| 1. |
- Bjursten, Malin, 1976, et al.
(författare)
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Dietary antigen-specific T-cell responses: switch from an interleukin-10-dominated response in normal mice to a T-helper 1 cytokine profile in Galphai2-deficient mice prior to colitis.
- 2005
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Ingår i: Scandinavian journal of immunology. - : Wiley. - 0300-9475 .- 1365-3083. ; 61:1, s. 29-35
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Tidskriftsartikel (refereegranskat)abstract
- We investigated dietary antigen-specific T-cell responses in mesenteric lymph nodes (MLN) and Peyer's patches (PP) in noncolitic control mice as well as in colitis-prone mice prior to onset of histological active colitis. T cells were restimulated in vitro with constituents isolated from the mouse diet. Interestingly, MLN T cells of littermate G(alpha)i2+/- control mice responded to soya with high production of interleukin (IL)-10, but did not produce proinflammatory T-helper 1 (Th1) cytokines. Recall dietary antigen stimulation of G(alpha)i2+/- PP T cells did not result in increased IL-10 production above the spontaneous production in the absence of antigenic stimulation. In strong contrast, MLN T cells from precolitic G(alpha)i2-/- mice produced high levels of interferon-gamma (IFN-gamma) upon restimulation with soya, which could be abolished using a major histocompatibility complex class II-blocking antibody. In conclusion, the present study demonstrates that MLN T lymphocytes in normal healthy mice respond with a significantly increased production of the regulatory cytokine IL-10 on re-encounter with dietary proteins in vitro. In marked contrast precolitic G(alpha)i2-/- mice respond to dietary antigens with a Th1-dominated cytokine response in the mucosa, prior to onset of colitis, with excessive IFN-gamma production. These results suggest that aberrant immune responses to dietary antigens could contribute as a potential pathogenic mechanism in the onset of colitis in G(alpha)i2-deficient mice.
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| 2. |
- Bjursten, Malin, 1976, et al.
(författare)
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Enhanced pro-inflammatory cytokine production in Galphai2-deficient mice on colitis prone and colitis resistant 129Sv genetic backgrounds.
- 2004
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Ingår i: Cellular immunology. - : Elsevier BV. - 0008-8749. ; 228:2, s. 77-80
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Tidskriftsartikel (refereegranskat)abstract
- Mice deficient in G-protein subunit alphai2 develop colitis closely resembling human ulcerative colitis when raised on 129SvEv background. When backcrossing the Galphai2-deficiency into a 129SvJBom genetic background, surprisingly, mice did not develop colitis. In vitro stimulation of splenocytes with formalin-killed Staphylococcus aureus resulted in significantly increased production of interleukin-1beta, tumor necrosis factor, and interleukin-12p40 in Galphai2(-/-) as compared to control mice. The enhanced production of pro-inflammatory cytokines was seen in colitis prone as well as in colitis resistant genetic background. A similar outcome was seen upon stimulation with toxic shock syndrome toxin-1, a T cell superantigen, except that Galphai2(-/-) colitis resistant 129SvJBom splenocytes did not show increased production of IL-12p40 as compared to their controls.
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| 3. |
- Bjursten, Malin, 1976, et al.
(författare)
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Long-term treatment with anti-alpha 4 integrin antibodies aggravates colitis in G alpha i2-deficient mice.
- 2005
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Ingår i: European journal of immunology. - : Wiley. - 0014-2980 .- 1521-4141. ; 35:8, s. 2274-83
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Tidskriftsartikel (refereegranskat)abstract
- Targeted deletion of the heterotrimeric G protein, Galphai2, in mice induces lethal colitis closely resembling ulcerative colitis. In chronic colitis, migration of circulating leukocytes into the intestinal mucosa is partially dependent on alpha4 integrins. In previous studies, short-term administration of anti-alpha4 integrin antibodies has been shown to attenuate intestinal inflammation, and here we elucidate the effect of long-term administration of anti-alpha4 integrin antibodies on colitis in Galphai2(-/- )mice. Long-term blockade of alpha4 integrin significantly increased the severity of colitis in Galphai2(-/-) mice. The inflammation was confined to the colon, associated with increased cancer in situ, destruction of crypt architecture, and increased production of IL-1beta, TNF-alpha and IFN-gamma. Blockade of alpha4 integrin reduced the recruitment of activated T cells to the small intestine. In strong contrast, there were significantly higher numbers of activated T cells in the colonic lamina propria and epithelium, most probably due to in situ proliferation. Furthermore, treatment with alpha4 integrin antibodies induced decreased levels of total IgA and IgG in sera, whereas total IgM levels were unchanged. These new findings may have implications in the understanding of the progression of chronic intestinal inflammation.
