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PubMed2001

Role of T lymphocytes in rat 2,4,6-trinitrobenzene sulphonic acid (TNBS) induced colitis: increased mortality after gammadelta T cell depletion and no effect of alphabeta T cell depletion.

BACKGROUND AND AIM: Indirect evidence suggests that CD4+ T cells have a pathogenic while gammadelta T cells have a protective role in the initiation and perpetuation of inflammatory bowel disease. To define the role of T cell subsets in a rat colitis model (2,4,6-trinitrobenzene sulphonic acid (TNBS)) we analysed colitis severity after effective depletion of T helper cells, alphabeta T cells, or gammadelta T cells. METHODS: T helper cells, alphabeta T cells, or gammadelta T cells were depleted using previously described monoclonal antibodies directed at the CD4 molecule (OX38), the CD2 molecule (OX34, both depleting CD4+ T cells), the alphabeta T cell receptor (R73), and the gammadelta T cell receptor (V65). Depletion was verified by flow cytometry and/or immunohistology. Colitis was induced using intracolonic application of TNBS. RESULTS: Surprisingly, depletion of T helper cells or alphabeta T cells had no influence on survival, macroscopic or microscopic scores, or myeloperoxidase activity following colitis induction. In contrast, depletion of gammadelta T cells resulted in significantly increased mortality (V65: 73%, n=15) compared with controls (30%, n=13; p<0.03). In addition, colitis was histologically more severe in the gammadelta T cell depleted group compared with controls (p<0.05). CONCLUSIONS: T helper cells or alphabeta T cells did not influence the initiation or perpetuation of rat TNBS colitis. In contrast, gammadelta T cells had a protective role in rat TNBS colitis as depletion caused increased mortality.

Animals↗
PubMed1994

Evidence for an altered T-cell receptor repertoire in Crohn's disease.

We have compared the frequencies of T cells expressing each of four different T cell receptor (TCR) V beta segments in lamina propria and peripheral blood lymphocytes of 12 Crohn's disease (CD), six ulcerative colitis (UC), and 10 control patients in an attempt to identify disease-specific changes. The frequencies of CD4+ and CD8+ cells reacting with each of four fluoresceinated TCR-specific monoclonal antibodies directed against V beta 5, V beta 6.7a, V beta 8, and V beta 12 were determined by flow cytometry. There was no difference among the groups in the average frequency of any single V beta segment in either the CD4+ or CD8+ subpopulations. However, when the sum of the differences in V beta frequencies (delta score) between peripheral blood lymphocytes (PBL) and lamina propria lymphocytes (LPL) were determined for each individual, significant differences were observed between the CD4+ and CD8+ populations and among the patient groups. In all three patient groups, there were significant individual differences between LPL and PBL in the frequencies of CD8+ and CD4+ cells reacting with the four V beta-specific mAb. In Controls and UC, this difference was, on average, two-fold greater in CD8+ cells than in CD4+. In CD, however, this difference was, on average, the same for CD8+ and CD4+ cells. These observations suggest that (1) the human colonic LPL TCR repertoire is normally different from that of PBL, especially in the CD8+ population and (2) there is an alteration in the LPL TCR repertoire in CD which is not observed in Controls or UC.

Antibodies, Monoclonal↗
PubMed1993

Cooccurrence of collagenous colitis with seronegative spondyloarthropathy: report of a case and literature review.

Collagenous colitis is an uncommon cause of chronic watery diarrhea, characterized by colonic deposition of collagen. Nonerosive, oligoarticular, peripheral arthritis has previously been noted in about 7% of patients with collagenous colitis. We describe a patient with collagenous colitis who concurrently developed erosive, seronegative spondyloarthropathy affecting peripheral and axial joints. Synovial histology was characterized by a conspicuous inflammatory infiltrate comprised of histiocytes, lymphocytes and plasma cells. Collagenous colitis is suggested to be a systemic autoimmune disorder, with extraintestinal features such as thyroiditis and arthritis.

Colitis↗
PubMed2004

Regulation of chronic colitis in athymic nu/nu (nude) mice.

