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Query: UMLS:C0009319 (colitis)
 19,384 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Callithrix jacchus is an outbred New World primate characterized by a naturally occurring bone marrow chimerism, restricted polymorphism at many MHC loci, and unusual susceptibility to viral pathogens, adenocarcinoma, colitis, and, following immunization with myelin antigens, a demyelinating disease of the central nervous system closely resembling human multiple sclerosis. Here we characterize the TCRB repertoire in this species, representing the first such analysis in a New World monkey. Two TCRBC, 13 BJ, 2 BD, and 15 BV genes were identified. Overall, a high degree of similarity with human TCRBV-D-J-C gene sequences was observed, indicating a close phylogenetic relationship. Biased usage in favor of genes from the TCRBC1-BJ1 cluster was present in 77% of sequences, in contrast to preferential usage of BC2-BJ2 genes known to occur in humans and mice. Complementarity-determining region 3 averaged 10 amino acids in length and were diverse. Framework regions of TCRBV genes were extensively conserved. Phylogenetic analysis of TCRBV sequences from different species indicated that TCR genes are highly stable across primates. Thus, a diverse TCRB repertoire is generated in C. jacchus despite the limited polymorphism of class I MHC loci. Extensive homology to human TCR genes, natural chimerism, and susceptibility to inflammatory disorders are characteristics of C. jacchus that create a useful model system for the study of human autoimmunity.
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PMID:Characterization of the TCRB chain repertoire in the New World monkey Callithrix jacchus. 901 60

An inflammatory bowel disease (IBD) comparable to human ulcerative colitis is induced upon transfer of T cell-depleted wild-type (F1) bone marrow into syngeneic T cell-deficient (tg epsilon26) mice (F1 --> tg epsilon26). Previously we have shown that activated CD4+ T cells predominate in transplanted tg epsilon26 mice, and adoptive transfer experiments verified the potential of these cells to cause disease in immunodeficient recipient mice. Using flow cytometry for the detection of intracellular cytokine expression, we demonstrate in the present study that large numbers of CD4+ and CD8+ TCR alphabeta+ T cells from the intraepithelial region and lamina propria of the colon of diseased, but not from disease-free mice, produced interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha). Large numbers of T cells from peripheral lymphoid tissues of these animals also expressed IFN-gamma and TNF-alpha, but few expressed interleukin-4, demonstrating a strong bias towards Th1-type T cell responses in these animals. TCR gammadelta+ T cells, typically minor constituents of the inflammatory infiltrate of the colon in F1 --> tg epsilon26 mice, also expressed IFN-gamma at a high frequency upon CD3 stimulation. In light of these findings we examined the potential involvement of TCR gammadelta+ T cells by testing their ability to induce colitis in tg epsilon26 mice. We report here that tg epsilon26 mice transplanted with T cell-depleted bone marrow from TCR alpha(null) and TCR beta(null) animals developed IBD. Furthermore, disease in these mice correlated with the development of peripheral and colonic TCR gammadelta+ T cells capable of IFN-gamma production. These results suggest that IFN-gamma may be a common mediator of IBD utilized by pathogenic T cells of distinct phenotype.
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PMID:Expression of pro-inflammatory cytokines by TCR alpha beta+ and TCR gamma delta+ T cells in an experimental model of colitis. 902 93