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| 4. |
- Bjursten, Malin, 1976
(författare)
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T Cell Ontogeny and Effector Functions in Galphai2-deficient Colitis
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Inflammatory bowel disease (IBD) comprising Crohn s disease and ulcerative colitis is a disease that affects millions of people worldwide, especially in northern countries such as Sweden, and is characterised by chronic uncontrolled inflammation of the intestinal mucosa. It is the general belief that multiple factors such as genetic and environmental aspects are involved in disease pathogenesis. Alterations in T cell subsets, an important cell type in cell-mediated immune responses in the adaptive immune system, are certainly one element contributing to disease development. The present work was aimed at elucidating the role of the T cells in the pathogenesis of a mouse model for inflammatory bowel disease, Galphai2-deficient (Galphai2-/-) mice. These mice spontaneously develop a lethal colitis strikingly similar to ulcerative colitis in humans. This study demonstrates that one or several secondary genetic factor(s) in addition to the Galphai2 deficiency, possibly involving regulation of IL-12p40 production, has to be fulfilled for colitis to develop. Galphai2-deficient mice were shown to have a seriously impaired T cell development associated with accelerated thymic involution, decreased recruitment of T cell precursors to the thymus due to diminished responsiveness to CXCL12, reduced frequency of apoptotic CD4+CD8- and CD4-CD8+ thymocytes suggesting impaired negative selection, and insufficient down regulation of CD69 on mature CD4+ T cells, indicating impaired thymic egression. The impaired T cell ontogeny in Galphai2-/- mice was demonstrated to have great implications on the ability of the peripheral T cell repertoire to regulate the normal state of "physiologic inflammation" in the intestinal mucosa: Splenic, but not mesenteric lymph node Galphai2-/- T cells, were shown to be highly colitogenic when adoptively transferred into immunodeficient hosts. The effector function of peripheral as well as mucosal T cells from Galphai2-/- mice were shown to be T helper 1 (Th1) dominated following stimulation with superantigens, bacterial products or dietary proteins. Th1 associated and pro-inflammatory mediators such as IFN-gamma and IL-12 are likely to instigate the immune response initiating what will result in established chronic colitis in Galphai2-/- mice. Furthermore, we show that the lifespan of Galphai2-/- mice could be substantially prolonged following reconstitution with wild type bone marrow cells. Finally and surprisingly, by inhibiting the recruitment of T cells to the inflamed tissue by administration of antibodies specific for integrin alpha4, the colonic inflammation was aggravated. The aggravated colitis was accompanied by increased production of pro-inflammatory cytokines such as IL-1beta, TNF-alpha and IFN-gamma and was believed to be, at least in part, explained by in situ proliferation of activated mucosal resident T cells. Collectively these results conclude that T cells are highly important for disease development in Galphai2-/- mice.
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| 5. |
- Bjursten, Malin, 1976, et al.
(författare)
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Transfer of colitis by Galphai2-deficient T lymphocytes: impact of subpopulations and tissue origin.
- 2005
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Ingår i: Inflammatory bowel diseases. - 1078-0998. ; 11:11, s. 997-1005
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Tidskriftsartikel (refereegranskat)abstract
- To elucidate the potential cell population(s) involved in the induction of colitis in inhibitory G protein Galphai2(-/-) mice, Galphai2-deficient or competent bone marrow or splenic and mesenteric lymph node (MLN) T cells were transferred into immunodeficient mice. The mice were followed up to 23 weeks after transfer, recording changes in body weight. Colitis was graded on hematoxylin and eosin-stained colonic tissue, and production of serum interleukin-18 and colon-derived interferon-gamma was measured using ELISA. After adoptive transfer of Galphai2(-/-) bone marrow, severe colitis developed in irradiated wild type recipients, whereas irradiated Galphai2(-/-) mice increased their life span more than 3 times after transfer of wild type bone marrow, accompanied by significant amelioration of colitis. Neither purified Galphai2(-/-) CD4(+), nor CD8(+) splenic or MLN-derived T cells could induce colitis in recombination-activating gene V(RAG) 2(-/-) recipient mice, whereas transfer of splenic Galphai2(-/-) CD3(+) T cells induced severe colitis. In contrast, transfer of Galphai2(-/-) CD3(+) T cells from the MLN caused only minor histopathological changes in the intestinal mucosa. Finally, serum levels of interleukin-18 and interferon-gamma production from colonic tissue cultures correlated well with disease severity. Our results show that bone marrow transplantation can prolong the life of Galphai2(-/-) mice and ameliorate intestinal inflammation. Splenic CD4(+) or CD8(+) T cells on their own were poor inducers of colitis, whereas the combination of both was highly involved in the induction of intestinal inflammation. Furthermore, we show that the tissue origin of CD3(+) T cells is critical for their potency to induce colitis.
