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F Powrie

Publications and source records attributed to F Powrie.

At least 37 records · Page 2Linked to original sources
PubMed1996

A critical role for transforming growth factor-beta but not interleukin 4 in the suppression of T helper type 1-mediated colitis by CD45RB(low) CD4+ T cells.

A T helper type 1 (Th1)-mediated colitis with similarities to inflammatory bowel disease in humans developed in severe combined immunodeficiency mice reconstituted with CD45RB(high) CD4+ splenic T cells and could be prevented by cotransfer of CD45RB(low) CD4+ T cells. Inhibition of this Th1 response by the CD45RB(low) T cell population could be reversed in vivo by an anti-transforming growth factor (TGF) beta antibody. Interleukin (IL) 4 was not required for either the differentiation of function of protective cells as CD45RB(low) CD4+ cells from IL-4-deficient mice were fully effective. These results identify a subpopulation of peripheral CD4+ cells and TGF-beta as critical components of the natural immune regulatory mechanism, which prevents the development of pathogenic Th1 responses in the gut, and suggests that this immunoregulatory population is distinct from Th2 cells.

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PubMed1996

Inflammatory bowel disease in C.B-17 scid mice reconstituted with the CD45RBhigh subset of CD4+ T cells.

Chronic inflammation developed spontaneously in the large intestine of C.B-17 scid mice restored with the CD45RBhigh subset of CD4+ T cells obtained from normal BALB/c mice. The inflammation, which extended diffusely from the cecum to the rectum, was localized to the lamina propria of mildly affected mice but became transmural in severely affected mice. Immunohistochemical and flow cytometric analyses showed that the inflammatory infiltrate contained numerous macrophages accompanied by moderate numbers of activated CD4+ lymphocytes. Some mice also had scattered multinucleated giant cells. Mucin depletion and epithelial hyperplasia resulting in glandular elongation and mucosal thickening were also consistently seen. Less frequent findings included ulceration with fibrosis, crypt abscesses, crypt loss, and granulomatous inflammation. Immunofluorescent analysis of inflamed large intestinal sections demonstrated increased epithelial expression of major histocompatibility class II antigens. The changes in the large intestine of these mice are similar to those seen in patients with idiopathic inflammatory bowel disease (Crohn's disease and ulcerative colitis). This murine model may be useful for studying mucosal immunoregulation as it relates to the pathogenesis and treatment of chronic inflammatory bowel diseases in the large intestine of human patients.

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PubMed1995

The role of subsets of CD4+ T cells in autoimmunity.

It is generally considered that T cells which are reactive with self-antigens are effectively eliminated by two processes: clonal deletion and the induction of T cell anergy. More recently, it has been shown that some potentially autoreactive T cells remain unactivated because the self-antigens for which they are specific are not presented on competent antigen-presenting cells. All these mechanisms of self-tolerance may be regarded as passive in the sense that the autoreactive cells are either deleted or are intrinsically non-responsive. If this view of self-tolerance is adopted, then one would predict that rendering animals relatively lymphopoenic should not give rise to autoimmune disease. This prediction is not verified by experiment. Rats rendered relatively lymphopoenic by adult thymectomy followed by repeated low dose gamma-irradiation develop a high incidence of autoimmune diabetes. Furthermore, it has been shown that the reconstitution of these rats with a specific subset of CD4+ T cells from syngeneic donors prevents the development of this disease. The protective cells have the CD45RClow phenotype, they are resistant to adult thymectomy and the majority of them appear to be non-activated in the donor rats. In contrast, the CD45RChigh CD4+ subset does not provide protection from diabetes. Instead, on injection into athymic rats, it gives rise to pathological changes in a variety of organs: stomach, pancreas, liver, thyroid and lung. In addition, the CD45RClow CD4+ subset prevents these manifestations of autoimmunity in these circumstances. Recently, we have shown that CD4+ CD8- thymocytes are a highly potent source of cells that have the ability to control autoimmune diabetes in rats. It appears that the thymus has three distinct functions: positive selection; negative selection; and the generation of a population of cells that seem specialized for the control of autoimmunity.

