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PubMed2003

Engineered lymphocytes to treat dinitrobenzene sulphonic acid colitis in mice.

Current treatments of inflammatory bowel diseases are limited either by their lack of efficacy or their potential toxicity. In recent years, major advances have been obtained by the development of biological therapies. However, these types of treatment are systemic and can lead to serious adverse events. The new venue of local biological treatments would be most welcome. In this issue of the Journal, Castagliuolo et al. show that lymphocytes engineered to produce TGF-beta1 can reverse dinitrobenzene sulphonic acid-induced colitis in mice. These engineered lymphocytes selectively accumulate in the intestinal mucosa due to the homing properties of their alpha4beta7 integrins, a ligand for MAdCAM1. A local treatment restricted to the inflamed mucosa can thus be obtained. This opens a brand new area of research with the hope of restoring the immunoregulatory balance selectively in the inflamed tissues.

Animals↗
PubMed2005

Leukocytapheresis therapy modulates circulating t cell subsets in patients with ulcerative colitis.

The aim of this study was to elucidate the molecular mechanisms responsible for the therapeutic effects of leukocytapheresis (LCAP). We investigated the alterations in circulating T cell subsets after LCAP therapy in ulcerative colitis (UC) patients. Eighteen patients with UC were enrolled. Fourteen patients were responders, and four patients were non-responders. Peripheral venous blood was obtained within 5 min before and 5 min after LCAP therapy. Flow cytometric analysis for T cell markers and intracellular interferon (IFN)-gamma (Th1) and interleukin (IL)-4 (Th2) was then performed. The average numbers of lymphocytes, T and B cells were significantly decreased after LCAP therapy, respectively (P < 0.01). The numbers of CD4+ and CD8+ T cells were also significantly decreased, respectively (P < 0.01), but the CD4+/CD8+ ratio was not changed. The number of CD45RO+ CD4+ memory T cells was significantly decreased. The number of CD25+ CD4+ T cells tended to decrease after LCAP therapy (not significant). However, the ratio of CD25+ CD4+-cells/CD25- CD4+-cells was significantly increased (P < 0.05). The number of IFN-gamma-positive (Th1) cells was significantly decreased after LCAP therapy, but there was no significant change in the number of IL-4-positive (Th2) cells. The Th1/Th2 ratio was significantly decreased after LCAP therapy. Some of the immuno-suppressive effects of LCAP therapy may be associated with a modulation of circulating T cell subsets.

Adult↗
PubMed2005

Colitic scid mice fed Lactobacillus spp. show an ameliorated gut histopathology and an altered cytokine profile by local T cells.

BACKGROUND: Scid mice transplanted with CD4 T blast cells develop colitis. We investigated if the disease was influenced in colitic mice treated with antibiotic and fed Lactobacillus spp. METHODS: Colitic scid mice were treated for 1 week with antibiotics (vancomycin/meropenem) followed or not followed by a 3-week administration of Lactobacillus reuteri DSM-12246 and Lactobacillus rhamnosus 19070-2 at 2x10 live bacteria/mouse/24 hours. After 12 weeks, the rectums were removed for histology, and CD4 T cells from the mesenteric lymph nodes (MLN) were polyclonally activated for cytokine measurements. RESULTS: Irrespective of no treatment or treatments with antibiotics and probiotics, all mice transplanted with T cell blasts lost 10% of their body weight during the 12-week experimental period, whereas the nontransplanted mice had a 10% weight increase (P<0.001). All mice treated with antibiotics but not fed probiotics showed severe gut inflammation, whereas only 2 of the 7 mice fed probiotics showed signs of severe colitis (P<0.05). MLN-derived CD4 T cells from this latter group of mice showed lower levels of interleukin-4 secretion (P<0.05) and a tendency to higher interferon-gamma production than mice not fed probiotics. CONCLUSIONS: Our data suggest that probiotics added to the drinking water may ameliorate local histopathological changes and influence local cytokine levels in colitic mice but not alter the colitis-associated weight loss.

Animal Feed↗
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.

Animals↗
PubMed1988

T-cell immunoregulation in patients with inflammatory bowel disease. I. Differential helper T-cell function in ulcerative colitis and Crohn's disease.