The objective of this study was to assess the roles of NK cells, B cells and/or intraepithelial lymphocytes (IEL) in suppressing the development of colitis in nude mice reconstituted with CD4(+)CD45RB(high) T cells. BALB/c nude mice were lethally irradiated and reconstituted with bone marrow from different immunodeficient mice to generate athymic chimeras devoid of one or more lymphocyte populations. Transfer of CD4(+)C45RB(high) T cells into chimeric recipients devoid of B cells, T cells and IEL produced severe colitis within 6-8 weeks, whereas transfer of these same T cells into B cell- and T cell-deficient or T cell-deficient chimeras produced little to no gut inflammation. In addition, we found that nude mice depleted of NK cells or RAG-1(-/-) mice reconstituted with IEL failed to develop colitis following transfer of CD45RB(high) T cells. Severe colitis could, however, be induced in nude mice by transfer of activated/T(h)1 CD4(+)CD45RB(low) T cells. Taken together, our data suggest that IEL, but not B cells or NK cells, play an important role in suppressing the development of chronic colitis in this model. In addition, our data demonstrate that suppression of disease may be due to polarization of naive CD4(+) cells toward a non-pathogenic and/or regulatory phenotype.

Adoptive Transfer↗
PubMed2005

Systemic administration of the chemokine macrophage inflammatory protein 1alpha exacerbates inflammatory bowel disease in a mouse model.

INTRODUCTION: Exacerbations of inflammatory bowel disease are thought to be related to concurrent infections. As infections are associated with elevated local and serum concentrations of chemokines, we have determined whether systemic administration of the CC chemokine macrophage inflammatory protein 1alpha (MIP-1alpha) exacerbates colitis in a mouse model. METHODS: Colitis was induced in Balb/c mice using trinitrobenzene sulfonic acid (TNBS). Starting four days later, animals received daily intraperitoneal injections of recombinant MIP-1alpha. On day 7, mice were killed and pieces of colon taken for immunohistology and polymerase chain reaction analysis. The direct effects of MIP-1alpha on mucosal T cells and fibroblasts in vitro were also investigated. RESULTS: Systemic administration of MIP-1alpha markedly enhanced colitis with mice developing large transmural ulcers filled with granulation tissue. Treatment resulted in increased numbers of CD4 cells infiltrating the colonic lamina propria, increased interferon gamma (IFN-gamma) levels, and increased transcripts for tumour necrosis factor alpha (TNF-alpha) and matrix metalloproteinase 3 (MMP3). Isolated lamina propria lymphocytes from mice with TNBS colitis contained increased numbers of IFN-gamma and TNF-alpha transcripts when stimulated with MIP-1alpha in vitro. Colonic lamina propria fibroblasts also responded to MIP-1alpha with increased proliferation and decreased collagen 1 synthesis but fibroblast proliferation was not seen in vivo. CONCLUSIONS: These experiments show that increasing serum concentrations of a chemokine, MIP-1alpha, exacerbates immune mediated colitis. The effect seems to be due to the ability of MIP-1alpha to boost Th1 responses in the gut wall. Our findings also suggest a potential pathway by which peripheral infections can exacerbate inflammatory bowel disease.

Animals↗
PubMed1991

Increased activation of isolated intestinal lamina propria mononuclear cells in inflammatory bowel disease.

Normal human lamina propria lymphocytes are in a heightened state of activation compared with peripheral blood with regard to cell-surface activation antigen expression (transferrin receptor, interleukin-2 receptor, 4F2) and the increased spontaneous secretion of immunoglobulins in vitro. This study evaluates the cell-surface expression of activation-associated antigens in different subpopulations of isolated colonic lamina propria mononuclear cells in inflammatory bowel disease. In pilot studies using three-color flow cytometry, autofluorescence was observed that was emitted by unstained lamina propria mononuclear cells, which interfered with both the sensitivity and the specificity of the analyses. Because a major portion of the intestinal lymphocyte populations of interest were autofluorescent, a method to remove autofluorescence signals was developed by designing a computer program for the subtraction of autofluorescence from the emissions of each individual cell. This technique increases both the sensitivity and specificity of flow-cytometric analyses of intestinal lamina propria mononuclear cells. Using fluorescence-activated cell-sorter analyses with subtraction of autofluorescence on a single-cell basis, increased expression of lymphocyte activation antigens (interleukin-2 receptor, transferrin receptor, 4F2) was found on the cell surface of isolated intestinal B cells, T cells, CD4+ T cells, and CD8+ T cells in both Crohn's disease and ulcerative colitis. Therefore, markedly increased intestinal lymphocyte activation is a major immunological alteration in inflammatory bowel disease and includes all lymphocyte subpopulations investigated in this study. In addition, 5-aminosalicylic acid, which is used for the treatment of intestinal inflammation in inflammatory bowel disease, inhibits the expression of cell-surface activation antigens on mitogen-activated peripheral blood lymphocytes in a dose-dependent manner. These observations suggest that lymphocyte activation may play an important role in underlying immune processes that lead to chronicity and perpetuation of inflammatory bowel disease and may implicate an additional mechanism for the therapeutic action of 5-aminosalicylic acid.