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PubMed1995

Genetic and spontaneous models of inflammatory bowel disease in rodents: evidence for abnormalities in mucosal immune regulation.

A number of models of spontaneous chronic intestinal inflammation in mice and rats have recently been developed. A characteristic of the majority of these models is that disease developed as a consequence of immune manipulations, suggesting a central role for the immune system in the regulation of intestinal inflammation. Analysis of cytokine patterns in disease showed elevations in TNF-alpha and IFN-gamma, characteristic of the T-helper-1 (Th1) pathway, implicating Th1 cells and their cytokines in disease pathogenesis. Strikingly, inflammation did not develop in mice maintained in germ-free conditions, suggesting disease may develop due to a dysregulated inflammatory response to components of the normal flora. Evidence from a number of these models suggests that this potentially pathogenic inflammatory response does not develop in normal animals as it is actively inhibited by a population of CD4+ alpha beta + regulatory T cells and immunosuppressive cytokines such as IL-10 and TGF-beta 1. These new models will allow further investigation into the mechanisms of natural immune regulation and protection in the intestinal tract and how these mechanisms relate to the etiopathogenesis of inflammatory bowel disease (IBD). Furthermore, these models should provide useful insights for the design of effective immunomodulatory therapies for the treatment of IBD in humans.

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PubMed1994

Regulatory interactions between CD45RBhigh and CD45RBlow CD4+ T cells are important for the balance between protective and pathogenic cell-mediated immunity.

BALB/c mice infected with the intracellular protozoan Leishmania major mount a T helper cell 2 (Th2) response that fails to control growth of the parasite and results in the development of visceral leishmaniasis. Separation of CD4+ T cells into CD45RBhigh and CD45RBlow subsets showed that the L. major-specific Th2 cells were contained within the CD45RBlow population as these cells produced high levels of antigen-specific interleukin 4 (IL-4) in vitro and transferred a nonhealing response to L. major-infected C.B-17 scid mice. In contrast, the CD45RBhighCD4+ population contained L. major-reactive cells that produced interferon gamma (IFN-gamma) in vitro and transferred a healing Th1 response to L. major-infected C.B-17 scid mice. Transfer of the Th1 response by the CD45RBhigh population was inhibited by the CD45RBlow population by a mechanism that was dependent on IL-4. These data indicate that L. major-specific Th1 cells do develop in BALB/c mice, but their functional expression is actively inhibited by production of IL-4 by Th2 cells. In this response, the suppressed Th1 cells can be phenotypically distinguished from the suppressive Th2 cells by the level of expression of CD45RB. Although the CD45RBhigh population mediated a protective response to L. major, C.B-17 scid mice restored with this population developed a severe inflammatory response in the colon that was independent of L. major infection, and was prevented by cotransfer of the CD45RBlow population. The colitis appeared to be due to a dysregulated Th1 response as anti-IFN-gamma, but not anti-IL-4, prevented it. Taken together, the data show that the CD4+ T cell population identified by high level expression of the CD45RB antigen contains cells that mediate both protective and pathogenic Th1 responses and that the reciprocal CD45RBlow population can suppress both of these responses. Whether suppression of cell-mediated immunity is beneficial or not depends on the nature of the stimulus, being deleterious during L. major infection but crucial for control of potentially pathogenic inflammatory responses developing in the gut.

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PubMed1994

Inhibition of Th1 responses prevents inflammatory bowel disease in scid mice reconstituted with CD45RBhi CD4+ T cells.