The role of helper T-cells in patients with ulcerative colitis (UC) and Crohn's disease (CD) was investigated. Peripheral blood B- and T-cells with or without monocytes were obtained from patients and normal adults of the same age and sex, and co-cultured for 10 days with pokeweed mitogen (PWM). Immunoglobulins (Ig) M, G and A were measured in the culture supernatants using a sensitive enzyme-linked immunosorbent assay. The quantity of Ig present in the culture supernatants was determined from a standard curve. Immunoglobulins M, G and A synthesis and secretion by B-cells in the presence of T-cells required monocytes and PWM. The data indicate that co-cultures of heterologous normal adult T-cells and B-cells with PWM did not significantly affect Ig synthesis as compared with autologous cultures. Autologous cultures of CD patients' B- and T-cells were found not to be significantly different from normals in their capacity to synthesize Ig. In contrast, autologous UC patients' B- and T-cells were found to be significantly less effective as compared with normal adults' co-cultures in the synthesis Ig. When CD patients' T-cells were in co-culture with normal adults' B-cells, Ig synthesis was maintained. However, a marked diminution in Ig synthesis was seen when UC patients' T-cells were used in co-culture with normal adults' B-cells. The degree of inhibition of immunoglobulin synthesis did not correlate with disease activity, duration of illness, location of disease, or corticosteroid treatment. These results suggest that patients with ulcerative colitis have an altered helper T-cell population while CD patients' T-cells are either normal or hyperactive in the capacity to provide helper function in PWM-induced immunoglobulin secretion by peripheral blood B-cells.

Adult↗
PubMed1985

Elevated numbers of peripheral T cells in inflammatory bowel diseases displaying T9 antigen and Fc alpha receptors.

Elevated numbers of peripheral T cells expressing the activation associated antigen T9 are found in patients with active Crohn's disease. Expression of T9 is found to be correlated to the activity of the disease. However the presence of activated peripheral T cells is not restricted to Crohn's disease, but could also be found in other maladies with a supposed involvement of the immune system, e.g. ulcerative colitis, sarcoidosis, connective tissue disease and after organ transplantation. Significant elevation of the number of activated T cells could not be detected in cases of viral or bacterial enteritis and coeliac disease. Analysing the subset of T9 positive T cells with regard to the expression of Fc alpha receptors, a significantly increased number of Fc alpha receptor positive cells, within the subset of T9 positive cells in the peripheral blood of patients with Crohn's disease and ulcerative colitis was found, which could not be demonstrated in the case of other diseases analysed in this study. Thus the T9+ Fc alpha receptor +T cell subset may be considered to be pathognomonic for inflammatory bowel diseases. Analysis of the regulatory properties of T9 positive cells, with regard to the immunoglobulin isotype secretion in a pokeweed mitogen stimulated autologeous B cell assay, suggests that peripheral T9 positive T cells are involved in the suppression of IgA synthesis or secretion.

Antigens↗
PubMed1986

Direct demonstration of immunoregulatory T-cell defects in patients with systemic lupus erythematosus.

The present study was undertaken to determine directly whether immunoregulatory T cells have a defective suppressor function in patients with systemic lupus erythematosus (SLE), and whether anti-T-cell antibodies are essential for immunoregulatory T-cell defects. Peripheral blood T cells and T-cell subsets were determined in 52 SLE patients. The ratio of T4 to T8 cells was distributed over a wider range in patients with SLE than in the controls. Patients with SLE were divided into three groups (low, normal and high) by the T4/T8 ratio. Lymphocytes from 12 SLE patients (7 with low and 5 with high T4/T8 ratios) were studied extensively. Their disease was inactive or in remission. Anti-T-cell antibodies were not detected, and yet the patients had immunological abnormalities characterized by the presence of antinuclear antibodies and hypergammaglobulinaemia. The SLE patients with high T4/T8 ratios had a decreased number of T8 cells, and defective suppressor-effector cells. In contrast, patients with low T4/T8 ratios had decreased T4 cells and/or increased T8 cells, and defective suppressor-inducer cells. Two patients with low T4/T8 ratios had both suppressor-effector and suppressor-inducer cell defects. These results indicate that immunoregulatory circuits in SLE patients are heterogeneous and that immunoregulatory defects exist even when the disease is inactive or in remission. Anti-T-cell antibodies were not essential for such immunoregulatory defects. Thus, immunoregulatory T-cell defects and the development of SLE may be independent conditions due to other unknown causes.

Adult↗
PubMed1999

Functional expression of costimulatory molecule CD86 on epithelial cells in the inflamed colonic mucosa.

