Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018133 (graft-versus-host disease)
 18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Matrix metalloproteinases (MMPs) have been implicated in the pathobiology of various T-cell-mediated inflammatory disorders of the intestine and skin. Their synthetic inhibitor has been shown to prevent lethal acute graft-versus-host disease in animal models. We intended to determine the expression of MMPs 1, 3, 7, 9, 10, 12, and 19 and tissue inhibitors of metalloproteinases (TIMPs) 1 and 3 in intestinal and cutaneous lesions of patients suffering from graft-versus-host disease after bone marrow transplantation. In situ hybridizations for MMPs 1, 3, 7, 10, and 12 as well as TIMPs 1 and 3 were performed using (35)S-labeled cRNA probes on intestinal (n = 13) and cutaneous specimens (n = 9) from patients with graft-versus-host disease. Immunohistochemical stainings were carried out to localize MMP-9, MMP-19, TIMP-3, and TGF-beta1 proteins, and TUNEL staining, to detect apoptotic cells. TIMP-3 mRNA and protein were detected in cutaneous lesions in areas with vacuolar degeneration of the basal epidermal layer in all skin samples, and they colocalized with apoptotic keratinocytes and partly with staining for TGF-beta. None of the MMPs examined were overexpressed in skin lesions. Signals for MMP-1 and MMP-3 mRNA was found in 10/13 and 5/13 intestinal biopsies, respectively. In the gut, MMP-19-positive epithelial cells, particularly in the crypts, were found in 10/13 samples. Expression of MMPs 7, 9, 10, and 12 was absent or very low. TIMPs 1 and 3 were expressed by stromal cells in 12/13 and 10/13 gut samples, respectively. Whereas TIMP-1 was expressed particularly by subepithelial cells where epithelium had shed away, TIMP-3 was detected in deeper areas. We conclude that MMPs are differentially regulated in the skin and gut lesions of graft-versus-host disease. In agreement with previous data on cancer cells, TIMP-3, induced by TGF-beta1, may contribute to the apoptosis of keratinocytes in cutaneous graft-versus-host disease lesions, leading to typical histopathological changes. We also conclude that MMPs play a less important role as effector molecules in intestinal graft-versus-host disease than in celiac or inflammatory bowel disease.
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PMID:Overexpression of tissue inhibitor of metalloproteinases-3 in intestinal and cutaneous lesions of graft-versus-host disease. 1259 62

Anti-thymocyte globulin (ATG) is an established approach to decrease chronic GVHD (cGVHD), yet the exact mechanism is uncertain. To better understand the mechanism of action of ATG in preventing cGVHD, we evaluated the day 100 immune reconstitution of known cGVHD cellular biomarkers using patients from the randomized Canadian Bone Marrow Transplant Group (CBMTG) 0801 trial, which demonstrated a significant impact of ATG on cGVHD. In a separate companion biology study, we evaluated the impact of ATG prophylaxis on cGVHD cellular markers at day 100 in 40 CBMTG 0801 patients. Analysis focused on previously identified cGVHD cellular biomarkers, including naive helper T (Th) cells, recent thymic emigrant (RTE) Th cells, CD21low B cells, CD56bright NKreg cells, and Treg cells ST2, osteopontin, soluble B-cell activating factor (sBAFF), Interleukin-2 receptor alpha (sCD25), T-cell immunoglobulin and mucin domain-3 (TIM-3), matrix metallopeptidase 3, ICAM-1, C-X-C motif chemokine 10 (CXCL10), and soluble aminopeptidase N. The ATG-treated group had a >10-fold decrease in both RTE naive Th and naive Th cells (P < .0001) and a 10-fold increase in CD56bright NKreg cells (P < .0001). Treg cells, conventional Th cells, CD21low B cells, and all plasma markers were not affected. In the populations most affected by ATG, changes in naive Th cells were associated with the later development of cGVHD. This analysis suggests that ATG primarily impacts on cGVHD through suppression of naive Th cell expansion after transplantation. These associations need to be validated in additional studies.
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PMID:Anti-Thymocyte Globulin Prophylaxis Induces a Decrease in Naive Th Cells to Inhibit the Onset of Chronic Graft-versus-Host Disease: Results from the Canadian Bone Marrow Transplant Group (CBMTG) 0801 Study. 3175 35