the response was 204 and 248 days, respectively. The IgE-enhancing properties of ricin were compared in low, mid (Hooded Lister) and high IgE responder rats, Total IgE and PLA2-specific IgE but not IgG antibody (Ab) responses were enhanced in all animals given ricin and PLA2 but not in animals given ricin or PLA2 alone. The increase was greater in Wistar rats (48-fold) than in Brown Norway rats (eightfold) and by Day 24 the levels of both total and PLA2specific IgE in the three different strains were indistinguishable. PLA2-specific IgE antibody-secreting cells were detected in the spleen at a frequency of 1:5000. These results show: (i) that repeated immunization of rats with antigen and ricin produce a very large IgE response which was long-lived; (ii) that this response was indistinguishable in different IgE responder strains of rat; and (iii) that the IgE response declines earlier in low IgE responder strains of rats. [ABSTRACT FROM AUTHOR]

Immunization of rats with soluble antigen (ovalbumin) and the castor bean toxin, ricin, eliminates a subpopulation of CD8 + T cells which suppress lgE responses in vivo. This treatment also reduces the ability of splenic T cells to produce interferon-γ (IFN-γ) and enhances their capacity to make interleukin-4 (IL-4). In this report we describe the effect of immunization with ricin and antigen on the expression of mRNA for other T-helper type 2 (Th2) cytokines-IL-5 and IL-10-and their relationship to serum IgE and IL4 mRNA expression. Splenocytes were taken from rats at different times after immunization with antigen or ricin and antigen and activated in vitro with phorbol myristate acetate (PMA) and ionomycin for 6 hr and total RNA extracted and reverse transcribed. Cytokine gene expression was detected using a quantitative polymerase chain reaction (PCR). Expression of IL4, IL-5, and IL-10 was increased 7-20-fold 11 days after immunization with ricin and antigen (from 0.107% to 0.769% β-actin for IL-4, from 0.0167% to 0-381% β-actin for IL-5, and from 0.0581% to 0.954% β-actin for IL-10), and preceded maximum serum IgE levels by 4-5 days. There was no increase in lgE or mRNA for these cytokines in rats immunized with antigen alone. The level of IL4, IL-5, and IL-10 expression declined rapidly after 12 days. Our results suggest that immunization with antigen and ricin preferentially induces a Th2 response, and that CD8+ T cells may play a part in down-regulating the development of Th2 T cells. [ABSTRACT FROM AUTHOR]

Differentiation of naive T cells into effector cells producing T helper type 1 (Th1) and Th2 cytokines is regulated by the presence of specific cytokines in the T-cell microenvironment. The effect of interferon-γ, (IFN-γ) and interleukin-4 (IL-4) on Th1- and Th2-1ike cell development was investigated in cultures of mixed rat spleen cells. These cells were cultured for 4 days in medium containing concanavalin A (Con A) with or without additional IL-2, IFN-γ, or IL-4. The cells were then washed and their capacity to produce IL-4, IL-5 and IFN-γ determined following stimulation with phorbol 12-myristate 13-acetate (PMA) and ionomycin. Freshly isolated cells stimulated with PMA and ionomycin expressed detectable levels of IL-4 and IL-5 mRNA as measured by a quantitative polymerase chain reaction (PCR) procedure and much higher levels of IFN-γ mRNA. Cells cultured with Con A for 4 days, washed, and restimulated with PMA+ionomycin were unable to express detectable levels of IL-4 and IL-5 mRNA, but produced high levels of IFN-γ, mRNA. Addition of IL-4, or anti-IFN-γ, antibody, to Con A-driven splenocyte cultures restored the ability ofrestimulated cells to express IL-4 and iL-5. CD4+ T cells isolated from these cultures also showed an increased capacity to secrete IL-4 and IL-5 when anti-IFN-γ and IL-4 were present in the culture medium. When cultured for 4 days with Con-A, IL-4 and anti-IFN-γ splenocytes showed an increased capacity to proliferate in response to recombinant IL-2 and proliferated in response to IL-4 alone. IL-2 had no effect on cytokine production by cultured splenocytes. These results indicate that: (1) IL-4 is essential for the generation of Th2-like cells; (2) IFN-γ, inhibits IL-4 production by mixed spleen cells and suppresses generation of IL-4 responsive T cells; (3) in mixed spleen cell cultures mitogenic stimulation favours differentiation of naive rat T cells into effector cells expressing a Th1, and not Th2, cytokine profile. [ABSTRACT FROM AUTHOR]

The antigens present in an extract of dog hair and dander were examined by crossed immunoelectrophoresis (CIE) and the IgE-binding allergens by crossed radio-immunoelectrophoresis CRIE). respectively, using sera from 60 British and Finnish animal- allergic subjects. The extract was comprised of a minimum of 28 antigens, 11I of which were common to dog serum. IgE antibody in the sera of the clog-sensitive patients bound to 21 of the 28 antigens at varying frequencies and intensities. Binding of any intensity occurred most frequently to two serum proteins: antigen 23 (IgG) binding IgE in 88% of cases, and antigen 3 (dog serum albumin, DSA) in 77% of cases. Dander antigen 8 bound in 63% and antigen 1 in 42% of the sera. Strong IgE binding, however, was most commonly associated with dander antigen 8 followed by antigens 1 and 23 (lgG) then 3 (DSA). The ranking of the antigens as allergens was similar for the two populations except that DSA was more important for the British than for the Finnish subjects. [ABSTRACT FROM AUTHOR]

The aim of this study was to compare the effects of IL–4, IL–12 and IFN–γ on the production of T helper–1 (Th1) and T helper–2 (Th2)–type cytokines from human peripheral blood 'naive' CD45RA and 'memory' CD45RO CD4 T cells. CD45RA or CD45RO CD4 T cells were cultured for 4 days with phorbol myristate acetate (PMA) and ionomycin and either IL–4, IFN–γ or IL–12 and their ability to proliferate and secrete IFN–γ and IL–4 determined. Purified CD45RO CD4 T cells stimulated with PMA and ionomycin secreted higher levels of IL–4 and IFN–γ, as measured by ELISA, than CD45RA CD4 T cells which secreted little IL–4 or IFN–γ. However, CD45RA and CD45RO CD4 T cells proliferated to the same extent and IL–4, IFN–γ and IL–12 had no effect on this. IL–12 and IFN–γ had no effect on the amount of IL–4 secreted by PMA and ionomycin–stimulated CD45RO CD4 T cells, but culture with IL–4 enhanced IL–4 production 7–fold. IL–12 increased the amount of IFN–γ produced by CD45RO CD4 T cells 2– to 3–fold. Small amounts of IFN–γ production were induced in CD4 CD45RA T cells by IL–12 and IFN–γ. These results indicate: (1) that CD45RA cells cannot make significant amounts of IL–4 under the conditions used, (2) that CD45RO cells can produce both Th1 and Th2 cytokines immediately upon restimulation, (3) that IL–12 favours Th1 cytokine production in both CD45RA and CD45RO CD4 T cells, and (4) that IFN–γ favours IFN–γ production in CD45RA but not CD45RO cells. [ABSTRACT FROM AUTHOR]