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Journal ArticleDOI

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

30 Jan 1992-The New England Journal of Medicine (Massachusetts Medical Society)-Vol. 326, Iss: 5, pp 298-304
TL;DR: Atopic asthma is associated with activation in the bronchi of the interleukin-3, 4, and 5 and GM-CSF gene cluster, a pattern compatible with predominant activation of the TH2-like T-cell population.
Abstract: 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...
Citations
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Journal ArticleDOI
TL;DR: Findings that have advanced the understanding of IL-10 and its receptor are highlighted, as well as its in vivo function in health and disease.
Abstract: Interleukin-10 (IL-10), first recognized for its ability to inhibit activation and effector function of T cells, monocytes, and macrophages, is a multifunctional cytokine with diverse effects on most hemopoietic cell types. The principal routine function of IL-10 appears to be to limit and ultimately terminate inflammatory responses. In addition to these activities, IL-10 regulates growth and/or differentiation of B cells, NK cells, cytotoxic and helper T cells, mast cells, granulocytes, dendritic cells, keratinocytes, and endothelial cells. IL-10 plays a key role in differentiation and function of a newly appreciated type of T cell, the T regulatory cell, which may figure prominently in control of immune responses and tolerance in vivo. Uniquely among hemopoietic cytokines, IL-10 has closely related homologs in several virus genomes, which testify to its crucial role in regulating immune and inflammatory responses. This review highlights findings that have advanced our understanding of IL-10 and its receptor, as well as its in vivo function in health and disease.

6,308 citations

Journal ArticleDOI
31 Oct 1996-Nature
TL;DR: The existence of subsets of CD4+ helper T lymphocytes that differ in their cytokine secretion patterns and effector functions provides a framework for understanding the heterogeneity of normal and pathological immune responses.
Abstract: The existence of subsets of CD4+ helper T lymphocytes that differ in their cytokine secretion patterns and effector functions provides a framework for understanding the heterogeneity of normal and pathological immune responses. Defining the cellular and molecular mechanisms of helper-T-cell differentiation should lead to rational strategies for manipulating immune responses for prophylaxis and therapy.

4,578 citations

Journal ArticleDOI
18 Dec 1998-Science
TL;DR: In this paper, the type 2 cytokine IL-13, which shares a receptor component and signaling pathways with IL-4, was found to be necessary and sufficient for the expression of allergic asthma.
Abstract: The worldwide incidence, morbidity, and mortality of allergic asthma are increasing. The pathophysiological features of allergic asthma are thought to result from the aberrant expansion of CD4 + T cells producing the type 2 cytokines interleukin-4 (IL-4) and IL-5, although a necessary role for these cytokines in allergic asthma has not been demonstrable. The type 2 cytokine IL-13, which shares a receptor component and signaling pathways with IL-4, was found to be necessary and sufficient for the expression of allergic asthma. IL-13 induces the pathophysiological features of asthma in a manner that is independent of immunoglobulin E and eosinophils. Thus, IL-13 is critical to allergen-induced asthma but operates through mechanisms other than those that are classically implicated in allergic responses.

2,532 citations

Journal Article
TL;DR: In this article, the type 2 cytokine IL-13, which shares a receptor component and signaling pathways with IL-4, was found to be necessary and sufficient for the expression of allergic asthma.
Abstract: The worldwide incidence, morbidity, and mortality of allergic asthma are increasing. The pathophysiological features of allergic asthma are thought to result from the aberrant expansion of CD4 + T cells producing the type 2 cytokines interleukin-4 (IL-4) and IL-5, although a necessary role for these cytokines in allergic asthma has not been demonstrable. The type 2 cytokine IL-13, which shares a receptor component and signaling pathways with IL-4, was found to be necessary and sufficient for the expression of allergic asthma. IL-13 induces the pathophysiological features of asthma in a manner that is independent of immunoglobulin E and eosinophils. Thus, IL-13 is critical to allergen-induced asthma but operates through mechanisms other than those that are classically implicated in allergic responses.

2,429 citations

References
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Journal ArticleDOI
TL;DR: Two types of cloned helper T cells are described, defined primarily by differences in the pattern of lymphokines ynthesized, and the different functions of the two types of cells and their lymphokine synthesis are discussed.
Abstract: Effector functions in the immune system are carried out by a variety of cell types, and as our understanding of the complexity of the system expands, the number of recognized subdivisions of cell types also continues to increase. B lymphocytes, producing antibody, were initially distinguished from T lymphocytes, which provide help for B cells (1, 2). The T-cell population was further divided when surface markers allowed separation of helper cells from cytotoxic cells (3). Although there were persistent reports of heterogeneity in the helper T-cell compartment (reviewed below), only relatively recently were distinct types of helper cells resolved. In this review we describe the differences between two types of cloned helper T cells, defined primarily by differences in the pattern of lymphokines ynthesized, and we also discuss the different functions of the two types of cells and their lymphokines. Patterns of lymphokine synthesis are convenient and explicit markers to describe T-cell subclass differences, and evidence increases that many of the functions of helper T cells are predicted by the functions of the lymphokines that they synthesize after activation by antigen and presenting cells. The separation of many mouse helper T-cell clones into these two distinct types is now well established, but their origin in normal T-cell populations is still not clear. Further divisions of helper T cells may have to be recognized before a complete picture of helper T-cell function can be obtained.

