Background. In atopic asthma, activated T helper lymphocytes are present in bronchial-biopsy specimens and bronchoalveolar-lavage (BAL) fluid, and their production of cytokines may be important in the pathogenesis of this disorder. Different patterns of cytokine release are characteristic of certain subgroups of T helper cells, termed TH1 and TH2, the former mediating delayed-type hypersensitivity and the latter mediating IgE synthesis and eosinophilia. The pattern of cytokine production in atopic asthma is unknown. Methods. We assessed cells obtained by BAL in subjects with mild atopic asthma and in normal control subjects for the expression of messenger RNA (mRNA) for interleukin-2, 3, 4, and 5, granulocytemacrophage colony-stimulating factor (GM-CSF), and interferon gamma by in situ hybridization with 32P-labeled complementary RNA. Localization of mRNA to BAL T cells was assessed by simultaneous in situ hybridization and immunofluorescence and by in situ hybridization after immunomagnetic enrichment or...

Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma

The effects exerted on the in vitro development of antigen-specific T cell lines and T cell clones by addition or neutralization of interleukin 12 (IL-12) in lymphocyte bulk culture were examined. T cell lines specific for Dermatophagoides pteronyssinus group I (Der p I) derived in the presence of IL-12 exhibited reduced ability to produce IL-4 and increased ability to produce interferon gamma (IFN-gamma), and developed into Der p I-specific CD4+ T cell clones showing a T helper type 0 (Th0)- or Th1-, instead of Th2-, like cytokine profile. In contrast, purified protein derivative (PPD)-specific T cell lines derived in the presence of anti-IL-12 antibody exhibited an increased ability to produce IL-4 and developed into PPD-specific CD4+ T cell clones showing a Th0-, instead of Th1-, like profile. The influence of IL-12 on the cytokine secretion profile of Der p I-specific T cell lines was not prevented by addition to lymphocyte bulk cultures of anti-IFN-gamma antibody, but could be at least partially inhibited by the removal from bulk cultures of CD16+ cells. Thus, IL-12 and CD16+ cells appear to have inhibitory effects on the development of IL-4-producing cells and to play an inductive role in promoting Th1-like responses.

https://rupress.org/jem/article-pdf/177/4/1199/1103637/1199.pdf

Natural killer cell stimulatory factor (interleukin 12 [IL-12]) induces T helper type 1 (Th1)-specific immune responses and inhibits the development of IL-4-producing Th cells.

Functional subsets of human T cells were delineated by analyzing patterns of lymphokines produced by clones from individuals with leprosy and by T cell clones of known function CD4 clones from individuals with strong cell-mediated immunity produced predominantly interferon-gamma, whereas those clones that enhanced antibody formation produced interleukin-4 CD8 cytotoxic T cells secreted interferon-gamma Interleukin-4 was produced by CD8 T suppressor clones from immunologically unresponsive individuals with leprosy and was found to be necessary for suppression in vitro Both the classic reciprocal relation between antibody formation and cell-mediated immunity and resistance or susceptibility to certain infections may be explained by T cell subsets differing in patterns of lymphokine production

https://science.sciencemag.org/content/sci/254/5029/279.full.pdf

Differing lymphokine profiles of functional subsets of human CD4 and CD8 T cell clones.

Reversible airway hyperreactivity underlies the pathophysiology of asthma, yet the precise mediators of the response remain unclear. Human studies have correlated aberrant activation of T helper (Th) 2-like effector systems in the airways with disease. A murine model of airway hyperreactivity in response to acetylcholine was established using mice immunized with ovalbumin and challenged with aerosolized antigen. No airway hyperractivity occurred in severe combined immunodeficient mice. Identically immunized BALB/c mice developed an influx of cells, with a predominance of eosinophils and CD4+ T cells, into the lungs and bronchoalveolar lavage fluid at the time that substantial changes in airway pressure and resistance were quantitated. Challenged animals developed marked increases in Th2 cytokine production, eosinophil influx, and serum immunoglobulin E levels. Neutralization of interleukin (IL) 4 using monoclonal antibodies administered during the period of systemic immunization abrogated airway hyperractivity but had little effect on the influx of eosinophils. Administration of anti-IL-4 only during the period of the aerosol challenge did not affect the subsequent response to acetylcholine. Finally, administration of anti-IL-5 antibodies at levels that suppressed eosinophils to < 1% of recruited cells had no effect on the subsequent airway responses. BALB/c mice had significantly greater airway responses than C57BL/6 mice, consistent with enhanced IL-4 responses to antigen in BALB/c mice. Taken together, these data implicate IL-4 generated during the period of lymphocyte priming with antigen in establishing the cascade of responses required to generate airway hyperractivity to inhaled antigen. No role for IL-5 or eosinophils could be demonstrated.