Aminosalicylic Acids↗
PubMed2004

Leptin receptor expression on T lymphocytes modulates chronic intestinal inflammation in mice.

BACKGROUND: Leptin regulates appetite through the long isoform of its receptor in the hypothalamus. Although leptin regulates immune responses, it is still unknown whether a direct effect of leptin on lymphocytes is required. AIMS: To clarify whether expression of leptin receptors on T lymphocytes modulates intestinal inflammation in mice. METHODS: The model of colitis induced by transfer of CD4(+)CD45RB(high) (RB(high)) cells into scid mice was used. Wild-type (WT) or leptin receptor deficient (db/db) RB(high) cells were transferred into scid mice and development of colitis evaluated. RESULTS: Leptin receptors were expressed on both RB(high) and RB(low) cells. Intestinal lymphocytes of mice with colitis expressed high leptin levels compared with healthy controls whereas the opposite was true for serum leptin levels. Transfer of RB(high) cells from db/db mice induced delayed disease compared with transfer of WT cells. A high rate of apoptosis in lamina propria lymphocytes and reduced cytokine production were observed early on in scid mice receiving db/db RB(high) cells. These effects were not due to the high levels of glucocorticoids present in db/db mice as administration of corticosterone to WT mice failed to reproduce this phenomenon. High expression of peroxisome proliferator activated receptor gamma was observed in the colon of recipients of db/db compared with WT cells. Freshly isolated db/db RB(high) cells produced low levels of interferon gamma. Despite delayed onset of colitis, as disease progressed differences between mice receiving WT or db/db cells were no longer apparent. CONCLUSIONS: These results suggest that leptin affects the immune response, partly by acting on the long isoform of its receptor expressed on T lymphocytes.

Animals↗
PubMed2006

SHP1 phosphatase-dependent T cell inhibition by CEACAM1 adhesion molecule isoforms.

T cell activation through the T cell receptor (TCR) is subsequently modified by secondary signals that are either stimulatory or inhibitory. We show that CEACAM1 adhesion molecule isoforms containing a long cytoplasmic domain inhibited multiple T cell functions as a consequence of TCR ligation. Overexpression of CEACAM1 resulted in decreased proliferation, allogeneic reactivity, and cytokine production in vitro and delayed type hypersensitivity and inflammatory bowel disease in mouse models in vivo. Conditioned deletion of CEACAM1 in T cells caused increased TCR-CD3 complex signaling. This T cell regulation was dependent upon the presence of immunoreceptor tyrosine-based inhibition motifs (ITIM) within the cytoplasmic domain of CEACAM1 and the Src homology 2 domain-containing protein tyrosine-phosphatase 1 (SHP1) in the T cell. Thus, CEACAM1 overexpression or deletion in T cells resulted in T cell inhibition or activation, respectively, revealing a role for CEACAM1 as a class of inhibitory receptors potentially amenable to therapeutic manipulation.

Adoptive Transfer↗
PubMed1989

[Characteristics of lymphoid subpopulations isolated from healthy subjects and those suffering from nonspecific ulcerative colitis].

Results of the studies of functional activity of lymphocyte subpopulations T+G, T-G, "O" subpopulations isolated peripheral blood of healthy persons and those with nonspecific ulcerative colitis (NUC) have been presented in this paper. The functional activity of the cells was assessed by means of local xenogeneic graft-vs-host reaction performed on CBA mice and by determination of nonspecific esterase enzyme. It has been established that analogous lymphocyte subpopulations influence the graft-vs-host reaction development in different ways depending on the condition of cell donor state: health/pathology. "O" subpopulations isolated from healthy persons hampered the graft-vs-host reaction development, and on the contrary stimulated it in patients with NUC. The assay of nonspecific esterase in lymphocytes showed that the least activity was noted in T+G and "O" cells in nonspecific ulcerative colitis.

Animals↗
PubMedDate not supplied

[Ulcerative rectocolitis. Somatic aspects (author's transl)].