7,814 citations

Journal Article
TL;DR: A panel of antigen-specific mouse helper T cell clones was characterized according to patterns of lymphokine activity production, and two types of T cell were distinguished.
Abstract: A panel of antigen-specific mouse helper T cell clones was characterized according to patterns of lymphokine activity production, and two types of T cell were distinguished. Type 1 T helper cells (TH1) produced IL 2, interferon-gamma, GM-CSF, and IL 3 in response to antigen + presenting cells or to Con A, whereas type 2 helper T cells (TH2) produced IL 3, BSF1, and two other activities unique to the TH2 subset, a mast cell growth factor distinct from IL 3 and a T cell growth factor distinct from IL 2. Clones representing each type of T cell were characterized, and the pattern of lymphokine activities was consistent within each set. The secreted proteins induced by Con A were analyzed by biosynthetic labeling and SDS gel electrophoresis, and significant differences were seen between the two groups of T cell line. Both types of T cell grew in response to alternating cycles of antigen stimulation, followed by growth in IL 2-containing medium. Examples of both types of T cell were also specific for or restricted by the I region of the MHC, and the surface marker phenotype of the majority of both types was Ly-1+, Lyt-2-, L3T4+, Both types of helper T cell could provide help for B cells, but the nature of the help differed. TH1 cells were found among examples of T cell clones specific for chicken RBC and mouse alloantigens. TH2 cells were found among clones specific for mouse alloantigens, fowl gamma-globulin, and KLH. The relationship between these two types of T cells and previously described subsets of T helper cells is discussed.

7,567 citations

Journal Article
TL;DR: The concept that different subsets of helper cells, which correspond roughly to Th1 and Th2 subsets, can develop rapidly in short term culture with respectively low vs high levels of IL-4 support the concept that such distinct phenotypes arise from alternate pathways of differentiation.
Abstract: Our studies show that the presence of IL-4 during the response of naive Th cells causes precursors to develop into a population comprised largely of "Th2-like" effectors that secrete IL-4 and IL-5, but little IL-2 or IFN-gamma We find that the levels of IL-4 and IL-2 determine both the level of effectors developed in response to mitogen or Ag and the patterns of lymphokines they secrete when restimulated IL-2 is required for optimum generation of effectors, and increasing levels of IL-2, augments the expansion of effectors secreting both IL-4/IL-5 and IFN-gamma In contrast, IL-4 is required for the development of IL-4/IL-5 secreting effectors but suppresses the development of IL-2 and at higher doses IFN-gamma-secreting effectors detected after 4 days Also dramatic are the effects of the presence or absence of IL-4 evaluated after an additional 1 to 2 wk When cultures with or without initial IL-4 are cultured in IL-2 alone from days 4 to 11, they retain their distinct patterns of lymphokine production Those cells that developed in cultures without IL-4 progressively secrete more IL-2 and can be maintained and expanded in IL-2 They continue to produce IFN-gamma, though the levels decrease somewhat with time, but they do not acquire the ability to produce IL-4 or IL-5 These cells thus increasingly resemble Th1 cell lines In contrast, those cells in cultures initially exposed to IL-4, generate effectors which secrete high levels of IL-4/IL-5 (plus variable levels of IFN-gamma) at days 4 to 5, but the populations of cells developed, are not maintained well on IL-2 alone Those cells that do survive continue to secrete IL-4 and IL-5 but not IL-2 In addition, IFN-gamma production, if present, falls off with time Thus the cells in these cultures take on an increasingly Th2-like phenotype It appears that the effects of low levels of IL-4 in suppressing IL-2 production by day 4 effectors appear to be transient whereas the higher levels appear to drive the development along a distinct pathway which is irreversible These studies support the concept that different subsets of helper cells, which correspond roughly to Th1 and Th2 subsets, can develop rapidly in short term culture with respectively low vs high levels of IL-4 They support the concept that such distinct phenotypes arise from alternate pathways of differentiation that can be expected to reflect pathways available for helper T cell differentiation in the animal

1,273 citations

Journal ArticleDOI
08 Jun 1990-Science
TL;DR: The predicted protein sequence shows extensive homology with an uncharacterized open reading frame, BCRFI, in the Epstein-Barr virus genome, suggesting the possibility that this herpes virus exploits the biological activity of a captured cytokine gene to enhance its survival in the host.
Abstract: Complementary DNA clones encoding mouse cytokine synthesis inhibitory factor (CSIF; interleukin-10), which inhibits cytokine synthesis by TH1 helper T cells, were isolated and expressed. The predicted protein sequence shows extensive homology with an uncharacterized open reading frame, BCRFI, in the Epstein-Barr virus genome, suggesting the possibility that this herpes virus exploits the biological activity of a captured cytokine gene to enhance its survival in the host.

1,167 citations

Journal ArticleDOI
04 May 1989-Nature
TL;DR: It is shown that cross-linkage of FcεRI on a series of non-transformed murine mast cell lines, or treatment of these cells with calcium ionophores, stimulates increased messenger RNA levels and secretion of a group of lymphokines classically produced by a subset of murine T cell lines (TH2cells).
Abstract: The cross-linkage of high affinity Fc epsilon receptors (Fc epsilon RI) on mast cells and basophils is central to the induction of allergic inflammatory responses. As a result of such cross-linkage, mast cells secrete a variety of preformed biologically active substances, such as histamine, and newly synthesized arachidonic acid metabolites. Here we show that cross-linkage of Fc epsilon RI on a series of nontransformed murine mast cell lines, or treatment of these cells with calcium ionophores, stimulates increased messenger RNA levels and secretion of a group of lymphokines classically produced by a subset of murine T cell lines (TH2 cells). These factors include interleukin-3 (a mast cell growth factor)s interleukin-4 (an IgE 'switch factor'), interleukin-5 (an eosinophil differentiation factor) and interleukin-6 (a factor controlling immunoglobulin secretion). The production of these polypeptide factors by mast cells may have great importance in the induction of allergic and anti-parasite inflammatory responses.

1,155 citations