The above new findings concerning the immunological mechanisms governing mucosa, immune responses and oral tolerance in TCR-transgenic mice, as well as those operative in mice with experimental colitis, greatly expand our understanding of the processes that normally control mucosal inflammation and possibly other types of inflammation as well (Fig. 1). They indicate that, in the nondiseased mouse, ingested proteins evoke a Th1-cell (IFN-gamma) response in the mucosal follicles that is quickly counter-regulated by induction of T-cell anergy/deletion, if this Th1-cell response is inhibited (experimentally by anti-IL-12), TGF beta-producing cells appear, and these are capable of active immune suppression. This reciprocal relationship between IFN-gamma production and TGF-beta production is further supported in mouse models of mucosal inflammation. Thus, in the TNBS-colitis model, there is direct stimulation of the immune cells in the lamina propria as a result of diffuse haptenization of mucosal proteins, which leads to a massive Th1-cell response capable of overwhelming any suppressive counter-regulatory mechanisms normally generated in the PPs. This highly polarized Th1-cell response is controlled only by direct abrogation of IL-12 production with exogenous administration of anti-IL-12, or with indirect inhibition of this response via induction of oral tolerance and accompanying production of TGF-beta (Refs 6-8). The data obtained from this model are consistent with those obtained with another model of intestinal inflammation--inflammation in severe combined immunodeficiency (SCID) mice following lymphoid repletion with CD45Rbhi (naive) T cells. In this model, inflammation is again mediated by Th1 cells and is prevented by co-repletion with CD45Rbhi (memory) T cells, which appear to work by secreting TGF-beta (Refs 9, 10). Thus, a common feature of the various experimental models of intestinal inflammation studied to date is the Yin-Yang relationship of IFN-gamma and TGF-beta, with the former being proinflammatory and the latter anti-inflammatory. Is the IFN-gamma TGF-beta dichotomy that is evident both in the normal state and in models of inflammation simply a reflection of an underlying Th1 Th2 dichotomy? The answer to this important question is not yet known. Thus, while it is clear from the in vitro studies already discussed that IL-12 and/or IFN-gamma inhibit TGF-beta production, the role of IL-4 in this process is more elusive. These in vitro studies indicate that IL-4 is not required for TGF-beta production, a finding that is consistent with studies in which the transfer of CD45Rbhi, T cells from IL-4-/- mice protected SCID mice from colitis induced by CD45Rbhi T cells. However, the addition of IL-4 to in vitro cultures containing anti-IL-12 augmented TGF-beta production, most probably by IL-4 acting as a growth factor for TGF-beta-producing cells rather than as an inducing factor (T. Marth et al., unpublished). Obviously, more work will be necessary to resolve this issue. Finally, it should be noted that the above considerations apply to human inflammatory diseases of the gastrointestinal tract, such as Crohn's disease. Recently, it has been shown that T cells extracted from Crohn's disease tissues manifest skewed Th1-cell responses. The hypothesis can therefore be put forward that this disease results from a dysregulated Th1-cell response to ubiquitous mucosal antigens that is not appropriately controlled by normal counter-regulatory mechanisms. Interventions that artificially bring the excessive Th1-cell response back into balance, such as administration of IL-12 antagonists, should therefore find a central place in the treatment of the disease.
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PMID:Reciprocal IFN-gamma and TGF-beta responses regulate the occurrence of mucosal inflammation. 905 54

Chronic colitis develops spontaneously in mice mutant for T-cell receptor alpha (TCR alpha) genes maintained in pathogen-free conditions. Our previous studies indicate that the cytokine imbalance caused by a lack of TCR alpha beta + T cells may be associated with the development of chronic colitis in TCR alpha-mutant (TCR alpha -/-) mice. The histologic changes of chronic colitis are recognizable by 3 to 4 months of age and are characterized by marked crypt cell hyperplasia and the presence of an inflammatory cell infiltrate. Because early events in the development of chronic colitis may be important in the pathogenesis of the disorder, we investigated the changes in the colon at a time when chronic colitis was not yet histologically recognizable. In vivo labeling with 5-bromo-2'-deoxyuridine revealed increased epithelial proliferation in the crypts by 6 to 8 weeks of age. There was an increase in number of T cells in the colon of TCR alpha -/- mice compared with that in TCR alpha +/- (heterozygous TCR alpha-mutant) mice after 6 weeks of age. The predominant T-cell subsets were CD4+, TCR alpha- beta +, and TCR gamma delta + cells. Reverse transcription-PCR and immunohistochemistry of the colonic mucosa obtained from TCR alpha -/- mice (> 6 weeks old) showed a marked increase of IL-1 alpha and IL-1 beta but not of TNF alpha or transforming growth factor beta-1 compared with TCR alpha +/- mice. In vivo neutralization of IL-1 alpha or IL-1 beta by specific mAb suppressed colonic epithelial proliferation and decreased colonic mucosal T-cell infiltration in 8-week-old TCR alpha -/- mice. These results provide direct evidence that overproduction of IL-1 alpha and IL-1 beta in the colonic mucosa may play an important role in the early stages of development of chronic colitis in TCR alpha -/- mice.
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PMID:Role of cytokines in the early stages of chronic colitis in TCR alpha-mutant mice. 912 Nov 21

