Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0235394 (wasting)
 8,040 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

TNF plays a pivotal role in the pathogenesis of a broad spectrum of infectious, inflammatory, and autoimmune diseases. In addition to the secreted, mature 17 kD form, TNF exists as a bioactive precursor 26 kD transmembrane protein. Transmembrane TNF signaling has been directly associated with specific immune mechanisms, including the contact-dependent lymphocyte and monocyte-mediated cell killing and the CD40 ligand-independent, T cell-mediated polyclonal B cell activation. In previous studies, we have reported that mice expressing 3'-UTR modified human TNF transgenes develop chronic inflammatory polyarthritis with a 100% phenotypic penetrance and timed disease onset. In additional experiments, we have also shown that high-level expression of human TNF in lymphoid cells of transgenic mice results in both local (thymic hypoplasia) and systemic (ischaemia, tissue necrosis, and wasting) TNF-mediated pathology. In this study we show that transgenic mice expressing a T cell-targeted membrane-associated mutant human TNF alpha protein are displaying only local TNF-mediated pathologies, ranging from lymphoid tissue derangements to proliferative synovitis and chronic inflammatory arthritis. These results demonstrate that in vivo, at least part of the pathogenic activities of TNF alpha may be assigned to the functioning of its uncleaved, membrane-associated form.
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PMID:Transmembrane TNF is sufficient to induce localized tissue toxicity and chronic inflammatory arthritis in transgenic mice. 873 89

Increased expression of CD40 and CD40 ligand (CD40L or CD154) has been found in inflamed mucosa of human inflammatory bowel disease (IBD), and interactions between these molecules seem to be involved in local cytokine production by macrophages. However, the precise role of CD40 signaling in the pathogenesis of IBD is still poorly understood. The aim of the present study was to investigate the in vivo relevance of CD40 signaling in experimental colitis in SCID mice reconstituted with syngeneic CD45RBhighCD4+ T cells. The results demonstrated that CD40+ and CD40L+ cells as well as their mRNA levels were significantly increased in inflamed mucosa. Administration of anti-CD40L neutralizing mAb over an 8-wk period starting immediately after CD45RBhighCD4+ T cell reconstitution completely prevented symptoms of wasting disease. Intestinal mucosal inflammation was effectively prevented, as revealed by abrogated leukocyte infiltration and decreased CD54 expression and strongly diminished mRNA levels of the proinflammatory cytokines IFN-gamma, TNF, and IL-12. When colitic SCID mice were treated with anti-CD40L starting at 5 wk after T cell transfer up to 8 wk, this delayed treatment still led to significant clinical and histological improvement and down-regulated proinflammatory cytokine secretion. These data suggest that the CD40-CD40L interactions are essential for the Th1 inflammatory responses in the bowel in this experimental model of colitis. Blockade of CD40 signaling may be beneficial to human IBD.
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PMID:Prevention of experimental colitis in SCID mice reconstituted with CD45RBhigh CD4+ T cells by blocking the CD40-CD154 interactions. 1082 Feb 84