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Fiona Powrie

Publications and source records attributed to Fiona Powrie.

30 records · Page 2Linked to original sources
PubMed2004

Animal models of intestinal inflammation: clues to the pathogenesis of inflammatory bowel disease.

In the last decade a number of models of chronic intestinal inflammation have been described that resemble aspects of the pathology found in patients with inflammatory bowel disease. Several themes have emerged from these studies that are of relevance to the pathogenesis of inflammatory bowel disease. Firstly, intestinal inflammation is a consequence of an aberrant chronic immune response triggered by enteric bacteria. Both innate and adaptive immune mechanisms can cause colitis and in many models there is evidence of differential activation of T helper 1 (Th1)-type cells. Targeting the Th1 pathway prevents experimental colitis and there is also evidence that this may be useful in Crohn's disease. Secondly, specialized populations of regulatory T cells have been shown to prevent colitis and in some systems cure it, suggesting immune responses in the intestine are subject to dominant T cell-mediated control. Here we focus on new insights into the pathogenesis and regulation of intestinal inflammation as revealed by model systems and how these may be harnessed for the treatment of IBD.

Animals↗
PubMed2003

Colitogenic Th1 cells are present in the antigen-experienced T cell pool in normal mice: control by CD4+ regulatory T cells and IL-10.

CD4(+) regulatory T cells have been shown to prevent intestinal inflammation; however, it is not known whether they act to prevent the priming of colitogenic T cells or actively control these cells as part of the memory T cell pool. In this study, we describe the presence of colitogenic Th1 cells within the CD4(+)CD45RB(low) population. These pathogenic cells enrich within the CD25(-) subset and are not recent thymic emigrants. CD4(+)CD45RB(low) cells from germfree mice were significantly reduced in their ability to transfer colitis to immune deficient recipients, suggesting the presence of commensal bacteria in the donor mice drives colitogenic T cells into the Ag-experienced/memory T cell pool. This potentially pathogenic population of Ag-experienced T cells is subject to T cell-mediated regulation in vivo by both CD4(+)CD25(+) and CD4(+)CD25(-) cells in an IL-10-dependent manner. Furthermore, administration of an anti-IL-10R mAb to unmanipulated adult mice was sufficient to induce the development of colitis. Taken together, these data indicate that colitogenic Th1 cells enter into the Ag-experienced pool in normal mice, but that their function is controlled by regulatory T cells and IL-10. Interestingly, IL-10 was not absolutely required for CD4(+)CD25(+) T cell-mediated inhibition of colitis induced by transfer of naive CD4(+)CD45RB(high) cells, suggesting a differential requirement for IL-10 in the regulation of naive and Ag-experienced T cells.

Animals↗
PubMed2003

Cutting edge: cure of colitis by CD4+CD25+ regulatory T cells.

CD4(+)CD25(+) regulatory T cells have been shown to prevent T cell-mediated immune pathology; however, their ability to ameliorate established inflammation has not been tested. Using the CD4(+)CD45RB(high) T cell transfer model of inflammatory bowel disease, we show that CD4(+)CD25(+) but not CD4(+)CD25(-)CD45RB(low) T cells are able to cure intestinal inflammation. Transfer of CD4(+)CD25(+) T cells into mice with colitis led to resolution of the lamina propria infiltrate in the intestine and reappearance of normal intestinal architecture. CD4(+)CD25(+) T cells were found to proliferate in the mesenteric lymph nodes and inflamed colon. They were located between clusters of CD11c(+) cells and pathogenic T cells and found to be in contact with both cell types. These studies suggest that manipulation of CD4(+)CD25(+) T cells may be beneficial in the treatment of chronic inflammatory diseases.

Adoptive Transfer↗
PubMed2003

CD4+CD25+ T(R) cells suppress innate immune pathology through cytokine-dependent mechanisms.

CD4(+)CD25(+) regulatory T (T(R)) cells can inhibit a variety of autoimmune and inflammatory diseases, but the precise mechanisms by which they suppress immune responses in vivo remain unresolved. Here, we have used Helicobacter hepaticus infection of T cell-reconstituted recombination-activating gene (RAG)(-/-) mice as a model to study the ability of CD4(+)CD25(+) T(R) cells to inhibit bacterially triggered intestinal inflammation. H. hepaticus infection elicited both T cell-mediated and T cell-independent intestinal inflammation, both of which were inhibited by adoptively transferred CD4(+)CD25(+) T(R) cells. T cell-independent pathology was accompanied by activation of the innate immune system that was also inhibited by CD4(+)CD25(+) T(R) cells. Suppression of innate immune pathology was dependent on T cell-derived interleukin 10 and also on the production of transforming growth factor beta. Thus, CD4(+)CD25(+) T(R) cells do not only suppress adaptive T cell responses, but are also able to control pathology mediated by innate immune mechanisms.

Adoptive Transfer↗
PubMed2003

Control of immune pathology by regulatory T cells.