Over the past few years, application of targeted gene deletion and transgenic approaches has led to the often unanticipated development of rodent lines which develop inflammatory bowel disease. While none of these lines recapitulate the histopathological and clinical features usually associated with human inflammatory bowel disease (IBD) in their entirety, many exhibit key features comprising the development of "spontaneous" chronic and acute inflammation. These models include targeted deletion of the genes encoding IL-2, IL-10, TGF beta, T-cell receptor alpha/beta, keratin 8, and Gi2 alpha. In addition, animals expressing transgenes for the human WA-B27 (with beta-2 microglobulin) as well as a dominant negative construct which functionally blocks N-cadherin have also been observed to result in chronic inflammatory bowel disease. Most of the mutant murine lines experience a diffuse colitis, but some (HLA-B27 transgenic and IL-10-deficient) also experience small bowel inflammation. The variety of manipulations provides some important broad insights: (1) IBD can result from dysregulation of mucosal immune responses or impairment of epithelial barrier function, and (2) the natural history of inflammation resulting from mutation at a single genetic loci is substantially modulated by other genetic factors. With the rapidly-increasing variety of mutant mice, comparison of the residual components of immune system in lines developing IBD with those of lines not developing IBD, it is possible to deduce a requirement for TCR gamma/delta CD4+ lymphocytes as well as pivotal role of IFN gamma and (as a suppressive factor) IL-10. Study of a number of models has demonstrated the important interaction between environmental factors and genetic predisposition. Thus, in at least some of the lines (IL-2-deficient and HLA-B27) the inflammatory bowel disease is not observed when the mutant mice are maintained in a germ-free environment but does develop after reconstitution with a pathogen-free flora. In the TCR alpha/beta deficient mice, appendectomy in the neonatal period prevents the subsequent development of colitis. In still other models, inflammation may not occur without some challenge by an exogenous external agent, e.g., mice deficient in intestinal trefoil factor (ITF) exposed to dextran sodium sulfate (1). These models offer great promise to permit further dissection of the various constituents of the intestinal epithelium and mucosal immune response systems which are necessary for maintaining normal homeostasis and which can contribute to the development of inflammatory bowel disease. Further, they offer powerful tools for exploring the interaction between genetic and environmental factors to explicate the pathogenesis of inflammatory bowel disease and to develop new therapeutic intervention strategies.
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PMID:Lessons from genetic models of inflammatory bowel disease. 926 Mar 28

IL-2-deficient (IL-2(-/-)) mice develop disorders of the hemopoietic and immune systems characterized by anemia, lymphocytic hyperplasia, and colitis. The mechanisms responsible for these abnormalities remain unclear. To investigate the underlying basis of autoimmunity, the particular role of commensal gut flora in the initiation of colitis, and the role of IL-2 in the development of intestinal intraepithelial lymphocytes (iIEL), we evaluated IL-2(-/-) mice reared and maintained under gnotobiotic (germfree) conditions. By 8 wk of age, 80% (20 of 25) of germfree IL-2(-/-) mice show signs of disease, including anemia, disturbances in bone marrow hemopoietic cells, lymphocytic hyperplasia, and generalized autoimmunity, similar to those seen in specific pathogen-free (SPF) IL-2(-/-) mice. In striking contrast to SPF IL-2(-/-) mice, germfree IL-2(-/-) mice do not develop colitis. However, the numbers of gammadelta+ and TCR alphabeta+ CD8 alphaalpha+ iIELs are reduced, and in lethally irradiated SPF IL-2(+/+) mice, reconstituted with IL-2(-/-) bone marrow TCR gammadelta+ iIELs fail to develop, consistent with an important role of IL-2/IL-2R signaling in the development of gammadelta iIELs. Consequently, our findings demonstrate that the colitis seen in SPF IL-2(-/-) mice depends upon the presence of intestinal bacterial flora and that environmental Ags are not responsible for the anemia and extraintestinal lymphoid hyperplasia that occur in IL-2(-/-) mice. Thus, germfree IL-2(-/-) mice represent a unique system in which the role of IL-2 deficiency in hemopoietic and immune system disorders can be investigated in dissociation from complications that may arise due to colitis.
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PMID:Lymphoid hyperplasia, autoimmunity, and compromised intestinal intraepithelial lymphocyte development in colitis-free gnotobiotic IL-2-deficient mice. 955 95