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| 6. |
- Elgbratt, Kristina, 1969, et al.
(författare)
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Aberrant T-cell ontogeny and defective thymocyte and colonic T-cell chemotactic migration in colitis-prone Galphai2-deficient mice
- 2007
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Ingår i: Immunology. - : Wiley. - 0019-2805 .- 1365-2567. ; 122:2, s. 199-209
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Tidskriftsartikel (refereegranskat)abstract
- Galphai2-deficient mice, which spontaneously develop colitis, have previously been reported to have an increased frequency of mature, single positive thymocytes compared to wild-type mice. In this study we further characterized the intrathymic changes in these mice before and during overt colitis. Even before the onset of colitis, Galphai2(-/-) thymi weighed less and contained fewer thymocytes, and this was exacerbated with colitis development. Whereas precolitic Galphai2(-/-) mice had unchanged thymocyte density compared to Galphai2(+/-) mice of the same age, this was significantly decreased in mice with colitis. Thymic atrophy in Galphai2(-/-) mice involved mainly the cortex. Using a five-stage phenotypic characterization of thymocyte maturation based on expression of CD4, CD8, TCRalphabeta, CD69 and CD62L, we found that both precolitic and colitic Galphai2(-/-) mice had significantly increased frequencies of mature single-positive CD4(+) and CD8(+) medullary thymocytes, and significantly reduced frequencies and total numbers of immature CD4(+) CD8(+) double-positive thymocytes compared to Galphai2(+/-) mice. Furthermore, cortical and transitional precolitic Galphai2(-/-) thymocytes showed significantly reduced chemotactic migration towards CXCL12, and a trend towards reduced migration to CCL25, compared to wild-type thymocytes, a feature even more pronounced in colitic mice. This impaired chemotactic migration of Galphai2(-/-) thymocytes could not be reversed by increased chemokine concentrations. Galphai2(-/-) thymocytes also showed reduced expression of the CCL25 receptor CCR9, but not CXCR4, the receptor, for CXCL12. Finally, wild-type colonic lamina propria lymphocytes migrated in response to CXCL12, but not CCL25 and, as with thymocytes, the chemokine responsiveness was significantly reduced in Galphai2(-/-) mucosal lymphocytes.
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| 7. |
- Hultgren, Olof H., 1970, et al.
(författare)
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Serum interleukin-1 receptor antagonist is an early indicator of colitis onset in Galphai2-deficient mice.
- 2006
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Ingår i: World journal of gastroenterology : WJG. - 1007-9327. ; 12:4, s. 621-4
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Tidskriftsartikel (refereegranskat)abstract
- AIM: To study the serum concentration of IL-1beta, IL-1 receptor antagonist (IL-1Ra) and IL-18 in Galphai2-deficient mice at the age of 6 (healthy), 12 (pre-colitic) and 24 wk (colitic) and in healthy control mice. METHODS: At the time of killing, serum samples were collected and IL-1beta, IL-1Ra and IL-18 levels were measured using enzyme-linked immunosorbent assays. RESULTS: Serum concentration of IL-1Ra was significantly increased in pre-colitic (median: 524 ng/L; P=0.02) and colitic (450 ng/L; P=0.01), but not in healthy (196 ng/L) Galphai2-deficient mice as compared with controls (217 ng/L). Serum concentrations of IL-1beta did not differ between Galphai2-deficient mice and their controls, irrespective of age, IL-18 was significantly increased in colitic, but not in pre-colitic mice compared with controls (510 ng/L vs 190 ng/L; P=0.05). CONCLUSION: The increased serum concentrations of IL-18 and IL-1Ra in established diseases are suggested as markers of ongoing colitis. Interestingly, the significantly increased serum concentration of IL-1Ra in pre-colitic mice is found to be an early marker of disease progression.
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