Association between chronic liver and colon inflammation during the development of murine syngeneic graft-versus-host disease.
The murine model of cyclosporine A (CsA)-induced syngeneic graft-versus-host disease (SGVHD) is a bone marrow (BM) transplantation model that develops chronic colon inflammation identical to other murine models of CD4(+) T cell-mediated colitis. Interestingly, SGVHD animals develop chronic liver lesions that are similar to the early peribiliary inflammatory stages of clinical chronic liver disease, which is frequently associated with inflammatory bowel disease (IBD). Therefore, studies were initiated to investigate the chronic liver inflammation that develops in the SGVHD model. To induce SGVHD, mice were lethally irradiated, reconstituted with syngeneic BM, and treated with CsA. All of the SGVHD animals that developed colitis also develop chronic liver inflammation. Liver samples from control and SGVHD animals were monitored for tissue pathology, RNA for inflammatory mediators, and phenotypic analysis and in vitro reactivity of the inflammatory infiltrate. Diseased animals developed lesions of intrahepatic and extrahepatic bile ducts. Elevated levels of mRNA for molecules associated with chronic liver inflammation, including mucosal cellular adhesion molecule -1, the chemokines CCL25, CCL28, CCR9, and T(H)1- and T(H)17-associated cytokines were observed in livers of SGVHD mice. CD4(+) T cells were localized to the peribiliary region of the livers of diseased animals, and an enhanced proliferative response of liver-associated mononuclear cells against colonic bacterial antigens was observed. The murine model of SGVHD colitis may be a valuable tool to study the entero-hepatic linkage between chronic colon inflammation and inflammatory liver disease.
Brandon
J Anthony
JA
Departments of Microbiology Immunology and Molecular Genetics, University of Kentucky Medical Center, Lexington, USA.
Perez
Jacqueline
J
Jennings
C Darrell
CD
Cohen
Donald A
DA
Sindhava
V J
VJ
Bondada
S
S
Kaplan
Alan M
AM
Bryson
J Scott
JS
D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects*; D002908:Chronic Disease; D003108:Colonic Diseases / Q000209:etiology* / Q000473:pathology; D016572:Cyclosporine / Q000627:therapeutic use; D004195:Disease Models, Animal; D005260:Female; D006086:Graft vs Host Disease / Q000150:complications* / Q000473:pathology; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007249:Inflammation / Q000209:etiology; D008107:Liver Diseases / Q000209:etiology* / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D051193:Toll-Like Receptors / Q000378:metabolism; D014185:Transplantation, Isogeneic / Q000009:adverse effects
D007166:Immunosuppressive Agents; D051193:Toll-Like Receptors; D016572:Cyclosporine