We have described a murine model of IBD that was induced in C.B-17 scid mice by transfer of the CD45RBhi subpopulation of CD4+ T cells from normal BALB/c mice and could be prevented by cotransfer of the CD45RBlo CD4+ T cell subset. Here we have dissected the mechanism of pathogenesis of IBD in this model and used this information for rational immunotherapy of the disease. CD4+ cells from diseased mice displayed a highly polarized Th1 pattern of cytokine synthesis upon polyclonal stimulation in vitro. The administration of anti-IFN gamma MAb to mice soon after T cell transfer prevented development of colitis for up to 12 weeks. Continual neutralization of TNF with anti-TNF MAbs reduced the incidence of severe disease; however, neutralization of TNF during only the first 3-4 weeks had no effect. Severe colitis was completely abrogated in mice treated systemically with rIL-10, but not with rIL-4.

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PubMed1993

Interleukin-4 and interleukin-10 synergize to inhibit cell-mediated immunity in vivo.

The lack of cell-mediated (TH1-like) immunity that is often associated with strong humoral immune responses is thought to be due in part to the inhibition of Th1 effector function by the Th2-derived cytokine interleukin-10 (IL-10). This hypothesis, however, is based entirely on results from in vitro studies, wherein IL-10 has been shown to inhibit Th1 cytokine synthesis. In this study we have compared the regulatory effects of both IL-4 and IL-10 on the development of a more complex Th1 effector function in vivo, the development of delayed-type hypersensitivity (DTH) to Leishmania major in mice immune to Leishmania. The results revealed two findings unexpected from in vitro studies with Th1 clones. First, optimal inhibition of the DTH response (up to 70%), assessed by footpad swelling and leukocytic infiltration, required the combination of IL-4 and IL-10, indicating that these two activities synergized to inhibit DTH reactivity. Second, IL-4 inhibited interferon-gamma (IFN-gamma) production by lymph node cells draining the site of antigen challenge as well as did IL-10. The combination of both cytokines was no more effective than either alone. The mechanism by which IL-4 and IL-10 acted to inhibit DTH responses did not appear to be through inhibition of IFN-gamma or tumor necrosis factor production as treatment with antibodies which neutralized these activities failed to inhibit DTH responses. Inhibition of the DTH with IL-4 and IL-10 is the most effective specific regulator of DTH responses reported and the only one capable of modulating tuberculin DTH. These data establish IL-4 and IL-10 as potent inhibitors of Th1 effector function in vivo and suggest their utility in controlling deleterious Th1-mediated inflammatory responses such as occur in some infectious and autoimmune diseases.

Animals↗
PubMed1993

Interleukin-4 and interleukin-10 synergize to inhibit cell-mediated immunity in vivo.

The lack of cell-mediated (Th1-like) immunity that is often associated with strong humoral immune responses is thought to be due in part to the inhibition of Th1 effector function by the Th2-derived cytokine interleukin-10 (IL-10). This hypothesis, however, is based entirely on results from in vitro studies, wherein IL-10 has been shown to inhibit Th1 cytokine synthesis. In this study we have compared the regulatory effects of both IL-4 and IL-10 on the development of a more complex Th1 effector function in vivo, the development of delayed-type hypersensitivity (DTH) to Leishmania major in mice immune to Leishmania. The results revealed two findings unexpected from in vitro studies with Th1 clones. First, optimal inhibition of the DTH response (up to 70%), assessed by footpad swelling and leukocytic infiltration, required the combination of IL-4 and IL-10, indicating that these two activities synergized to inhibit DTH reactivity. Second, IL-4 inhibited interferon-gamma (IFN-gamma) production by lymph node cells draining the site of antigen challenge as well as did IL-10. The combination of both cytokines was no more effective than either alone. The mechanism by which IL-4 and IL-10 acted to inhibit DTH responses did not appear to be through inhibition of IFN-gamma or tumor necrosis factor production as treatment with antibodies which neutralized these activities failed to inhibit DTH responses. Inhibition of the DTH with IL-4 and IL-10 is the most effective specific regulator of DTH responses reported and the only one capable of modulating tuberculin DTH. These data establish IL-4 and IL-10 as potent inhibitors of Th1 effector function in vivo and suggest their utility in controlling deleterious Th1-mediated inflammatory responses such as occur in some infectious and autoimmune diseases.