BACKGROUND & AIMS: Costimulatory signals are essential for T-cell activation. The aim of this study was to demonstrate expression of costimulatory molecules CD86 and CD80 in human colonic epithelial cells and assess their functional roles in the activation of T cells in inflamed colonic mucosa. METHODS: CD86 and CD80 expression was assessed by immunohistochemistry of colonic mucosa, reverse-transcription polymerase chain reaction, and flow cytometric analysis of isolated colonic epithelial cells and cell lines. Costimulatory effect of CD86-expressing colonic epithelial cells on purified CD4(+) T-cell proliferation was also assessed at suboptimal phytohemagglutinin stimulation. RESULTS: CD86 and CD80 messenger RNA was detected in isolated colonic epithelial cells from normal and inflamed mucosa of patients with ulcerative colitis. Immunohistochemistry and flow cytometric analysis of colonic epithelial cells confirmed cell surface expression of CD86 protein in inflamed colonic mucosa. Cell surface expression of CD86 protein was increased in the colonic epithelial cell line HT29-18-N2 after interferon gamma stimulation. Purified CD4(+) T cells proliferated in response to suboptimal phytohemagglutinin costimulated with interferon gamma-stimulated HT29-18-N2, and these proliferative responses were efficiently inhibited by the addition of anti-CD86 monoclonal antibody. Costimulatory effect of CD86-expressing colonic epithelial cells isolated from inflamed mucosa of ulcerative colitis was also demonstrated at suboptimal phytohemagglutinin stimulation in CD4(+) T cells. CONCLUSIONS: Colonic epithelial cells may act as antigen-presenting cells, and contribute to the activation of T cells through costimulatory molecule CD86 expression in inflamed colonic mucosa.

Antigen-Presenting Cells↗
PubMed1997

Ulcerative colitis: an immunological disease?

Ulcerative colitis is an inflammatory disease of the large intestine of unknown aetiology. The nature of the inflammatory infiltrate together with the response to corticosteroids suggests that an abnormal immune response is at work. The key question of whether the immune system is responding to an abnormal breach in the mucosa due to another primary abnormality or whether the primary defect lies within the immune response itself has not been answered. Thus far, it is clear that both T and B cell compartments are involved in the persistence of inflammation but the initial interactions that take place in the mucosa in terms of antigen processing and presentation have not been adequately investigated. Those critical steps and potential defects that push T cells and B cells into a heightened state of activation need to be identified.

Animals↗
PubMed1986

Immunohistological characterization of intraepithelial and lamina propria lymphocytes in control ileum and colon and in inflammatory bowel disease.

Using monoclonal antibodies to T and B lymphocytes, to natural killer cells, and to HLA-DR antigen, we characterized the lymphocyte population within the epithelial and lamina propria regions in control intestine and colon, and in grossly involved and in grossly uninvolved intestine and colon of patients with active inflammatory bowel disease. There were significantly more intraepithelial T cells in control ileum than in control colon. In comparison to control, there was a heterogeneity of alterations in intraepithelial and lamina propria T lymphocyte subsets (T11+, T8+, T4+) in inflammatory bowel disease. B lymphocytes were not detected within the lamina propria, except when found in and adjacent to lymphoid aggregates. Leu 7+ cells were uncommon in the lamina propria of control ileum and colon and in diseased tissues. The majority of intraepithelial lymphocytes did not express HLA-DR. Epithelial cells of control colon did not express HLA-DR while epithelial cells of control ileal tissues and of diseased colonic and ileal specimens expressed HLA-DR antigen. Only small numbers of lamina propria T cells expressed HLA-DR in both control and disease tissues. There was intense expression of HLA-DR by monocytes and modest expression of HLA-DR by capillary and lymphatic endothelial cells. The induction of HLA-DR expression by diseased colonic epithelium and the observation that lymphatic endothelium expresses HLA-DR are new observations, and we established that Leu 7+ cells are present in very small numbers in both normal and diseased intestine and colon.

Antibodies, Monoclonal↗
PubMed2006

CD8+ cytotoxic T cells induce relapsing colitis in normal mice.

BACKGROUND & AIMS: Most mouse models of IBD have emphasized an effector role of type-1 CD4+ T cells in colitis. The aim of this study was to develop a model of antigen-specific relapsing colitis to investigate the relative contribution of CD4+ and CD8+ effectors. METHODS: Balb/C mice were sensitized and challenged with a suboptimal dose of 2.4 dinitrobenzene sulfonic acid to generate a colonic delayed-type hypersensitivity response. The respective role of CD4+ and CD8+ T cells in the initiation of colitis was analyzed by in vivo monoclonal antibody depletion and cell-transfer experiments. Dynamic and function of the colitogenic effectors were studied by immunohistochemistry, fluorescence-activated cell sorter analysis, enzyme-linked immunospot assay, quantitative polymerase chain reaction, and in vivo CTL assays. RESULTS: Relapsing colitis rapidly occurred only after challenge of previously sensitized mice. Interferon-gamma-producing cytotoxic CD8+ T cells (Tc1) specific for hapten-modified self-proteins were generated in colon-draining lymph nodes on day 5 after sensitization, before the onset of disease. These CD8+ T cells were rapidly recruited upon challenge into colon lamina propria as granzyme B-expressing effectors exerting ex vivo cytotoxicity against syngeneic hapten-modified colonic epithelial cells. Colitis was prevented by in vivo antibody depletion of CD8+, but not of CD4+, T cells and could be induced in naive recipients within 48 hours after transfer of CD8+, but not CD4+, T cells purified from sensitized mice. CONCLUSIONS: Our data show that antigen-specific CD8+ T cells can induce relapsing colitis in normal mice and suggest that the cytolytic function of CD8 Tc1 against epithelial cells may initiate the intestinal inflammatory process.

