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At least 343 records · Page 19Linked to original sources
PubMed1995

Activated CD4+ and CD8+ cells in the colonic mucosa of ulcerative colitis patients: their relationship to HLA-DR antigen expression on the colonic epithelium and serum soluble CD25 levels.

This study was performed to clarify the relationship between activated (HLA-DR-expressing) CD4+ and CD8+ cells in the colonic lamina propria of ulcerative colitis and other immunological factors, i.e., epithelial DR expression, serum soluble CD25 levels, and colonic mucosal CD25+ cells. The frequency of epithelial DR expression was positively correlated with the numbers of CD4+ and CD8+ cells. The percentages activated CD4+/CD4+ cells were higher in mucosae with DR- epithelium than in mucosae with DR+ epithelium. The serum soluble CD25 levels were increased in ulcerative colitis, and there was an inverse correlation between these levels and the relative number of activated CD4+ cells in untreated active disease. These results suggest that interactions among mucosal CD4+ cells, colonic epithelium, and serum soluble CD25 might play an important role in the pathogenesis of ulcerative colitis.

Adolescent↗
PubMed1979

Characteristics of isolated intestinal mucosal lymphoid cells in inflammatory bowel disease.

Immunologic characteristics of intestinal mucosal lymphoid cells from patients with inflammatory bowel disease and controls have been compared. Mononuclear cells isolated by enzymatic means from intestinal tissues involved with inflammatory bowel disease were present in greater numbers, with increased proportions of macrophages and B-lymphocytes, particularly cells bearing intrinsic membrane immunoglobulin G. Synthesis of immunoglobulin G, measured by radioimmunoassay, was increased tenfold in inflammatory bowel disease, while immunoglobulin A synthesis per 10(6) cells was unchanged. "Null" or K-lymphocytes were absent from all populations, and antibody-dependent cellular cytotoxicity (a K-cell-mediated function) was not demonstrable. Taken together, the results fail to support a role for antibody-dependent cellular cytotoxicity or a defect in secretory immunoglobulin A, but rather focus attention upon possible forms of immunoglobulin G-mediated tissue damage in the pathogenesis or perpetuation of inflammatory bowel disease.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1999

Differences in P-glycoprotein-170 expression and activity between Crohn's disease and ulcerative colitis.

The clinical benefit of Cyclosporine A (CsA) in IBD is controversial. Drugs including CsA are substrates of the P-glycoprotein-170 (Pgp-170) cell surface pump. Although the mechanism of action of CsA is complex, we determined that Pgp-170 might be expressed differentially between these two diseases. Intra-epithelial, lamina propria and peripheral blood lymphocytes were stained with the antibody MRK-16, which recognizes the surface antigen Pgp-170. Functional activity was assayed using a Rhodamine dye efflux assay (Rh123). RT-PCR was used to detect Pgp-170 mRNA. Overall, less P-gp-170 surface expression was found on UC CD3+ intestinal lymphocytes compared to controls and Crohn's disease. A decrease in Pgp-170 activity was also measured using the Rh123 functional assay. Fewer CD8+ intraepithelial lymphocytes (IEL) (which intrinsically have more Pgp-170 function) were also found in UC. Furthermore, UC IEL P-gp expression was under the limit of detection by RT-PCR. Overall, greater and differential expression, function and mRNA for Pgp-170 was found in Crohn's disease compared to the UC and normal tissues analyzed.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

Biologicals: principles, techniques and mechanisms of action.

Biological agents for the treatment of IBD are the result of both the explosion of knowledge precipitated by the techniques of molecular biology, and by the ability to use these same techniques to produce agents. Thus, there has been a greatly facilitated translation of basic knowledge into clinical therapy. An astounding number of biologic agents are currently in development for the treatment of IBD and other immune-mediated conditions. These include native microbiologic preparations isolated for beneficial properties, recombinant cytokines and anticytokines, monoclonal antibodies, antisense oligonucleotides, and in the future, somatic gene therapy. This work seeks to describe the principles and techniques of biologic agent development, as well as prime sites of action targeted by these agents. Recent advances in the techniques of molecular biology have made possible unprecedented progress in the treatment of many conditions. The techniques of molecular biology have provided new methods of drug discovery and at the same time have elucidated new therapeutic targets. Most notable has been the progress made in the treatment of chronic inflammatory and immune mediated conditions, including inflammatory bowel disease. This paper is intended to highlight the methodological principles behind biologic agents, methods of discovery and production, and to highlight potential therapeutic targets for these new agents.

Antibodies, Monoclonal↗
PubMed2006

TAK1 is indispensable for development of T cells and prevention of colitis by the generation of regulatory T cells.