CD4+CD25+ T(reg) cells inhibit colitis in the severe combined immune deficient (SCID) T cell adoptive transfer model. Cells with this function are present in the thymus suggesting that T(reg) cells capable of inhibiting bacteria-induced immune pathology are similar to those that inhibit organ-specific autoimmunity. CD4+CD25+ T(reg) cells inhibit both T cell-dependent and T cell-independent intestinal inflammation. The latter point illustrates that in addition to direct effects on other T cells, T(reg) cells can alsoprevent immune pathology in vivo by inhibiting the actions of innate immune cells. T(reg) cells suppress intestinal inflammation through mechanisms that involve interleukin 10 and transforming growth factor beta and blockade of the negative regulator of T cell activation CTLA4 abrogates T(reg) cell function in vivo. Importantly adoptive transfer of CD4+CD25+ T(reg) cells to mice with established colitis reverses inflammation and restores normal intestinal architecture suggesting that CD4+CD25+ T(reg) cells may be utilized for cellular therapy of inflammatory diseases.

Adoptive Transfer↗
PubMed2002

Depletion of CD25+ regulatory cells results in suppression of melanoma growth and induction of autoreactivity in mice.

Treatment with monoclonal antibodies (mAbs) specific for CD25 (anti-CD25 mAb) has been shown to suppress growth of a variety of different tumours in mice. These studies did not however determine whether or not anti-CD25 mAbs facilitate tumour rejection by depletion of regulatory T cells or by binding to tumour-specific effector cells. Using a murine model of melanoma we have found that treatment of mice with anti-CD25 mAb facilitates long-term CD4+ T cell-mediated tumour immunity through depletion of CD25+ regulatory cells. We further show that the effector CD4+ T cells confer long-term tumour immunity even in the presence of CD25+ regulatory cells and do not require CD8+ T cells for tumour rejection. The inhibitory impact of anti-CD25 mAb treatment on tumour growth may be the result of depleting CD25+ regulatory cells that normally inhibit the generation of immune responses to self-antigens that are shared by the tumour. We have performed experiments to determine whether or not immune responses to melanocyte antigens are generated in anti-CD25 mAb-treated, melanoma-immune mice. The results of the experiments indicate that a T cell response to the melanocyte antigen tyrosinase accompanies suppression of tumour growth in mice lacking CD25+ regulatory cells.

Animals↗
PubMed2002

CTLA-4 expression on antigen-specific cells but not IL-10 secretion is required for oral tolerance.

CD4(+) T cells play a vital role in mediating the tolerance induced at mucosal sites following exposure to non-pathogenic stimuli, and further understanding of the precise mechanisms by which these cells prevent aberrant responses is required. We have developed a model using transfer of DO11.10 TCR-transgenic bone marrow into irradiated recipients in which it has been possible to track antigen-specific CD4(+) cells in mesenteric lymph nodes (mLN), Peyer's patches (PP) and lamina propria following primary exposure to antigen. Using this model we have demonstrated initial activation in all three gut-associated lymphoid tissue compartments characterized by increases in the frequency of transgenic cells expressing CD69 and CD25. These cells subsequently enter a state of hyporesponsiveness both locally in the mLN and PP and in the periphery following feeding and challenge. Investigating the role of CTLA-4 either using anti-CTLA-4 mAb or by generating chimeras using DO11.10xCTLA-4(-/-) mice as donors we have clearly shown that antigen-specific cells require the expression of this regulatory molecule for oral tolerance. In contrast, oral tolerance was intact in chimeras generated using DO11.10xIL-10(-/-) cells, indicating that secretion of this cytokine by antigen-specific cells is not required.

Abatacept↗
PubMed2002

Depletion of CD25+ regulatory cells uncovers immune responses to shared murine tumor rejection antigens.

Although it is known that the immune system can mount responses to a variety of tumors it is clear that most tumors exhibit weak or even undetectable immunogenicity. Recent findings suggest that the lack of tumor immunogenicity is partly due to a population of cells called CD4+ CD25+ regulatory T cells since depletion of these cells in mice can result in tumor rejection. These cells have also been shown to inhibit the development of organ-specific autoimmune diseases suggesting that they inhibit immune responses to tissue-specific self-antigens. Such immune responses may also mediate tumor rejection. Alternatively, immune responses in mice depleted of regulatory cells may target tumor antigens that are not tissue-specific, but which are shared by tumors of diverse origins. In experiments performed to discriminate between these possibilities we found, using the murine colorectal tumor CT26, that tumor immunity stimulated in the absence of regulatory cells is not restricted to tumors of colorectal origin, but is effective against tumors of different histological types such as B cell lymphomas and a renal cell carcinoma. By comparing this to CT26-induced immunity through the use of adjuvant we show that the generation of cross-reactive tumor immunity is a specific manifestation of CD25+ regulatory cell depletion. The generation of CD4+ T cells capable of mediating tumor rejection is another important feature of tumor immunity induced in the absence of CD25+ cells.

Animals↗
PubMed2002

Homeostasis of intestinal immune regulation.

Regulatory CD4 T cells with the capacity to inhibit potentially harmful immune responses have been described in various experimental systems. Although the observations are converging towards the naturally activated CD25(+) CD4 T cells as a major population responsible for this protection, there is still considerable disagreement on the molecular and cellular requirements involved to achieve a stable immune homeostasis in vivo.

CD4-Positive T-Lymphocytes↗