Animals↗
PubMed1993

Cytokine regulation of T-cell function: potential for therapeutic intervention.

CD4+ T cells, via the cytokines that they produce, play a pivotal role in the induction and regulation of cell-mediated and humoral immunity. Recently it has become clear that the CD4+ T-cell population is heterogeneous and that distinct CD4+ T-cell subsets, defined by their cytokine repertoire, regulate cell-mediated and humoral immune responses. Protective responses to pathogens are dependent on activation of the appropriate TH subset accompanied by its characteristic set of immune effector functions. Evidence to date suggests that the cytokines produced by the TH cells themselves are important regulators of TH subset activation and differentiation. Fiona Powrie and Robert Coffman discuss how manipulation of the levels of these cytokines can be used to alter the balance of TH-cell subsets and illustrate some clinical situations where this may be beneficial.

Animals↗
PubMed1993

Cytokine regulation of T-cell function: potential for therapeutic intervention.

CD4+ T cells, via the cytokines that they produce, play a pivotal role in the induction and regulation of cell-mediated and humoral immunity. Recently it has become clear that the CD4+ T-cell population is heterogeneous and that distinct CD4+ T-cell subsets, defined by their cytokine repertoire, regulate cell-mediated and humoral immune responses. Protective responses to pathogens are dependent on activation of the appropriate TH subset accompanied by its characteristic set of immune effector functions. Evidence to date suggests that the cytokines produced by the TH cells themselves are important regulators of TH subset activation and differentiation. Here, Fiona Powrie and Robert Coffman discuss how manipulation of the levels of these cytokines can be used to alter the balance of TH cell subsets and illustrate some clinical situations where this may be beneficial.

Animals↗
PubMed1993

Phenotypically distinct subsets of CD4+ T cells induce or protect from chronic intestinal inflammation in C. B-17 scid mice.

CD4+ T cells in the mouse can be subdivided into two fractions based on the level of expression of the CD45RB determinant. Previous studies have shown that these subsets are functionally distinct. We have further characterized the properties of these subpopulations in vivo by injecting them into C. B-17 scid mice. The animals restored with the CD45RBhighCD4+ T cell population developed a lethal wasting disease with severe mononuclear cell infiltrates into the colon and elevated levels of IFN-gamma mRNA. In contrast, animals restored with the reciprocal CD45RBlow subset or with unfractionated CD4+ T cells did not develop the wasting or colitis. Importantly, the co-transfer of the CD45RBlow population with the CD45RBhigh population prevented the wasting disease and colitis. These data indicate that important regulatory interactions occur between the CD45RBhigh and CD45RBlowCD4+ T cell subsets and that disruption of this mechanism has fatal consequences.

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PubMed1990

OX-22high CD4+ T cells induce wasting disease with multiple organ pathology: prevention by the OX-22low subset.

Congenitally athymic rats injected with CD45RBhigh CD4+ T cells from congenic euthymic donors developed a severe wasting disease with inflammatory infiltrates in liver, lung, stomach, thyroid, and pancreas. In contrast, recipients of CD45RBlow CD4+ T cells remained well and continued to gain weight. Animals given unfractionated CD4+ T cells, i.e., a mixture of approximately two-thirds CD45RBhigh and one-third CD45RBlow, were protected from the wasting disease, and the incidence of organ-specific inflammation was much reduced compared with that found in recipients of CD45RBhigh cells alone. The data suggest that this latter subset of CD4+ T cells has autoaggressive potential that is inhibited in normal animals by cells of the CD45RBlow CD4+ phenotype. The possible consequences of a breakdown in this immunoregulatory mechanism are briefly discussed.

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