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Biomedical subjects

F Powrie

Publications and source records attributed to F Powrie.

At least 19 recordsLinked to original sources
PubMed2001

CD134L expression on dendritic cells in the mesenteric lymph nodes drives colitis in T cell-restored SCID mice.

Transfer of CD45RB(high) CD4+ T cells to immune-deficient mice in the absence of regulatory T cells leads to a Th1-mediated colitis. In this study, we show that intestinal inflammation is characterized by a 15-fold increase in the number of CD134L+ (OX40L+)-activated DC in the mesenteric lymph nodes (MLNs) compared with BALB/c mice. This was important functionally, as administration of an anti-CD134L mAb inhibited the proliferation of T cells in the MLNs as well as their expression of the gut-homing integrin alpha(4)beta(7). Most importantly, the anti-CD134L mAb completely blocked development of colitis. Surprisingly, CD134L was found to be expressed by a proportion of dendritic cells (DC) in the MLNs of unreconstituted SCID mice, suggesting that CD134L can be induced on DC in the absence of T cell-derived signals. These results indicate that some DC in the MLNs of SCID mice express an activated phenotype and that CD134L expression by these cells is involved in the development of colitis induced by T cell transfer. Accumulation of CD134L+ DC was inhibited by cotransfer of regulatory T cells, suggesting that inhibition of the accumulation of activated DC is one mechanism by which these cells prevent immune pathology.

Animals↗
PubMed2001

IL-10 is required for regulatory T cells to mediate tolerance to alloantigens in vivo.

We present evidence that donor-reactive CD4(+) T cells present in mice tolerant to donor alloantigens are phenotypically and functionally heterogeneous. CD4(+) T cells contained within the CD45RB(high) fraction remained capable of mediating graft rejection when transferred to donor alloantigen-grafted T cell-depleted mice. In contrast, the CD45RB(low) CD4(+) and CD25(+)CD4(+) populations failed to induce rejection, but rather, were able to inhibit rejection initiated by naive CD45RB(high) CD4(+) T cells. Analysis of the mechanism of immunoregulation transferred by CD45RB(low) CD4(+) T cells in vivo revealed that it was donor Ag specific and could be inhibited by neutralizing Abs reactive with IL-10, but not IL-4. CD45RB(low) CD4(+) T cells from tolerant mice were also immune suppressive in vitro, as coculture of these cells with naive CD45RB(high) CD4(+) T cells inhibited proliferation and Th1 cytokine production in response to donor alloantigens presented via the indirect pathway. These results demonstrate that alloantigen-specific regulatory T cells contained within the CD45RB(low) CD4(+) T cell population are responsible for the maintenance of tolerance to donor alloantigens in vivo and require IL-10 for functional activity.

Adoptive Transfer↗
PubMed2001

Human CD4(+)CD25(+) thymocytes and peripheral T cells have immune suppressive activity in vitro.

CD4(+)CD25(+) T cells in mice and rats are capable of transferring protection against organ-specific autoimmune disease and colitis and suppressing the proliferation of other T cells after polyclonal stimulation in vitro. Here we describe the existence in humans of CD4(+)CD25(+) T cells with the same in vitro characteristics. CD4(+)CD8(-)CD25(+) T cells are present in both the thymus and peripheral blood of humans ( approximately 10 % of CD4(+)CD8(-) T cells), proliferate poorly in response to mitogenic stimulation and suppress the proliferation of CD4(+)CD25(-) cells in co-culture. This suppression requires cell contact and can be overcome by the addition of exogenous IL-2. CD4(+)CD25(+) cells from thymus and blood were poor producers of IL-2 and IFN-gamma, and suppressed the levels of these cytokines produced by CD4(+)CD25(-) cells. However, CD4(+)CD25(+) PBL produced higher levels of IL-4 and similar amounts of IL-10 as CD4(+)CD25(-) cells. Regulatory CD4(+)CD25(+) T cells have an activated phenotype in the thymus with expression of CTLA-4 and CD122 (IL-2Rbeta). The fact that CD4(+)CD25(+) regulatory T cells are present with a similar frequency in the thymus of humans, rats and mice, suggests that the role of these cells in the maintenance of immunological tolerance is an evolutionarily conserved mechanism.