Spontaneous colitis resembling ulcerative colitis developed in 3 of 10 independent TCR transgenic (Tg) mouse lines maintained under specific pathogen-free conditions. All three susceptible lines were CD4 lymphopenic, whereas resistant lines had normal numbers of CD4+ T cells. Thus, cytochrome c-specific 5C.C7 TCR Tg mice developed colitis only when crossed onto a SCID- or Rag-1-deficient background. A second line of lymphopenic cytochrome c-specific Tg mice bearing the AND TCR also developed colitis. In both cases, CD4+ T cells expressing the Tg-encoded TCR were preferentially activated in inflamed colons compared with lymph nodes or spleens. In contrast, Tg+CD4+ T cells remained quiescent in both inflamed and unaffected colons in another line of susceptible Tg mice carrying a TCR specific for myelin basic protein, suggesting a fortuitous cross-reactivity of the IEk-restricted cytochrome c-reactive AND and 5C.C7 TCRs with an Ag present in the gut. The percentage of CD4+ T cells expressing only endogenous TCR alpha-chains was increased consistently in inflamed colons in AND as well as 5C.C7 Rag-1-/- TCR Tg mice, suggesting that polyclonal CD4+ T cells were also involved in the pathogenesis of spontaneous colitis. Moreover, our data indicate that some alpha-chain rearrangement was still occurring in TCR Tg mice on a Rag-1-/- background, since activated CD4+ T cells expressing endogenously rearranged alpha-chains paired with the Tg-encoded beta-chain were detected consistently in the colons of such mice.
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PMID:TCR-mediated involvement of CD4+ transgenic T cells in spontaneous inflammatory bowel disease in lymphopenic mice. 1035 67

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.
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PMID:Colitis in transgenic and knockout animals as models of human inflammatory bowel disease. 1045 May 18

T cell receptor alpha chain-deficient (TCR-alpha(-/-)) mice are known to spontaneously develop inflammatory bowel disease (IBD). The colitis that develops in these mice is associated with increased numbers of T helper cell (Th)2-type CD4(+)TCR-betabeta (CD4(+)betabeta) T cells producing predominantly interleukin (IL)-4. To investigate the role of these Th2-type CD4(+)betabeta T cells, we treated TCR-alpha(-/-) mice with anti-IL-4 monoclonal antibody (mAb). Approximately 60% of TCR-alpha(-/-) mice, including those treated with mock Ab and those left untreated, spontaneously developed IBD. However, anti-IL-4 mAb-treated mice exhibited no clinical or histological signs of IBD, and their levels of mucosal and systemic Ab responses were lower than those of mock Ab-treated mice. Although TCR-alpha(-/-) mice treated with either specific or mock Ab developed CD4(+)betabeta T cells, only those treated with anti-IL-4 mAb showed a decrease in Th2-type cytokine production at the level of mRNA and protein and an increase in interferon gamma-specific expression. These findings suggest that IL-4-producing Th2-type CD4(+)betabeta T cells play a major immunopathological role in the induction of IBD in TCR-alpha(-/-) mice, a role that anti-IL-4 mAb inhibits by causing Th2-type CD4(+)betabeta T cells to shift to the Th1 type.
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PMID:Alteration of interleukin 4 production results in the inhibition of T helper type 2 cell-dominated inflammatory bowel disease in T cell receptor alpha chain-deficient mice. 1047 46

Transfer of CD4+CD45RBhigh T cells into immunodeficient mice results in both the expansion of the transferred T cells and colitis. Here we show that colitis pathogenesis requires expression of MHC class II molecules by the immune-deficient host. Analysis of the TCRbeta repertoire of the cells found in the large intestine of diseased mice revealed a population with restricted TCR diversity. Furthermore, nucleotide sequence analysis demonstrated the selection for particular CDR3beta amino acid sequence motifs. Collectively, these data indicate that the expansion of T cells in the intestine and colitis pathogenesis are likely to require the activation of Ag-specific T cells, as opposed to nonspecific or superantigen-mediated events. There is relatively little overlap, however, when the TCR repertoires of different individuals are compared, suggesting that a number of Ags can contribute to T cell expansion and the generation of a T cell population in the intestine. Surprisingly, many of the expanded clones found in the large intestine also were found in the spleen and elsewhere, although inflammation is localized to the colon. Additionally, donor-derived T cells appear to be activated in both the intestine and the spleen at early time points after cell transfer. Together, these results strongly suggest that disease induction in this model involves either the early and systemic activation of antigen-specific T cells or the rapid dispersal of T cells activated at a particular site.
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PMID:Systemic activation and antigen-driven oligoclonal expansion of T cells in a mouse model of colitis. 1067 23


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