Regional enteritis (Crohn's disease) and ulcerative rectocolitis, both "non specific inflammatory diseases of the bowel", might be diseases with a common etiology but with clinical features corresponding to a different tissular response to a noxious factor. Both diseases are however characterized by distinct clinical, radiological, histological peculiarities; evolution also is different, as appears from the rarity of malignant degeneration in Crohn's disease and its frequence in ulcerative colitis; a psychological support seems to be classical in ulcerative colitis but is on the contrary unusual in regional ileitis. Besides the interference of psychological factors in the outbreak of an ulcerative colitis, besides the infectious and genetic theories, the immunological theory appears as one of the most interesting and promising. In a significant percentage of cases of ulcerative colitis, anticolon antibodies are evidenced, which exhibit a crossed reaction with bacterial antigens, especially with those of Escherichia coli 014. Besides this humoral immunity a cellular immunity exists also: lymphocytes of patients with ulcerative colitis behave as a toxic agent towards colic tissue cultures; this cytotoxicity parallels the course of the disease and provides an explanation for the sometimes dramatic therapeutic effects observed after administration of immunosuppressive drugs and antilymphocytic serum. Moreover, colic antigen can block this cytotoxicity; the immunologically active portion of this antigen may be isolated and its administration in patients with ulcerative colitis may perhaps induce a specific immunosuppression and influence the evolution of the disease.

Adrenal Cortex Hormones↗
PubMed2005

Impaired B cell responses to orally administered antigens in lamina propria but not Peyer's patches of Galphai2-deficient mice prior to colitis.

Despite numerous studies on the intestinal immune system in patients with inflammatory bowel disease (IBD) and animal models of IBD, very little is known about the immune reactivity of mucosal lymphocytes following oral immunizations under these circumstances. The reactivity of Peyer's patch (PP) and lamina propria (LP) T and B lymphocytes in inhibitory G-protein alpha2 subunit-deficient (Galphai2-/-) mice developing an IBD resembling ulcerative colitis was investigated following repeated oral immunizations with keyhole limpet haemocyanin (KLH), together with the adjuvant cholera toxin, prior to colitis. The antigen-specific B-cell response in the LP of both the small and the large intestines was significantly reduced in Galphai2-/- as compared to wild-type mice. In contrast, the frequency of KLH-specific immunoglobulin (Ig)-producing cells in the PP did not differ between Galphai2-/- and wild-type mice, whereas the total frequency of Ig-producing cells as well as the frequency of enteric flora-specific Ig-producing cells in the PP was significantly increased in Galphai2-/- as compared to wild-type mice. Analysis of T cell responses following restimulation ex vivo with KLH revealed a dramatic increase in the production of interferon-gamma in mesenteric lymph node, PP and LP lymphocytes from Galphai2-deficient as compared to wild-type mice, together with decreased production of interleukin-10 in all locations except the PP.

Administration, Oral↗
PubMed1983

Impaired natural killer cell activity in patients with inflammatory bowel disease: evidence for a qualitative defect.

The natural killer cell lymphocyte may represent an important element in immune defense. Since host defense may be abnormal in patients with inflammatory bowel disease, we assessed natural killer cell function in 34 patients with ulcerative colitis and Crohn's disease. Lymphocytes from 31 of 34 patients (91%) exhibited decreased natural killer cell activity (mean cytotoxicity +/- SEM was 25% +/- 7.5% of the mean normal values, p less than 0.01). Disease activity, type of disease, and steroid therapy had no influence on these values. None of the 10 age-matched disease controls with other intestinal inflammatory conditions had natural killer cell activity outside the normal range. The numbers of circulating killer cells present in patients with impaired activity were quantified using a cytofluorometric detection system. All patients tested had normal numbers of cells binding nonaggregated immunoglobulin G (Fc receptor positive) despite decreased natural killer cell activity. It appears that by using this cytofluorometric detection technique, decreased natural killer cell activity is not the consequence of diminished numbers of natural killer cells.

Adolescent↗
PubMed1999

Cutting edge: chronic intestinal inflammation in STAT-4 transgenic mice: characterization of disease and adoptive transfer by TNF- plus IFN-gamma-producing CD4+ T cells that respond to bacterial antigens.

We generated transgenic mice for STAT-4, a regulatory protein specifically associated with IL-12 signaling, under the control of a CMV promoter. These mice expressed strikingly increased nuclear STAT-4 levels in lamina propria CD4+ T lymphocytes upon systemic administration of dinitrophenyl-keyhole limpet hemocyanin and developed chronic transmural colitis characterized by infiltrates of mainly CD4+ T lymphocytes. The latter cells produced predominantly TNF and IFN-gamma but not IL-4 upon activation with alphaCD3/CD28 or autologous bacterial Ags, consistent with a Th1-type cell response. Furthermore, chronic colitis in STAT-4 transgenic mice could be adoptively transferred to SCID mice by colonic and splenic CD4+ T cells that were activated with Ags from autologous bacterial flora. These data establish a critical molecular signaling pathway involving STAT-4 for the pathogenesis of chronic intestinal inflammation, and targeting of this pathway may be relevant for the treatment of colitis in humans.

Adoptive Transfer↗