Autoimmunity↗
PubMed2001

The transmembrane form of the CX3CL1 chemokine fractalkine is expressed predominantly by epithelial cells in vivo.

Fractalkine (CX3CL1) is synthesized as a type I transmembrane protein. Its unique CX(3)C chemokine domain is attached to a 241-amino acid mucin stalk, a 19-amino acid transmembrane domain, and a 37-amino acid intracellular domain of unknown function. A soluble form of fractalkine can be generated by proteolytic cleavage at the base of the mucin stalk. Novel monoclonal and polyclonal antibodies that specifically recognize only the amino- or carboxyl-terminal ends of the human fractalkine molecule have revealed that epithelial cells are the predominant cell type expressing transmembrane forms of fractalkine in human skin, the tonsil, and the large intestine. Using these specific anti-fractalkine reagents we do not detect high-level expression of fractalkine on endothelial cells in normal or inflamed colon samples obtained from patients with Crohn's disease or ulcerative colitis. In contrast to previous reports we do not detect fractalkine expression by Langerhans cells or immature dendritic cells in mucosal-associated lymphoid tissues in vivo. We show that the reagent used in previous studies, an anti-fractalkine N-terminal peptide antisera, cross-reacts with human CD84. Finally we discuss potential roles for fractalkine in constitutive leukocyte trafficking based on its observed pattern of expression in epithelia.

Adenocarcinoma↗
PubMed2001

CD4(+) regulatory T cells.

There is now compelling evidence that CD4(+) T cells that specialize in the suppression of immune responses play a key role in the control of immune pathology. Recently, there have been a number of reports that have provided information on the generation of CD4(+) regulatory T cells in the thymus and in the periphery. These cells have also been identified in humans, paving the way for analysis of the function of CD4(+) regulatory T cells in immune-mediated disease.

Animals↗
PubMed2001

Control of intestinal inflammation by regulatory T cells.

Regulatory T(Treg)-cell populations have been identified in a number of disease models. In this review we focus on the role of naturally occurring Treg cells in the control of intestinal inflammation. Specifically, we discuss their mechanism of action with particular emphasis on the role of anti-inflammatory cytokines and cell surface molecules.

Animals↗
PubMed2001

Control of intestinal inflammation by regulatory T cells.

Transfer of CD4+ T cells to immune-deficient mice in the absence of the CD25+ subset leads to the development of colitis, indicating that regulatory cells capable of controlling a bacteria-driven inflammatory response are present in normal mice. Cells with this function are present in the thymus as well as in the periphery of germ-free mice, suggesting they may be reactive with self-antigen. These cells resemble CD4+CD25+ cells that inhibit organ-specific autoimmunity, suggesting that a similar subset of regulatory T cells may control responses to self and foreign antigens. Development of colitis is dependent on accumulation of activated CD134L+ dendritic cells (DC) in the mesenteric lymph nodes, which is inhibited by CD4+CD25+ cells, indicating that regulatory T cells may control DC activation in vivo. Whilst inhibition of T-cell activation in vitro by CD4+CD25+ cells does not involve interleukin-10 and transforming growth factor-beta, these cytokines are required for the suppression of colitis. It may be that control of responses that activate the innate immune system requires multiple mechanisms of immune suppression. Recently, we identified CD4+CD25+ cells with immune suppressive activity in the thymus and peripheral blood of humans, raising the possibility that dysfunction in this mechanism of immune regulation may be involved in the development of autoimmune and inflammatory diseases.

ADP-ribosyl Cyclase↗
PubMed2001

Regulatory T cells in the control of immune pathology.

It is now well established that regulatory T (T(R)) cells can inhibit harmful immunopathological responses directed against self or foreign antigens. However, many key aspects of T(R) cell biology remain unresolved, especially with regard to their antigen specificities and the cellular and molecular pathways involved in their development and mechanisms of action. We will review here recent findings in these areas, outline a model for how T(R) cells may inhibit the development of immune pathology and discuss potential therapeutic benefits that may arise from the manipulation of T(R) cell function.

Abatacept↗
PubMed2001

Immune therapy in inflammatory bowel disease and models of colitis.