Animals↗
PubMed2005

MyD88-deficient mice develop severe intestinal inflammation in dextran sodium sulfate colitis.

BACKGROUND: Gut commensal microbes affect the development and activation of the mucosal and systemic immune systems. However, the exact molecular mechanism of these microbes that is involved in the development of colitis remains unclear. METHODS: The present study was conducted to determine the distinct role of the innate immune system in the development of a dextran sulfate sodium (DSS) colitis model in MyD88(-/-) mice, because myeloid differentiation protein (MyD88) is a major adaptor molecule essential for signaling via Toll-like receptors (TLRs). To this end, MyD88(-/-) and wild-type (WT) mice received sterile distilled water containing 1.2% DSS for 8 days. The survival rate, total clinical score (body weight loss, stool consistency, and rectal bleeding), colon length, and histological score were assessed. The expression of surface markers (F4/80 and CD4) on infiltrating lamina propria mononuclear cells was analyzed immunohistochemistrically. RESULTS: MyD88(-/-) mice exhibited increased susceptibility to DSS-induced colitis, as reflected by significantly higher lethality and higher clinical and histological scores, and more severe colonic shortening compared to WT mice. Immunohistochemical analysis revealed a significant increase of both F4/80+ macrophages and CD4+ T cells in the inflamed mucosa in DSS-fed MyD88(-/-) mice compared to DSS-fed WT mice. CONCLUSIONS: These findings suggest that, via MyD88 signaling, the innate immune system in the gut plays an important protective role in colitis.

Adaptor Proteins, Signal Transducing↗
PubMed1995

Perinuclear anti-neutrophil cytoplasmic antibodies are spontaneously produced by mucosal B cells of ulcerative colitis patients.

Approximately 60% of sera from ulcerative colitis (UC) patients contains Igs reactive with neutrophil components, raising the question of the origin of these anti-neutrophil cytoplasmic Abs (ANCA). Our assertion that ANCA is a marker for a mucosal disease-related immune response predicts the existence of ANCA producing B cell clones in the lamina propria lymphocyte (LPL) fraction of UC patients. This hypothesis was tested by examining 12-day culture supernatants of LPL ANCA expression. LPL were isolated from surgically removed mucosa from patients with UC, Crohn's disease (CD), and diverticulitis. Normal mucosa was obtained from accident victims or normal margins of colon cancer resections. Supernatants were assayed by a fixed neutrophil ELISA. The ANCA staining pattern of supernatants expressing ANCA, as determined by ELISA, was assessed by indirect immunofluorescent staining of alcohol-fixed neutrophils. ANCA was found in 70% of culture supernatants from UC LPL fractions. In contrast, only approximately 11% of supernatants from CD and diverticulitis/normal (noninflammatory bowel disease (IBD)) LPL displayed ANCA binding. A perinuclear (pANCA) staining pattern was obtained with 70% of ANCA-expressing UC LPL supernatants, whereas ANCA-expressing CD and non-IBD LPL supernatants displayed a cytoplasmic reaction. PBL and mesenteric lymph node lymphocytes lacked spontaneous pANCA production, and pANCA production from PBL was not inducible. These findings indicate the existence of pANCA-producing B cell clones in mucosal lesions of UC patients and support our hypothesis that pANCA production is a consequence of a mucosal immune response specific to UC.

Autoantibodies↗
PubMed1999

Colitis in transgenic and knockout animals as models of human inflammatory bowel disease.

Spontaneous colitis in knockout (KO) and transgenic rodents provides experimental models to study the development of mucosal inflammation and inflammatory bowel disease (Crohn's disease and ulcerative colitis). Genetic and environmental factors, particularly the normal enteric flora, are important factors in the development of mucosal inflammation. The normal mucosal homeostasis is disrupted when there is either cytokine imbalance, abrogation of oral tolerance, alteration of epithelial barrier and function or loss of immunoregulatory cells. Some but not all immunodeficiencies, in the appropriate setting, lead to colitis. CD4+ T cells have been identified as the pathogenic T cells in colitis, which mediate inflammation by either the Th1 or the Th2 pathway. The Th1 pathway dominates most colitis models and in Crohn's disease. In contrast, the colitis in TCR alpha KO mice shares many features of ulcerative colitis including the dominance of Th2 pathway in colonic inflammation. A major benefit of these models is in the development of therapeutic strategies for the treatment of inflammatory bowel disease.

Animals↗