/pdf/interleukin-4-but-not-interleukin-5-or-eosinophils-is-13wra5yq65.pdf

Interleukin 4, but not interleukin 5 or eosinophils, is required in a murine model of acute airway hyperreactivity.

In parallel with changes in lifestyle over the last 50 years (sedentary living in warm houses with extensive furnishing and low ventilation rates), there has been a progressive increase in the prevalence and morbidity of asthma in many parts of the world. The increase has been in perennial rather than seasonal asthma, and a large proportion of the patients are sensitized to one or more of the allergens found predominantly inside houses, that is, indoor allergens. The Third International Workshop on Indoor Allergens and Asthma was designed to discuss recent progress in basic and clinical research in this area, to formulate recommendations for allergen-specific management of asthma, and to consider future research directions. As with the two previous workshops, discussion topics included biology; allergen immunochemistry; molecular biology and immune response; epidemiology of asthma; and the role of allergen avoidance, a, 2 Because of dramatic progress in recent years, the Third International Workshop was expanded to cover not only house dust mite allergens but also allergens from cat, dog, and cockroach, for which immunochemical and epidemiologic data are available. Over the past 5 years there have been significant advances in several areas of research on indoor allergens, including: (1) cloning and expression of recombinant allergens, 3-7 (2) analysis of T-cell responses to indoor allergens, derivation of T-cell clones, and analysis of T-cell epitope specificity and cytokine profiles, s, 9 (3) investigation of the dose-response relationship between exposure to mite, cat, and cockroach allergens and sensitization, 1°-13 and (4) epidemiologic studies on indoor allergens as risk factors for the symptoms of asthma and bronchial hyperreactivity (BHR)? 4-17 Better definition of the allergens has made it possible to analyze their structure and biologic function and to define epitopes recognized by antibodies or T cells. Information obtained from those studies has provided exciting possibilities for developing new vaccines for safe and effective immunotherapy. 9, 18. 19 Studies of T-cell responses to dust mites have confirmed the dominance of T-helper cell (Tin) responses in allergic individuals.

https://www.jacionline.org/article/S0091-6749(97)70292-6/pdf

Indoor allergens and asthma : Report of the third international workshop

We have established a large panel of T-cell clones (TCCs) specific for Dermatophagoides pteronyssinus and Lolium perenne group I grass pollen allergens (total, 61) and for tetanus toxoid and protein purified derivative bacterial antigens (total, 38) from the peripheral blood of two atopic individuals and then analyzed their ability to produce interleukin 4 (IL-4), IL-5, and interferon gamma (IFN-gamma). Upon stimulation with phorbol 12-myristate 13-acetate plus anti-CD3 antibody, the great majority of TCCs specific for bacterial components was able to produce both IL-4 and IFN-gamma, whereas most D. pteronyssinus- and L. perenne group I-specific TCCs produced IL-4, but no, or limited, IFN-gamma. Moreover, the mean amounts of IL-4 and IFN-gamma released by allergen-specific TCCs were significantly higher and lower, respectively, than the mean amounts produced by TCCs specific for bacterial components. Under the same experimental conditions, virtually all allergen-specific TCCs, but only one-third of tested TCCs specific for bacterial components, expressed IL-5 RNA and secreted IL-5 in their supernatants. Eighteen TCCs (nine specific for allergens and nine specific for bacterial components) were also assessed for their ability to induce IgE synthesis by autologous B cells in response to stimulation with the specific antigen. Under these experimental conditions, all allergen-specific TCCs, but only one-third of TCCs specific for bacterial components that produced IL-4 but no, or little, IFN-gamma induced the synthesis of detectable amounts of IgE. The demonstration that most allergen-specific helper T cells in atopic individuals are able to produce high amounts of IL-4 (and IL-5), but no IFN-gamma, may explain why allergens induce production of IgE antibodies and increase eosinophils.

https://www.pnas.org/content/pnas/88/10/4538.full.pdf

Aftab A. Ansari

Papers

Allergen- and bacterial antigen-specific T-cell clones established from atopic donors show a different profile of cytokine production.