BACKGROUND: A proliferation of animal models has not only improved our understanding of inflammatory bowel disease, it has also formed the basis of new treatment strategies. METHODS: A search was conducted using the National Library of Medicine for articles discussing immune therapies for inflammatory bowel disease. This was supplemented by findings from the authors' own laboratory. RESULTS: An overview of the different animal models is presented. These models are used to highlight the recent human trials of immune therapies. Potential future therapies are also discussed. CONCLUSION: Immune therapies have altered the management of patients with inflammatory bowel disease. In future they will influence not only the indications for surgery but also its timing and outcome.

Animals↗
PubMed2000

Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation.

It is now clear that functionally specialized regulatory T (Treg) cells exist as part of the normal immune repertoire, preventing the development of pathogenic responses to both self- and intestinal antigens. Here, we report that the Treg cells that control intestinal inflammation express the same phenotype (CD25(+)CD45RB(low)CD4(+)) as those that control autoimmunity. Previous studies have failed to identify how CD25(+) Treg cells function in vivo. Our studies reveal that the immune-suppressive function of these cells in vivo is dependent on signaling via the negative regulator of T cell activation cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), as well as secretion of the immune-suppressive cytokine transforming growth factor beta. Strikingly, constitutive expression of CTLA-4 among CD4(+) cells was restricted primarily to Treg cells, suggesting that CTLA-4 expression by these cells is involved in their immune-suppressive function. These findings raise the possibility that Treg cell function contributes to the immune suppression characteristic of CTLA-4 signaling. Identification of costimulatory molecules involved in the function of Treg cells may facilitate further characterization of these cells and development of new therapeutic strategies for the treatment of inflammatory diseases.

Abatacept↗
PubMed2000

Control of experimental inflammatory bowel disease by regulatory T cells.

A helper T cell type 1-mediated colitis driven by enteric bacteria develops in severe combined immunodeficient mice after transfer of CD45RB(high)CD4(+) T cells. Development of disease can be prevented by cotransfer of the reciprocal CD45RB(low) subset. Analysis of the mechanism of immune suppression transferred by CD45RB(low)CD4(+) cells revealed essential roles for both IL-10 and TGF-beta. These data indicate that a functionally specialized population of regulatory T (Treg) cells exists in normal mice and that these can prevent the development of pathogenic responses toward commensal bacteria. The role of Treg cells in the control of the immune response is discussed.

Adoptive Transfer↗
PubMed1999

An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation.

A T helper cell type 1-mediated colitis develops in severe combined immunodeficient mice after transfer of CD45RB(high) CD4(+) T cells and can be prevented by cotransfer of the CD45RB(low) subset. The immune-suppressive activities of the CD45RB(low) T cell population can be reversed in vivo by administration of an anti-transforming growth factor beta antibody. Here we show that interleukin (IL)-10 is an essential mediator of the regulatory functions of the CD45RB(low) population. This population isolated from IL-10-deficient (IL-10(-/-)) mice was unable to protect from colitis and when transferred alone to immune-deficient recipients induced colitis. Treatment with an anti-murine IL-10 receptor monoclonal antibody abrogated inhibition of colitis mediated by wild-type (WT) CD45RB(low) CD4(+) cells, suggesting that IL-10 was necessary for the effector function of the regulatory T cell population. Inhibition of colitis by WT regulatory T cells was not dependent on IL-10 production by progeny of the CD45RB(high) CD4(+) cells, as CD45RB(low) CD4(+) cells from WT mice were able to inhibit colitis induced by IL-10(-/-) CD45RB(high) CD4(+) cells. These findings provide the first clear evidence that IL-10 plays a nonredundant role in the functioning of regulatory T cells that control inflammatory responses towards intestinal antigens.

Animals↗
PubMed1999

Regulatory T cells and inflammatory bowel disease.

Recent studies have identified interleukin 10 as a differentiation factor for a novel subset of immune suppressive regulatory T cells. Here, Hervé Groux and Fiona Powrie discuss the role that these cells play in the regulation of immune responses to enteric antigens and suggest that a deficiency in these cells might be involved in the pathogenesis of inflammatory bowel disease.

Animals↗
PubMed1998

CD38+ CD45RB(low) CD4+ T cells: a population of T cells with immune regulatory activities in vitro.

