Tumor necrosis factor inhibitor ameliorates murine intestinal graft-versus-host disease.
OBJECTIVE
Transfer of T helper cells from DBA/2 mice to irradiated allogeneic B6D2F1 mice leads to development of colonic graft-versus-host disease with pathological features of inflammatory bowel disease. To examine the role of tumor necrosis factor (TNF) in graft-versus-host disease enteropathy, an adenoviral vector encoding a TNF inhibitor protein was administered.


METHODS
Irradiated B6D2F1 mice were infused with DBA/2 bone marrow and spleen cells. Mice then received either a control beta-galactosidase-encoding adenovirus or an adenovirus encoding a TNF inhibitor, composed of the extracellular domain of the human 55-kilodalton TNF receptor linked to the murine immunoglobulin G1 heavy chain. Mucosal permeability to sucralose and colonic histology were assessed 14 and 25 days after transplantation.


RESULTS
Less diarrhea was observed in DBA/2 --> B6D2F1 mice expressing the TNF inhibitor, and colonic sections from these mice had significantly less inflammation and epithelial cell abnormalities. In TNF inhibitor recipients, mucosal permeability to sucralose was similar to that in nonirradiated control mice and significantly less than in recipients of the control adenovirus.


CONCLUSIONS
TNF inhibition decreases the severity of enteropathy in the DBA/2 --> B6D2F1 murine model of colonic graft-versus-host disease.
Liver Unit, Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., Dallas, 75235-9151, USA.
G R
GR
Brown
G
G
Lindberg
J
J
Meddings
M
M
Silva
B
B
Beutler
D
D
Thiele
D000818:Animals; D016026:Bone Marrow Transplantation; D003106:Colon / Q000502:physiology / Q000637:transplantation*; D006086:Graft vs Host Disease / Q000628:therapy*; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000235:genetics; D007143:Immunoglobulin Heavy Chains / Q000096:biosynthesis / Q000235:genetics; D007165:Immunosuppression Therapy / Q000379:methods; D017710:Lymphocyte Transfusion; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis* / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D013154:Spleen / Q000276:immunology; D013395:Sucrose / Q000031:analogs & derivatives / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000637:transplantation*; D014162:Transfection; D014184:Transplantation, Homologous / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*; D014916:Whole-Body Irradiation; D001616:beta-Galactosidase / Q000096:biosynthesis / Q000235:genetics
D007074:Immunoglobulin G; D007143:Immunoglobulin Heavy Chains; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D013395:Sucrose; C026285:trichlorosucrose; D001616:beta-Galactosidase