Transforming growth factor (TGF)-beta-activating kinase 1 (TAK1) is critical for Toll-like receptor- and tumor necrosis factor-mediated cellular responses. In B cells, TAK1 is essential for the activation of mitogen-activated protein kinases (MAPKs), but not nuclear factor-kappaB (NF-kappaB), in antigen receptor signaling. In this study, we generate T cell-specific TAK1-deficient (Lck(Cre/(+))Tak1(flox/flox)) mice and show that TAK1 is indispensable for the maintenance of peripheral CD4 and CD8 T cells. In thymocytes, TAK1 is essential for TCR-mediated activation of both NF-kappaB and MAPKs. Additionally, Lck(Cre/(+))Tak1(flox/flox) mice developed colitis as they aged. In these mice, accumulations of activated/memory T cells as well as B cells were observed. Development of regulatory T (Treg) cells in thymus was abrogated in Lck(Cre/(+))Tak1(flox/flox) mice, suggesting that the loss of Treg cells is the cause of the disease. Together, the results show that TAK1, by controlling the generation of central Treg cells, is important for preventing spontaneously developing colitis.

Aging↗
PubMed2002

The transcription factor T-bet regulates mucosal T cell activation in experimental colitis and Crohn's disease.

The balance between pro and antiinflammatory cytokines secreted by T cells regulates both the initiation and perpetuation of inflammatory bowel diseases (IBD). In particular, the balance between interferon (IFN)-gamma/interleukin (IL)-4 and transforming growth factor (TGF)-beta activity controls chronic intestinal inflammation. However, the molecular pathways that evoke these responses are not well understood. Here, we describe a critical role for the transcription factor T-bet in controlling the mucosal cytokine balance and clinical disease. We studied the expression and function of T-bet in patients with IBD and in mucosal T cells in various T helper (Th)1- and Th2-mediated animal models of chronic intestinal inflammation by taking advantage of mice that lack T-bet and retroviral transduction techniques, respectively. Whereas retroviral transduction of T-bet in CD62L(+) CD4(+) T cells exacerbated colitis in reconstituted SCID mice, T-bet-deficient T cells failed to induce colitis in adoptive transfer experiments suggesting that overexpression of T-bet is essential and sufficient to promote Th1-mediated colitis in vivo. Furthermore, T-bet-deficient CD62L(-) CD4(+) T cells showed enhanced protective functions in Th1-mediated colitis and exhibited increased TGF-beta signaling suggesting that a T-bet driven pathway of T cell activation controls the intestinal balance between IFN-gamma/IL-4 and TGF-beta responses and the development of chronic intestinal inflammation in T cell-mediated colitis. Furthermore, TGF-beta was found to suppress T-bet expression suggesting a reciprocal relationship between TGF-beta and T-bet in mucosal T cells. In summary, our data suggest a key regulatory role of T-bet in the pathogenesis of T cell-mediated colitis. Specific targeting of this pathway may be a promising novel approach for the treatment of patients with Crohn's disease and other autoimmune diseases mediated by Th1 T lymphocytes.

Adult↗
PubMed2002

Development of antigen induced colitis in SCID mice reconstituted with spleen derived memory type CD4(+) CD45RB(+) T cells.

BACKGROUND AND AIMS: Enteric bacterial and/or food antigens may be crucial in the development of colitis but little is known of the exact mechanism of antigen specific reactions in this condition. The aim of this study was to determine whether systemically primed antigen specific CD4(+) T cells containing both CD45RB(high) and CD45RB(low) populations participate as a pathogenic subset that in turn leads to inflammatory reactions selectively in the large intestine. METHODS: SCID mice were reconstituted with splenic CD4(+) CD45RB(+) T cells or CD4(+) CD45RB(low) T cells isolated from donor mice systemically primed with ovalbumin (OVA) plus CFA. The reconstituted mice were then fed OVA for several weeks. RESULTS: Reconstitution of SCID mice with OVA primed splenic CD4(+) T cells, containing populations of CD45RB(high) and CD45RB(low), resulted in the development of colitis by 4-5 weeks following repeated administration of oral OVA. Histopathological study revealed thickened wall, inflammatory cell infiltration, crypt elongation, and loss of goblet cells in the large intestine. The CD4(+) CD45RB(low) population of cells extracted from the affected large intestine secreted high levels of interferon gamma (IFN-gamma) and tumour necrosis factor alpha (TNF-alpha) at the protein and mRNA levels. Administration of neutralising antibodies to TNF-alpha, but not to IFN-gamma, prevented the development of colitis. Furthermore, adoptive transfer with OVA primed splenic CD4(+) CD45RB(low) T cells evoked severe colitis. CONCLUSIONS: These results demonstrate that systemically primed activated/memory CD4(+) CD45RB(low) T cells can mediate the development of specific antigen induced colitis in SCID mice, and also that TNF-alpha is critical in the induction of this type of colitis. Our results contrast with those from studies in some colitis models in which CD45RB(low) T cells appeared to prevent colitis through secretion of immunosuppressive cytokines.