An antibody reactive with CD38 revealed both phenotypic and functional heterogeneity amongst CD45RB(low) cells. Functional analysis of the CD38+ and CD38- fractions showed that the latter contained T cells which responded to recall antigens and produced high levels of cytokine in response to polyclonal stimulation. In contrast, the CD38+ population failed to proliferate or to produce detectable levels of cytokines. Despite appearing unresponsive, the CD38+ population significantly inhibited anti-CD3-induced proliferation and cytokine secretion by the reciprocal CD38- population. Immune suppression required stimulation through the TCR and was dependent on a physical interaction between regulatory and responding CD4+ populations. It did not involve killing of the responding T cells or secretion of IL-10 or TGF-beta. Despite some similarities there is no direct correlation between the in vitro suppression characteristic of the CD38+ CD45RB(low) subset and in vivo suppression which has been shown to be mediated by unseparated CD45RB(low) CD4+ T cells. However, these results demonstrate that two functionally distinct subsets of T cells reside within the antigen-exposed or CD45RB(low) CD4+ T cell population and are thus generated in vivo: (1) conventional memory T cells which proliferate and secrete cytokines in response to activation and (2) a population of regulatory T cells which inhibit T cell activation in vitro. Antibodies reactive with CD38 may provide a useful tool with which to study the role of these T cell subsets in the induction and regulation of the immune response.

ADP-ribosyl Cyclase↗
PubMed1998

Control of immune pathology by regulatory T cells.

There is now compelling evidence that immune responses for both foreign and self antigens are downregulated by T cells that are specialised for this function; these are known as regulatory T (T reg) cells. This review describes progress in the characterisation of the T reg cells that mediate both mucosal tolerance and tolerance to self antigens. The recent work on the antigen specificity, generation and mode of action of T reg cells is also reviewed.

Animals↗
PubMed1998

Interleukin 10 is a growth factor for a population of regulatory T cells.

Induction and maintenance of peripheral tolerance are important mechanisms to maintain the balance of the immune system. In addition to the deletion of T cells and their failure to respond in certain circumstances, active suppression mediated by T cells or T-cell factors has been proposed as a mechanism for maintaining peripheral tolerance. However, the inability to isolate and clone regulatory T cells involved in antigen-specific inhibition of immune responses has made it difficult to understand the mechanisms underlying such suppression. Here, we show that chronic activation of both human and murine CD4+ T cells in the presence of interleukin (IL)-10 gives rise to CD4+ T-cell clones with low proliferative capacity, producing high levels of IL-10, low levels of IL-2 and no IL-4. These antigen-specific T-cell clones suppress the proliferation of CD4+ T cells in response to antigen, and prevent colitis induced in SCID mice by pathogenic CD4+CD45RBhigh splenic T cells. Thus IL-10 drives the generation of a CD4+ T-cell subset, designated T regulatory cells 1 (Tr1), which suppresses antigen-specific immune responses and actively downregulates a pathological immune response in vivo.

Animals↗
PubMed1997

Inflammatory bowel disease: an immunity-mediated condition triggered by bacterial infection with Helicobacter hepaticus.

Inflammatory bowel disease (IBD) is thought to result from either an abnormal immunological response to enteric flora or a normal immunological response to a specific pathogen. No study to date has combined both factors. The present studies were carried out with an immunologically manipulated mouse model of IBD. Mice homozygous for the severe combined immunodeficiency (scid) mutation develop IBD with adoptive transfer of CD4+ T cells expressing high levels of CD45RB (CD45RB(high) CD4+ T cells). These mice do not develop IBD in germfree conditions, implicating undefined intestinal flora in the pathogenesis of lesions. In controlled duplicate studies, the influence of a single murine pathogen, Helicobacter hepaticus, in combination with the abnormal immunological response on the development of IBD was assessed. The combination of H. hepaticus infection and CD45RB(high) CD4+ T-cell reconstitution resulted in severe disease expression similar to that observed in human IBD. This study demonstrates that IBD develops in mice as a consequence of an abnormal immune response in the presence of a single murine pathogen, H. hepaticus. The interaction of host immunity and a single pathogen in this murine system provides a novel model of human IBD, an immunity-mediated condition triggered by bacterial infection.

Animals↗