Adoptive Transfer↗
PubMed2005

Keratin-8-deficient mice develop chronic spontaneous Th2 colitis amenable to antibiotic treatment.

Keratin 8 (K8) is the major intermediate filament protein present in intestinal epithelia. Depending on the mouse genetic background, absence of K8 causes embryonic lethality or colonic hyperplasia and colitis. We studied disease progression, the inflammatory responses, and role of luminal bacteria in K8-null mice in order to characterize the intestinal pathology of K8-associated colitis. Colon lymphocytes were isolated for analysis of their phenotype and cytokine production, and vascular and lymphocyte adhesion molecule expression in K8-/- mice of varying ages. K8-/- mice had a marked increase in TCR(beta)-positive/CD4-positive T cells infiltrating the colon lamina propria, in association with enhanced Th2 cytokine (IL-4, IL-5 and IL-13) production. K8-/- mice show early signs of inflammation even prior to weaning, that increases with age, and their epithelial cells overexpress MHC class II antigens. The chronic colitis is related to increased CD4-positive infiltrating T cells displaying memory and naive phenotypes, and an altered vascular endothelium with aberrant expression of peripheral node addressin. Analysis of normal gut-specific homing molecules, reveals an increased number of alpha(4)beta(7)-positive cells and vascular mucosal addressin cell adhesion molecule-1 in K8-null colons. Antibiotic treatment markedly decreased colon inflammation and ion transporter AE1/2 mistargeting, indicating that luminal bacteria play an important role in the observed phenotype. Therefore, K8-null mice develop chronic spontaneous Th2-type colitis due to a primary epithelial rather than immune cell defect, which is amenable to antibiotic therapy. These mice provide a model to investigate epithelial-leukocyte and epithelial-microbial cross-talk.

Animals↗
PubMed2003

Viral escape and T-cell immunity during ganciclovir treatment of cytomegalovirus infection: case report of a pancreatico-renal transplant recipient.

BACKGROUND: Pancreas-kidney transplant recipients are at high risk for cytomegalovirus (CMV) disease despite prophylactic ganciclovir therapy. Because the impact of antiviral therapy on anti-CMV immune reactions is unknown, CMV-specific T-cell subsets in primary and recurrent CMV infection were analyzed in a pancreas-kidney transplant case study. METHODS: Major histocompatibility complex class I tetramers were used to detect peripheral CMV pp65-specific CD8 T cells. Intracellular cytokine staining was used to determine the frequency of CMV-specific CD4 T cells. Conventional virologic parameters and routine laboratory parameters were monitored. For ganciclovir resistance testing, CMV-UL97 genotyping was performed. RESULTS: Despite prophylactic ganciclovir therapy, primary CMV infection induced in vivo expansion of activated CMV-specific CD8 T cells. Interestingly, viral dissemination during recurrent CMV disease was a result of partially ganciclovir-resistant CMV. Recovery after discontinued ganciclovir treatment was associated with the expansion of CMV-specific CD4 T cells. CONCLUSION: Immunologic monitoring may contribute to clinical management of recurrent CMV disease.

Antiviral Agents↗
PubMed2000

Helicobacter hepaticus does not induce or potentiate colitis in interleukin-10-deficient mice.

Helicobacter hepaticus has been reported to induce colitis, hepatitis, and hepatocellular carcinoma in several different murine models. The aim of this study was to determine if H. hepaticus will cause colitis in monoassociated mice lacking the interleukin-10 gene (IL-10(-/-) mice) and potentiate colitis in specific-pathogen-free (SPF) IL-10(-/-) mice. Germfree IL-10(-/-) mice on either a mixed (C57BL/6 x 129/Ola) or inbred (129/SvEv) genetic background were monoassociated with H. hepaticus ATCC 51448 by oral feeding and rectal enemas. In a second experiment, germfree IL-10(-/-) mice were colonized with stool from SPF mice that harbored or did not harbor endogenous H. hepaticus. After 7 to 9 weeks of colonization, weight loss and mortality were assessed, the colon was isolated for histology and IL-12 secretion, and mesenteric lymph node cells were assessed for T-cell activation markers. It was found that IL-10(-/-) mice monoassociated with H. hepaticus for up to 16 weeks showed almost no histologic colitis or increased IL-12 production. SPF IL-10-knockout mice had no significant difference in weight loss, mortality rate, histologic scores, colonic IL-12 secretion, or T-cell activation with or without H. hepaticus. We conclude that H. hepaticus does not induce or potentiate disease in our IL-10(-/-) mice and therefore is not required to induce colitis in genetically susceptible hosts.

Animals↗